Chemoimmunotherapy versus chemotherapy for metastatic ... · [Intervention Review]...
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Chemoimmunotherapy versus chemotherapy for metastatic
malignant melanoma (Review)
Sasse AD Sasse EC Clark LGO Ulloa L Clark OAC
This is a reprint of a Cochrane review prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2013 Issue 8
httpwwwthecochranelibrarycom
Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
T A B L E O F C O N T E N T S
1HEADER
1ABSTRACT
2PLAIN LANGUAGE SUMMARY
2BACKGROUND
4OBJECTIVES
4METHODS
Figure 1 6
7RESULTS
9DISCUSSION
10AUTHORSrsquo CONCLUSIONS
10ACKNOWLEDGEMENTS
11REFERENCES
14CHARACTERISTICS OF STUDIES
30DATA AND ANALYSES
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival 31
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival 32
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival 34
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival 35
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate 36
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate 37
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate 38
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival 39
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3 40
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3 41
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality 42
42ADDITIONAL TABLES
45APPENDICES
46FEEDBACK
47WHATrsquoS NEW
47HISTORY
48CONTRIBUTIONS OF AUTHORS
48DECLARATIONS OF INTEREST
48NOTES
48INDEX TERMS
iChemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
[Intervention Review]
Chemoimmunotherapy versus chemotherapy for metastaticmalignant melanoma
Andre D Sasse1 Emma C Sasse1 Luciana GO Clark2 Luciana Ulloa3 Otavio Augusto Camara Clark4
1Internal Medicine UNICAMP (Universidade Estadual de Campinas) Campinas Brazil 2Oncology Hospital Celso PierroPUC-
Campinas e Instituto do Radium de Campinas Campinas Brazil 3Public Health Unit Blumenau-SC Brazil 4Evidecircncias Scientific
Solutions in Healthcare Satildeo Paulo Brazil
Contact address Andre D Sasse Internal Medicine UNICAMP (Universidade Estadual de Campinas) Av Dr Luiz de Tella 1515
Cidade Universitaria Campinas Sao Paulo 13083 000 Brazil andresassecom
Editorial group Cochrane Skin Group
Publication status and date Edited (no change to conclusions) published in Issue 8 2013
Review content assessed as up-to-date 15 November 2006
Citation Sasse AD Sasse EC Clark LGO Ulloa L Clark OAC Chemoimmunotherapy versus chemotherapy for metastatic malignant
melanoma Cochrane Database of Systematic Reviews 2007 Issue 1 Art No CD005413 DOI 10100214651858CD005413pub2
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
A B S T R A C T
Background
Malignant melanoma one of the most aggressive of all skin cancers is increasing in incidence throughout the world Surgery remains
the cornerstone of curative treatment in earlier stages Metastatic disease is incurable in most affected people because melanoma does
not respond to most systemic treatments A number of novel approaches are under evaluation and have shown promising results but
they are usually associated with increased toxicity and cost The combination of chemotherapy and immunotherapy has been reported
to improve treatment results but it is still unclear whether evidence exists to support this choice compared with chemotherapy alone
No language restrictions were imposed
Objectives
To compare the effects of therapy with chemotherapy and immunotherapy (chemoimmunotherapy) versus chemotherapy alone in
people with metastatic malignant melanoma
Search methods
We searched the Cochrane Skin Group Specialised Register (14 February 2006) the Cochrane Central Register of Controlled Trials
(The Cochrane Library Issue 3 2005) MEDLINE (2003 to 30 January 2006 ) EMBASE (2003 to 20 July 2005) and LILACS (1982
to 20 February 2006) References conference proceedings and databases of ongoing trials were also used to locate trials
Selection criteria
All randomised controlled trials that compared the use of chemotherapy versus chemoimmunotherapy on people of any age diagnosed
with metastatic melanoma
Data collection and analysis
Two authors independently assessed each study to determine whether it met the pre-defined selection criteria with differences being
resolved through discussion with the review team Two authors independently extracted the data from the articles using data extraction
forms Quality assessment included an evaluation of various components associated with biased estimates of treatment effect Whenever
possible a meta-analysis was performed on the extracted data in order to calculate a weighed treatment effect across trials
1Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Main results
Eighteen studies met our criteria and were included in the meta-analysis with a total of 2625 participants We found evidence of an
increase of objective response rates in people treated with chemoimmunotherapy in comparison with people treated with chemotherapy
Nevertheless the impact of these increased response rates was not translated into a survival benefit We found no difference in survival
to support the addition of immunotherapy to chemotherapy in the systemic treatment of metastatic melanoma with a hazard ratio
of 089 (95 CI 072 to 111 P = 031) Additionally we found increased hematological and non-hematological toxicities in people
treated with chemoimmunotherapy
Authorsrsquo conclusions
We failed to find any clear evidence that the addition of immunotherapy to chemotherapy increases survival of people with metastatic
melanoma Further use of combined immunotherapy and chemotherapy should only be done in the context of clinical trials
P L A I N L A N G U A G E S U M M A R Y
Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Malignant melanoma is one of the most aggressive of all skin cancers If it is confined to the skin it can often be cured by surgery
However if it has spread melanoma is usually incurable because it does not respond to most treatments Recently clinicians have been
trying a combination of chemotherapy and immunotherapy in the hope of improving the outcome The review of trials showed an
increased response to treatment when immunotherapy was added to chemotherapy but no difference was seen in survival rate and toxic
effects were increased
There is not enough evidence to support the use of a combination of combined immunotherapy and chemotherapy in treatment of
metastatic malignant melanoma
B A C K G R O U N D
Description of the condition
Epidemiology and progress of melanoma
Malignant melanomas develop due to changes in the melanocytes
cells that produce melanin pigment Melanomas are most com-
monly found in the skin but can also be found in the uveal tract
(back of the eye) upper digestive tract anal canal rectum and
vagina
Malignant melanoma of the skin accounts for 1 to 3 of all ma-
lignant tumors and there has been an increase in its incidence of
6 to 7 each year since 1985 (La Vecchia 1999 Wingo 1995)
However the overall mortality rate has only slightly increased
probably due to an increase in the early diagnosis of lesions that
have a better prognosis (Leong 2003)
As with other tumors the stage (progress) of the disease is still an
important determinant of survival In the earlier stages melanoma
is confined to the skin where the disease is curable in a high
percentage of cases through surgical removal of the tumor (Nathan
1998) The 5 year survival rate for melanoma that is confined to
the skin is 80 to 100 (Nathan 1998) depending on the thickness
of the primary tumor
In people where the cancer has spread to the lymph nodes (nodal
disease) three variables independently affect the prognosis
1 the number of positive lymph nodes
2 the presence of ulceration within the primary tumor
3 whether the nodal disease is macroscopic (an enlarged
lymph node can be felt by a doctor) or microscopic (the lymph
node cannot be felt but abnormal melanoma cells are present
and can be seen when viewed under a microscope) (Balch 2001)
In people with macroscopic disease more than one positive node
and an ulcerated primary tumor the 5 year survival rate is only
16 In people with one microscopically positive lymph node and
without ulceration in the primary lesion the 5 year survival rate
is 71 (Balch 2001)
The detection of lymph node metastases previously relied on crude
clinical or regional elective lymph node dissection (removal of a
2Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
whole group of lymph nodes responsible for draining a partic-
ular area of the body) but several large randomised controlled
trials have shown no improvement in survival using this tech-
nique Currently sentinel lymph node mapping and directed se-
lective lymphadenectomy (ie only removing those nodes that
show up as positive using the sentinel node imaging technique) has
been shown to identify lymph node metastases more precisely and
with less surgical morbidity than elective dissection (Gershenwald
1999)
Causes
Although the cause of melanoma is unknown major risk factors
have been identified (Koh 1991) Epidemiological studies suggest
that sunlight (ultraviolet radiation) is the most common environ-
mental factor Pale skin a tendency to sunburn fair or red hair
large numbers of melanocytic nevi (moles) and multiple dysplastic
nevi (atypical moles) have been shown to be independent risk fac-
tors for the development of melanoma Fair skin that does not tan
easily in combination with high sun exposure provides the largest
cumulative risk factor for melanoma development (Rigel 1989)
Impact
Malignant melanoma that has spread to distant sites by dissemi-
nation is associated with extremely poor survival median survival
is approximately 8 months and less than 5 of such people will
survive for more than 5 years (Lee 2000)
There are large prospective randomised multicenter trials that
have answered some basic management questions improved the
care of melanoma sufferers and expanded our understanding of
the disease However many aspects of treatment such as the thera-
peutic role of cytotoxic chemotherapy and biologic therapy alone
or in combination remain controversial and inconclusive (Crosby
2000 Leong 2003)
Description of the intervention
Systemic therapy
This has little or no impact on survival for advanced disease
There is no evidence derived from randomised controlled trials to
show superiority of systemic therapy over supportive care (Crosby
2000) The minority of people with metastatic melanoma who do
respond to systemic treatment have remissions which are generally
of short duration (Nathan 1998) Few agents have demonstrated
substantial anti-tumor activity against metastatic melanoma The
alkylating agent dacarbazine (DTIC) is considered to be the most
active drug for the treatment of this disease with a response rate of
20 and a median duration of response of 4 to 5 months (Khayat
2002 Nathan 1998) Other cytotoxic compounds such as temo-
zolomide (a dacarbazine analogue) (Middleton 2000) cisplatin
and carboplatin (Bajetta 2002) vinca alkaloids (Khayat 2002)
taxanes (Bafaloukos 2002) and nitrosoureas (Cure 1999) have not
improved these results All of these treatments are associated with
response rates of less than 15 and all are associated with signif-
icant adverse effects (Bafaloukos 2002 Bajetta 2002 Cure 1999
Khayat 2002 Middleton 2000)
Combination chemotherapy
The role of combination chemotherapy in advanced disease re-
mains unclear Prospective randomised studies have failed to
demonstrate any significant benefit for combination chemother-
apy when compared with single agents except for a slight increase
in response rates (Huncharek 2001)
Experimental treatments
Experimental treatments such as vaccines antibody treatments
and gene therapy are being developed and are of high scientific
interest However their efficacy in advanced melanoma has so
far been very limited with overall response rates of less than 5
(Keilholz 2002 Stopeck 2001) Since the 1970s immunostim-
ulating agents such as Bacillus Calmette-Guerin (BCG) (Lokich
1979 Osborn 1977) Corynebacterium parvum (Osborn 1977)
or isoprinosine (Tsang 1983) have been evaluated as local or sys-
temic treatments After some early hopes all these treatments have
also failed to demonstrate a significant and consistent effect in the
clinical management of advanced melanoma (Khayat 2002)
Immunotherapy
Two points have driven the attention of researchers in the im-
munology field to melanoma Firstly the spontaneous regression
of melanoma (ie the tumor occasionally appears to go away in
some people) Spontaneous regression is much more frequent than
in melanoma than with any other solid tumor and it is associated
with a specific cellular immune response (Kadison 2003) Sec-
ondly the fact that some people with melanoma also have tumor
rejection antigen recognized by CD4 and CD8 T cells (immune
cells that can help get rid of cancer cells) (Kadison 2003)
At least two types of immunotherapy have been used in advanced
melanoma interferon-alpha and interleukin-2
Interferon-alpha (IFN-α) belongs to a group of proteins known
to have antiproliferative and antitumor effects (Garbe 1990) In
addition IFN-α exhibits certain immunomodulatory effects - it
upregulates the expression of major histocompatibility complex
(MHC) class I antigens in melanoma cells and also the expres-
sion of co-stimulatory molecules rendering the cells more suscep-
tible to immunological defense mechanisms (Barth 1995) Phase
II studies of IFN-α as a single agent have demonstrated response
rates of approximately 20 with a slightly more durable response
3Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
than the one found with dacarbazine (DTIC) (Creagan 1984
Dorval 1986 Sertoli 1989)
Interleukin-2 (IL-2) is a major growth factor for lymphoid cells
including T cells and natural killer (NK) cells (Hanninen 1991
Smith 1993) Clinical trials have demonstrated modest anti-tumor
activity in people with metastatic melanoma (Rosenberg 1989)
responses were seen in approximately 15 of people with a
small proportion of complete responses (Dutcher 1989 Rosenberg
1989)
Chemoimmunotherapy
As chemotherapy and immunotherapy have different and per-
haps synergistic mechanisms of action their combination of im-
munotherapy with chemotherapy (chemoimmunotherapy) has
been studied since the early 1990s (Khayat 2002) Some reports
have suggested that chemotherapeutic agents administered in com-
bination with IL-2 or IFN or both can improve response rates
(Legha 1998 Richards 1992) with complete response rates in 10
to 20 of people as well as increases in median survival (Falkson
1991) Based on these results the use of chemoimmunotherapy is
currently preferred in some institutions as a first-line treatment in
advanced (stage IV) melanoma (Kadison 2003 Keilholz 2002)
although it is still considered an experimental therapy by oth-
ers(Crosby 2000)
Why it is important to do this review
There are substantial controversies about the real benefit of
chemoimmunotherapy some studies conclude that the combi-
nation of treatments did not improve survival (Rosenberg 1999
Young 2001) or even response rates (Falkson 1998 Gorbonova
2000 Johnston 1998 Thomson 1993) in people with metastatic
melanoma There is also concern that combined therapy may in-
crease treatment-related toxicity (Falkson 1998 Johnston 1998)
The lack of conclusive data coming from seemingly conflict-
ing studies about the impact of treatment demands a systematic
review This will provide the most reliable assessment for sup-
porting clinical decision-making with people who have advanced
melanoma
O B J E C T I V E S
To compare the effects of chemotherapy alone versus combined
therapy with chemotherapy and immunotherapy (chemoim-
munotherapy) in people with metastatic malignant melanoma
M E T H O D S
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs)
Types of participants
People of any age diagnosed with metastatic malignant melanoma
that has spread to distant sites by systemic dissemination
Types of interventions
1 Chemotherapy
2 Chemoimmunotherapy ie the combination of
chemotherapy and immunotherapy with interferon-alpha or
interleukin-2 or both
Types of outcome measures
Primary outcomes
Overall survival - number of participants alive at the end of the
trial
Secondary outcomes
1 One two and five-year survival rates - proportion of
participants alive at one two and five year follow-up
2 Response rates (partial and complete) - proportion of
participants that have achieved partial or complete responses as
defined by the trial authors
3 Progression-free survival - number of participants without
progression of disease at the end of the trial
4 Treatment morbidity (treatment-related toxicity) -
proportion of participants that have developed hematological or
non-hematological toxicities
5 Treatment related mortality - proportion of participants
that have died due to the treatment This outcome was not
described previously in the protocol and was added after
discussion between the reviewers that considered it relevant
Mortality related to treatment is a great concern in oncology
when comparing treatments with potential differences in toxicity
6 Quality of life measures
Search methods for identification of studies
We searched electronic databases and other resources to locate
reports of studies No language restrictions were imposed
4Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Electronic searches
Electronic databases
We searched the following electronic databases
1 MEDLINE (OVID) (Appendix 1)
2 The Cochrane Skin Group Specialised Register
3 The Cochrane Central Register of Controlled Trials
4 Medline (PubMed)
5 EMBASE
6 LILACS (Latin American and Caribbean Health Science
Information Database)
Search strategies for databases 2 to 6 are located in Appendix 2
Search of databases of ongoing trials (unpublished literature)
We asked trial authors and pharmaceutical companies about un-
published and ongoing trials Databases of major research groups
and registers of trials in the following databases were also searched
with the term rsquoMELANOMArsquo
bull Current Controlled Trials Register (httpwwwcontrolled-
trialscom) on 30th January 2006
bull European Organisation for Research and Treatment of
Cancer (httpwwweortcbe) on 20th February 2006
bull National Cancer Institute America (http
wwwcancergovclinicaltrials) on 16th November 2005
bull National Cancer Institute Canada (httphttp
wwwctgqueensucapublicClinical_Trialsclinical_trialshtml)
on 30th January 2006
bull Australian Clinical Trials Registry (httpwwwactrorgau)
on 30th January 2006
bull US Food and Drug Administration (httpwwwfdagov)
on 30th January 2006
bull ClinicalTrialsgov (httpwwwclinicaltrialsgov) on 16th
November 2005
Searching other resources
References from unpublished studies
All bibliographies of selected studies were scanned for possible
references to RCTs
Conference proceedings
We handsearched the abstracts from conference proceedings of
the ASCO (American Society of Clinical Oncology) and ESMO
(European Society of Medical Oncology)
Data collection and analysis
Where there was uncertainty we tried to contact trial authors for
clarification
A consumer (LU) was involved throughout the review process to
ensure the readability of the final review Updating will be done
every two years
Selection of studies
Two authors (ADS and ECS) checked the titles and abstracts iden-
tified from the searches If it was clear that the study did not refer
to a RCT on metastatic melanoma we excluded it Two authors
(ADS and OAC) independently assessed each remaining study to
determine whether it met the pre-defined selection criteria Any
differences were resolved through discussion with the review team
Excluded studies are listed in the Table of Excluded Studies
Data extraction and management
Two authors (ADS and ECS) independently extracted the data
from the studies All data were extracted directly from the text or
calculated according to the available information
Any differences were resolved by discussion with one author
(OAC) A data extraction form was developed and piloted in order
to summarize the trials One author (ADS) checked and entered
the data Two authors (ECS and LGC) independently checked the
data entry
Assessment of risk of bias in included studies
Assessment of methodological quality
The quality assessment included an evaluation of the following
components for each included study since there is some evidence
that these are associated with biased estimates of treatment effect
(Juni 2001)
(a) the method of generation of the randomisation sequence
(b) the method of allocation concealment - it was considered rsquoad-
equatersquo if the assignment could not be foreseen
(c) who was blindednot blinded (participants clinicians outcome
assessors)
(d) how many participants were lost to follow up in each arm and
whether participants were analysed in the groups to which they
were originally randomised (intention-to-treat)
In addition the quality assessment also included
(e) the source of funding
(f ) if the participant had a biopsy proven melanoma
(g) the baseline assessment of the participants for presence of liver
and brain metastases performance status
(h) whether the aims interventions (including drug doses and
duration of treatment) and outcome measures were clearly defined
5Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(i) the use and appropriateness of statistical analyses
We recorded all the information in a table of quality criteria and
gave a description of the quality of each study based on these
characteristics
Measures of treatment effect
Where possible we performed a meta-analysis for the outcomes
in order to calculate a weighted treatment effect across trials using
a random-effects model For binary endpoints we calculated the
risk ratio (RR) with 95 confidence intervals (Yusuf 1985) We
also expressed the results as a number needed to treat (NNT)
where appropriate for a range of plausible control event rates For
overall survival a time-to-event data we calculated the Hazard
Ratio (HR) When data were not available for direct extraction
we calculated indirectly (from different parameters using indirect
calculation of the variance and the number of observed minus
expected events) according to the method described by Parmar
(Parmar 1998) In the funnel plot (Figure 1) and comparison 1
rsquoPeto OR (IPD)rsquo is a Hazard Ratio For continuous data such as
quality of life we planned to use standardised mean differences
with 95 confidence intervals would have been used
Figure 1 Funnel plot using overall survival as the outcome
Assessment of heterogeneity
Heterogeneity was assessed using I2 Where the heterogeneity was
considerable (I2 gt 50) we explored possible reasons using the
type (interleukin-2 or interferon) and dose (high or low) of im-
munotherapy used as subgroups Where we were not able to find
an explanation we have recorded this along with appropriate cau-
tion in the interpretation of these data
Data synthesis
Analysis and presentation
Once studies had been selected critically appraised and the data
extracted we entered the data in the Characteristics of included
studies table
6Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Three studies (Bajetta 1994 Kirkwood 1990 Vorobiof 1994) eval-
uated three arms of treatment with one of them evaluating che-
motherapy alone and the two others using chemoimmunotherapy
One study (Falkson 1998) had four arms two using chemotherapy
and two using chemoimmunotherapy The data from the similar
arms were grouped considered as one and then compared to the
other arm
R E S U L T S
Description of studies
Results of the search
We scanned approximately 700 citations Initially 28 studies
were identified Four studies (Arance 2000 Chiarion-Sileni 2003
Danson 2002 Falkson 1995) had data that overlapped with three
included studies (Danson 2003 Falkson 1991 Ridolfi 2002)
Ongoing studies
No ongoing studies were available to be included in the meta-
analysis
Included studies
Eighteen studies with a total of 2625 participants met our criteria
and were included in the meta-analysis (please see Characteristics
of included studies) One study differed considerably from the oth-
ers because vindesine was used as the chemotherapy control a drug
without evidence of response in metastatic melanoma (Vorobiof
1994) Another study differed considerably as lower dose treat-
ment in the chemoimmunotherapy group was used (Middleton
2000) The first study was published in 1990 and the last studies
were published in 2003
Participants
The participants were between the ages of 16 and 88 years and
had an Eastern Cooperative Oncology Group performance status
from 0 to 3 Only three studies included participants with brain
metastasis (Atzpodien 2002 Danson 2003 Eton 2002)
Interventions
Seven studies compared chemotherapy to chemoimmunotherapy
with IFN plus IL-2 (Atkins 2003 Atzpodien 2002 Del Vecchio
2003 Eton 2002 Johnston 1998 Ridolfi 2002 Rosenberg 1999)
Eleven compared chemotherapy to chemoimmunotherapy with
IFN (Bajetta 1994 Danson 2003 Falkson 1991 Falkson 1998
Gorbonova 2000 Kirkwood 1990 Middleton 2000 Spieth 2003
Thomson 1993 Vorobiof 1994 Young 2001)
The drugs used in chemotherapeutic schemes varied between the
trials Seven trials evaluated DTIC combined with other drugs in
both arms (Atkins 2003 Atzpodien 2002 Del Vecchio 2003 Eton
2002 Johnston 1998 Ridolfi 2002 Rosenberg 1999) and six
evaluated DTIC alone as the control (Bajetta 1994 Falkson 1991
Falkson 1998 Kirkwood 1990 Thomson 1993 Young 2001)
Four studies evaluated other schemes without DTIC two trials
used temozolomide (Danson 2003 Spieth 2003) one trial used
vindesine (Vorobiof 1994) and one trial used combined drugs
based on cisplatin (Gorbonova 2000)
Only one study did not use the same scheme in both the arms
using combined drugs with DTIC as the chemotherapy control
and a lower dose for the chemoimmunotherapy group with DTIC
alone (Middleton 2000)
Setting
Ten studies were carried out in Europe four in the United States
two in South Africa and one was a multicentre worldwide trial
All trials were reported in the English language
Outcomes
Response rates were the primary outcome measures in most trials
and were described in all included studies Two studies did not
evaluate survival rates (Gorbonova 2000 Kirkwood 1990) Three
studies included quality of life analyses in the outcomes (Ridolfi
2002 Thomson 1993 Young 2001) The length of the follow-up
varied widely between the trials and sometimes it was not speci-
fied We did not find a reasonable definition about what could be
considered high or low doses of immunotherapy and the influence
of the immunotherapeutic doses on the outcomes could not be
assessed
Excluded studies
Six studies were excluded (see Characteristics of excluded studies)
The reasons for exclusion were that the study had immunotherapy
on both arms (Bajetta 2001 Richtig 2004 Sertoli 1999 Sparano
1993 Vuoristo 2005) or the study was not randomised (Legha
1996)
Risk of bias in included studies
The quality assessment consisted of a basic methodological eval-
uation of each included study and is shown in Table 1 Addi-
tional quality assessment is shown in Table 2 The criteria used for
methodological quality analysis of the studies are listed in Table 3
(Explanation of Quality Analysis Headings)
7Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Although blinding participants and clinicians is theoretically pos-
sible it is difficult to plan a double-blind study with immunother-
apy This is due to the substantial acute and late toxicities associ-
ated with immunotherapy in one group No study was described
as double-blinded The groups at baseline were in general similar
with a description of most prognostic factors related to metastatic
melanoma (gender performance status age prior therapy liver
metastasis)
In three studies almost all methodological aspects of the trials
were described poorly (Gorbonova 2000 Kirkwood 1990 Spieth
2003)
Allocation
All the included studies were described as randomised as this
was a selection criterion However most papers did not describe
the method of randomisation The method of generation of the
randomised sequence was described and considered adequate in
only 6 out of 18 studies Eleven of 18 studies provided information
on allocation concealment all of which were considered adequate
Blinding
Blinding of outcome assessment and detection bias
We did not find information about blinding of the outcome as-
sessors in any included study
Incomplete outcome data
Handling of losses and attrition bias
In general there were few participants lost to follow up in the
studies The highest number of people lost was 24 in a total of 262
participants (Bajetta 1994) Eleven studies included an intention-
to-treat analysis
Effects of interventions
Primary outcome
Overall survival (eight studies)
This was considered as the number of participants alive at the end
of the trial Sufficient data were available from 8 of the 18 studies
There was no statistically significant difference in survival between
chemoimmunotherapy and chemotherapy with a hazard ratio
(HR) of improved survival of 089 (95 CI 072 to 111 P = 031
Analysis 11) in favour of chemoimmunotherapy In other words
overall survival was slightly lower in the chemoimmunotherapy
group but this was not statistically significant There was no het-
erogeneity across trials (I2 = 0) The funnel plot method using
overall survival as the outcome is presented in Figure 1 It shows
that there was no evidence of substantial publication bias but in-
terpretation of the funnel plot is likely to be unreliable since only
eight relatively large studies were found
When we evaluated the influence of the type of immunotherapy
used in the chemoimmunotherapy group (IL-2 plus IFN-alpha
or IFN-alpha only) we found no statistically significant difference
between the groups with a HR of 096 (95 CI 074 to 124 P =
076 Analysis 11) for chemoimmunotherapy with IL-2 plus IFN-
alpha and a HR of 074 (95 CI 049 to 112 P = 015 Analysis
11) for chemoimmunotherapy associated with only IFN-alpha
Secondary outcomes
One two and five-year survival rates (13 studies)
The number of participants alive at one two and five year follow-
ups were analyzed Data from 13 trials evaluating one year survival
were pooled There was no statistically significant difference in one
year survival between the groups with a risk ratio (RR) of 106
(95 CI 091 to 124 P = 048 Analysis 12) and no significant
heterogeneity across trials (I2 = 363)
Data from 11 trials evaluating 2 year survival were extracted and
pooled Again there was no statistically significant difference be-
tween the groups with a RR of 108 (95 CI 086 to 136 P =
050 Analysis 13) without heterogeneity across trials (I2 = 0)
Only two trials reported data about five year survival The meta-
analysis showed no statistically significant difference in 5 year sur-
vival between the groups with a RR of survival of 234 (95
CI 097 to 565 P = 006 Analysis 14) favouring chemoim-
munotherapy There was no heterogeneity across trials (I2 = 0)
Response rates (17 studies)
Data regarding the number of participants with partial or com-
plete responses from 17 trials were used to evaluate objective re-
sponse rates The analysis detected a statistically significant differ-
ence in favor of chemoimmunotherapy in global response rates
with a RR of 140 (95 CI 120 to 163 P lt 00001 Analysis
21) There was no heterogeneity across trials (I2 = 42) We
tried to evaluate the influence of the type of immunotherapeutic
in the group of chemoimmunotherapy (IL-2 plus IFN-alpha or
IFN-alpha only) We found similar results with a RR of global
response of 146 (95 CI 119 to 179 p = 00002 Analysis 21)
in favor of chemoimmunotherapy with IL-2 plus IFN-alpha and
a RR of 132 (95 CI 102 to 171 p = 004 Analysis 21) in favor
of chemoimmunotherapy with IFN-alpha There was no hetero-
geneity across trials (I2 = 0)
8Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Data from 15 trials were used to evaluate partial and complete
response rates We found a statistically significant difference in
favour of chemoimmunotherapy in both analyses with an HR of
131 (95 CI 107 to 159 p = 0008 Analysis 23) for partial
response rates and an HR of 158 (95 CI 106 to 236 p = 003
Analysis 23) for complete response rates
Progression-free survival (3 studies)
Only three studies had extractable data about the number of par-
ticipants with no disease progression at the end of the trial When
pooled together there was no statistically significant difference be-
tween the groups with an HR of 076 (95 CI 057 to 102 p =
007 Analysis 31) There was no heterogeneity across these trials
(I2 = 0)
Treatment related toxicity (11 studies)
Data from 11 studies were collected with the number of partici-
pants developing clinically significant hematological toxicity (de-
fined as grade 3 or 4) Eight studies had estimated points that
showed enhanced toxicities in the chemoimmunotherapy group
The meta-analysis of the studies showed extreme heterogeneity
(I2 = 941) across the trials We performed a sensitivity anal-
ysis excluding the studies with relatively low doses of chemo-
therapeutic drugs in the chemoimmunotherapy group (Danson
2003 Middleton 2000) but we found similar heterogeneity (I2 =
978)
When we analyzed data from the four studies with similar rela-
tive doses of chemotherapeutics associated with interferon-alpha
without interleukin-2 we found an increase of clinically signifi-
cant hematological toxicities in the chemoimmunotherapy group
with a RR 454 (95 CI 235 to 879 p lt 000001) There was
no heterogeneity across these trials (I2 = 0) When we analyzed
data from studies with combination of interferon-alpha plus in-
terleukin-2 in the chemoimmunotherapy group we again found
extreme heterogeneity across the trials (I2 = 979)
Despite the heterogeneity in global meta-analysis we concluded
that it was not possible to quantify the differences in hematologi-
cal toxicity in such different trials In order to explore these differ-
ences we noted that one study referred to hematological toxicity
in 100 of participants treated with chemoimmunotherapy and
in 96 of participants treated with chemotherapy (Eton 2002)
Another study referred to hematological toxicity only in 2 and
1 respectively (Bajetta 1994)
Non-hematological toxicities were described in almost all stud-
ies and were mainly described as nausea vomiting flu-like syn-
drome asthenia hypotension and fever Data from six similar
studies were extractable and were pooled in the meta-analysis re-
sulting in a statistically significant difference against the chemoim-
munotherapy group with a RR of 274 (95 CI 206 to 364 p
lt 000001 Analysis 42) There was no heterogeneity across trials
(I2 = 0) These results must be treated with caution because of
similar difficulties in pooling these data on hematological toxici-
ties with different therapeutic schemes and several trials described
non-hematological toxicities but we were not able to extract the
data
Data about treatment-related mortality were available in 11 stud-
ies We found no significant difference between the groups with a
RR of 078 (95 CI 026 to 232 p = 065 Analysis 43) There
was no heterogeneity across the trials (I2 = 0)
Quality of life (three studies)
Only three studies reported data on quality of life (Ridolfi 2002
Thomson 1993 Young 2001) all using different methods One
trial described quality of life analysis in detail in an additional pub-
lication (Chiarion-Sileni 2003 Ridolfi 2002) This study found
a significant decrease of overall quality of life in the chemoim-
munotherapy group in comparison to the chemotherapy group
(p = 003) The other two studies did not find differences in global
quality of life between the groups (Thomson 1993 Young 2001)
Thomson did not report global quality of life (Thomson 1993)
Young found no significant differences in quality of life for the
change in scores over time (z = -129 p = 020) (Young 2001)
It was not possible to pool the data as all three studies did not
provide extractable data
Sensitivity analyses on the influence of source of funding baseline
assessment and allocation concealment on the survival analysis
and response rate analyses revealed that there was no relation be-
tween these methodological aspects and the outcome There was
no statistically significant difference in survival between the groups
in all analyses and the difference in response rates in favour of
chemoimmunotherapy was found to be significant
D I S C U S S I O N
Metastatic melanoma is reputed as refractory to most systemic
treatments and little progress has been made in treatment of
metastatic melanoma These concepts are supported by results
from previous systematic reviews One review concluded that there
is no evidence derived from RCTs that systemic treatment is better
than best supportive care (Crosby 2000) Another review of 20
randomised trials (involving 3273 participants) comparing single-
agent DTIC with DTIC in combination with other drugs with or
without immunotherapy concluded that combination of drugs in-
creased response rates but not overall survival (Huncharek 2001)
This systematic review summarises the evidence regarding the
use of chemoimmunotherapy compared to chemotherapy alone
to treat people with metastatic malignant melanoma There are
some important observations regarding the characteristics of the
included studies in this systematic review The ideal combination
9Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
of drugs for an investigation is not well established Seven studies
evaluated chemoimmunotherapy with interferon-alpha plus inter-
leukin-2 and 11 evaluated chemoimmunotherapy only with in-
terferon-alpha The treatment plans with drugs and dosages used
differed between studies
Most studies did not contribute in answering relevant questions
about the impact of chemoimmunotherapy in the treatment of
metastatic melanoma The outcomes were not clearly described in
several of the studies (Atkins 2003 Del Vecchio 2003 Gorbonova
2000 Kirkwood 1990 Spieth 2003 Thomson 1993) Two of
them did not report survival rates evaluating only response rates
(Gorbonova 2000 Kirkwood 1990) All these aspects influenced
the comparability of the trials and must be considered in the data
interpretation
On the basis of a meta-analysis of data coming from eight studies
this review showed no evidence of a difference in overall survival to
support the addition of immunotherapy to chemotherapy in the
systemic treatment of metastatic melanoma (Atkins 2003 Danson
2003 Eton 2002 Falkson 1991 Johnston 1998 Ridolfi 2002
Spieth 2003 Young 2001) Evaluation of one two and five-year
survival with data from other studies again showed no survival
advantage of the drug combination treatment
We found higher clinical response rates in people treated with
chemoimmunotherapy in comparison with people treated with
chemotherapy which was not translated into survival benefit
Additionally we found higher toxicity rates in people treated
with chemoimmunotherapy Despite the importance of evaluat-
ing quality of life there was no available data to perform the meta-
analysis in this systematic review Only three studies reported data
about quality of life all with different methods One trial described
poorer quality of life in people treated with chemoimmunother-
apy related to more intense side effects (Ridolfi 2002) Two trials
however showed no difference between groups (Thomson 1993
Young 2001) It is important that quality of life is included in all
future studies
Our meta-analysis did not find differences between treatment re-
lated mortality Subgroup analysis comparing combinations with
interferon-alpha and with interferon-alpha plus interleukin-2 did
not show different results in survival or response rates
The use of chemoimmunotherapy ie a combination of chemo-
therapy with interferon-alpha or interleukin-2 or both has not
been shown to be beneficial in this review Although short term
response rates were better overall in the chemoimmunotherapy
groups survival was not improved and drug-related toxicities were
higher in the combined chemoimmunotherapy group To date no
treatment regimen has shown efficiency in prolonging survival in
people with metastatic melanoma Little has changed in the sys-
temic management of metastatic melanoma in the last few years
The standard of care remains single-agent DTIC and the role of
immunotherapy remains in doubt
The use of chemoimmunotherapy in the treatment of melanoma
is justified only in the context of clinical trials
A U T H O R S rsquo C O N C L U S I O N S
Implications for practice
We failed to find any evidence to support the view that the
use of chemoimmunotherapy prolongs survival in people with
metastatic melanoma when compared to chemotherapy alone Al-
though short-term clinical responses were higher in the chemoim-
munotherapy group this was associated with a higher rate of
serious adverse events esp haematological toxicity Our review
does not support the use of a combination of immunother-
apy and chemotherapy in chemoimmunotherapy regimens out-
side of clinical trials The standard of care for people with
advanced melanoma remains chemotherapy with single-agent
DTIC Chemoimmunotherapy must not be recommended to peo-
ple in daily practice
Implications for research
Research related to the development of more effective treatments
for people with metastatic melanoma is urgently needed
For people with an incurable disease the primary outcome needs
to be overall survival and all studies should include a quality of life
analysis
Future trials should be designed to define the best systemic treat-
ment and should use chemotherapy with (DTIC) as a standard
control group in order to permit comparisons to be made
A C K N O W L E D G E M E N T S
The authors wish to thank Raquel Gebara Lima for her kind
support in grammar and style
The editorial base would like to thank the following people who
were external referees for this review Keith Wheatley and Pat
Lawton (content experts) and Kathie Godfrey (consumer)
10Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
R E F E R E N C E S
References to studies included in this review
Atkins 2003 published data only
Atkins MB Lee S Flaherty LE Sosman JA Sondak VK
Kirkwood JM A prospective randomized phase III trial
of concurrent biochemotherapy (BCT) with cisplatin
vinblastine dacarbazine (CVD) IL-2 and interferon alpha-
2b (IFN) versus CVD alone in patients with metastatic
melanoma (E3695) An ECOG-coordinated intergroup
trial In ASCO Annual Meeting 2003 2003 p ASCO
Annual Meeting - Proceedings 2003Abstract 2847
Atzpodien 2002 published data only
Atzpodien J Neuber K Kamanabrou D Fluck M Brocker
EB Neumann C et alCombination chemotherapy with or
without sc IL-2 and IFN-alpha results of a prospectively
randomized trial of the Cooperative Advanced Malignant
Melanoma Chemoimmunotherapy Group (ACIMM)
British journal of cancer 200286(2)179ndash84
Bajetta 1994 published data only
Bajetta E Di Leo A Zampino MG Sertoli MR Comella
G Barduagni M et alMulticenter randomized trial of
dacarbazine alone or in combination with two different
doses and schedules of interferon alfa-2a in the treatment
of advanced melanoma Journal of clinical oncology official
journal of the American Society of Clinical Oncology 199412
(4)806ndash11
Danson 2003 published data only
Danson S Lorigan P Arance A Clamp A Ranson
M Hodgetts J et alRandomized phase II study of
temozolomide given every 8 hours or daily with either
interferon alfa-2b or thalidomide in metastatic malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 200321(13)2551ndash7
Del Vecchio 2003 published data only
Del Vecchio M Bajetta E Vitali M Gattinoni L Santinami
M Daponte A et alMulticenter phase III randomized trial
of cisplatin vindesine and dacarbazine (CVD) versus CVD
plus subcutaneous (sc) interleukin-2 (IL-2) and interferon-
alpha-2b (IFN) in metastatic melanoma patients (pts) In
ASCO Annual Meeting 2003 2003 p ASCO Annual
Meeting - Proceedings 2003Abstract 2849
Eton 2002 published data only
Eton O Legha SS Bedikian AY Lee JJ Buzaid AC
Hodges C et alSequential biochemotherapy versus
chemotherapy for metastatic melanoma results from a
phase III randomized trial Journal of clinical oncology
official journal of the American Society of Clinical Oncology
200220(8)2045ndash52
Falkson 1991 published data only
Falkson CI Falkson G Falkson HC Improved results with
the addition of interferon alfa-2b to dacarbazine in the
treatment of patients with metastatic malignant melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 19919(8)1403ndash8
Falkson 1998 published data only
Falkson CI Ibrahim J Kirkwood JM Coates AS Atkins
MB Blum RH Phase III trial of dacarbazine versus
dacarbazine with interferon alpha-2b versus dacarbazine
with tamoxifen versus dacarbazine with interferon alpha-
2b and tamoxifen in patients with metastatic malignant
melanoma an Eastern Cooperative Oncology Group study
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199816(5)1743ndash51
Gorbonova 2000 published data only
Gorbonova VA Egorov GN Perevodchikova NI Orel
NF Combined chemotherapy with or without interferon
alpha N1 (IFN) for advanced malignant melanoma - a
randomized pilot phase III study Gan To Kagaku Ryoho
200027 Suppl (2)310ndash4
Johnston 1998 published data only
Johnston SR Constenla DO Moore J Atkinson H ArsquoHern
RP Dadian G et alRandomized phase II trial of BCDT
[carmustine (BCNU) cisplatin dacarbazine (DTIC)
and tamoxifen] with or without interferon alpha (IFN-
alpha) and interleukin (IL-2) in patients with metastatic
melanoma British Journal of Cancer 199877(8)1280ndash6
Kirkwood 1990 published data only
Kirkwood JM Ernstoff MS Giuliano A Gams R Robinson
WA Costanzi J et alInterferon alpha-2a and dacarbazine
in melanoma Journal of the National Cancer Institute 1990
82(12)1062ndash3
Middleton 2000 published data only
Middleton MR Grob JJ Aaronson N Fierlbeck G
Tilgen W Seiter S et alRandomized phase III study of
temozolomide versus dacarbazine in the treatment of
patients with advanced metastatic malignant melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200018(1)158ndash66
Ridolfi 2002 published data only
Ridolfi R Chiarion-Sileni V Guida M Romanini A
Labianca R Freschi A et alCisplatin dacarbazine with
or without subcutaneous interleukin-2 and interferon
alpha-2b in advanced melanoma outpatients results from
an Italian multicenter phase III randomized clinical trial
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200220(6)1600ndash7
Rosenberg 1999 published data only
Rosenberg SA Yang JC Schwartzentruber DJ Hwu P
Marincola FM Topalian SL et alProspective randomized
trial of the treatment of patients with metastatic melanoma
using chemotherapy with cisplatin dacarbazine and
tamoxifen alone or in combination with interleukin-2 and
interferon alfa-2b Journal of Clinical Oncology 199917(3)
968ndash75
Spieth 2003 published data only
Spieth K Dummer R Garbe C Mauch C Schuler G
Landthaler M et alTemozolomide in combination with
11Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
interferon alfa versus temozolomide alone in patients with
advanced metastatic melanoma A randomized phase
III multicenter study of the Dermatologic Cooperative
Oncology Group (DeCOG) In ASCO Annual Meeting
2003Abstract 2887
Thomson 1993 published data only
Thomson DB Adena M McLeod GR Hersey P Gill PG
Coates AS et alInterferon-alpha 2a does not improve
response or survival when combined with dacarbazine
in metastatic malignant melanoma results of a multi-
institutional Australian randomized trial Melanoma
Research 19933(2)133ndash8
Vorobiof 1994 published data only
Vorobiof DA Bezwoda WR A randomised trial of vindesine
plus interferon-alpha 2b compared with interferon-alpha 2b
or vindesine alone in the treatment of advanced malignant
melanoma European journal of cancer (Oxford England
1990) 199430A(6)797ndash800
Young 2001 published data only
Young AM Marsden J Goodman A Burton A Dunn
JA Prospective randomized comparison of dacarbazine
(DTIC) versus DTIC plus interferon-alpha (IFN-alpha) in
metastatic melanoma Clinical oncology (Royal College of
Radiologists (Great Britain)) 200113(6)458ndash65
References to studies excluded from this review
Bajetta 2001 published data only
Bajetta E Del Vecchio M Vitali M Martinetti A Ferrari L
Queirolo P et alA feasibility study using polychemotherapy
(cisplatin + vindesine + dacarbazine) plus interferon-alpha
or monochemotherapy with dacarbazine plus interferon-
alpha in metastatic melanoma Tumori 200187(4)219ndash22
Legha 1996 published data only
Legha SS Ring S Bedikian A Plager C Eton O Buzaid
AC et alTreatment of metastatic melanoma with combined
chemotherapy containing cisplatin vinblastine and
dacarbazine (CVD) and biotherapy using interleukin-2 and
interferon-alpha Annals of oncology official journal of the
European Society for Medical Oncology ESMO 19967(8)
827ndash35
Richtig 2004 published data only
Richtig E Hofmann-Wellenhof R Pehamberger H
Forstinger C Wolff K Mischer P et alTemozolomide and
interferon alpha 2b in metastatic melanoma stage IV British
Journal of Dermatology 2004151(1)91ndash8
Sertoli 1999 published data only
Sertoli MR Queirolo P Bajetta E DelVecchio M
Comella G Barduagni L et alMulti-institutional phase
II randomized trial of integrated therapy with cisplatin
dacarbazine vindesine subcutaneous interleukin-2
interferon alpha2a and tamoxifen in metastatic melanoma
BREMIM (Biological Response Modifiers in Melanoma)
Melanoma research 19999(5)503ndash9
Sparano 1993 published data only
Sparano JA Fisher RI Sunderland M Margolin K Ernest
ML Sznol M et alRandomized phase III trial of treatment
with high-dose interleukin-2 either alone or in combination
with interferon alfa-2a in patients with advanced melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199311(10)1969ndash77
Vuoristo 2005 published data only
Vuoristo MS Hahka-Kemppinen M Parvinen LM
Pyrhonen S Seppa H Korpela M et alRandomized trial of
dacarbazine versus bleomycin vincristine lomustine and
dacarbazine (BOLD) chemotherapy combined with natural
or recombinant interferon-alpha in patients with advanced
melanoma Melanoma research 200515(4)291ndash6
Additional references
Arance 2000
Arance A Middleton M Lorigan P Thatcher N Three-
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melanoma (MM) In ASCO Annual Meeting 2000
Abstract 2257
Bafaloukos 2002
Bafaloukos D Aravantinos G Fountzilas G Stathopoulos
G Gogas H Samonis G et alDocetaxel in combination
with dacarbazine in patients with advanced melanoma
Oncology 200263(4)333ndash7
Bajetta 2002
Bajetta E Del Vecchio M Bernard-Marty C Vitali
M Buzzoni R Rixe O et alMetastatic melanoma
chemotherapy Seminars in Oncology 200229(5)427ndash45
Balch 2001
Balch CM Soong SJ Gershenwald JE Thompson JF
Reintgen DS Cascinelli N et alPrognostic factors analysis
of 17600 melanoma patients validation of the American
Joint Committee on Cancer melanoma staging system
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200119(16)3622ndash34
Barth 1995
Barth A Morton DL The role of adjuvant therapy in
melanoma management Cancer 199575 Suppl (2)
726ndash34
Chiarion-Sileni 2003
Chiarion-Sileni V Del Bianco P De Salvo GL Lo Re G
Romanini A Labianca R et alQuality of life evaluation in a
randomised trial of chemotherapy versus bio-chemotherapy
in advanced melanoma patients European journal of cancer
(Oxford England 1990) 200339(11)1577ndash85
Creagan 1984
Creagan ET Ahmann DL Green SJ Long HJ Frytak S
OrsquoFallon JR et alPhase II study of low-dose recombinant
leukocyte A interferon in disseminated malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 19842(9)1002ndash5
Crosby 2000
Crosby T Fish R Coles B Mason MD Systemic treatments
for metastatic cutaneous melanoma Cochrane Database
of Systematic Reviews 2000 Issue 2 [DOI 101002
14651858CD001215]
12Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Cure 1999
Cure H Souteyrand P Ouabdesselam R Roche H
Ravaud A DrsquoIncan M et alResults of a phase II trial
with cystemustine at 90 mgm(2) as a first- or second-line
treatment in advanced malignant melanoma a trial of the
EORTC Clinical Studies Group Melanoma Research 1999
9(6)607ndash10
Danson 2002
Danson S Arance A Lorigan P Clamp A Hodgetts J
Lomax L Thatcher N Middleton MR A randomized
study of temozolomide (TMZ) alone with interferon-
alpha (TMZ-IFN) or with thalidomide (TMZ-THAL) in
metastatic malignant melanoma (MMM) ASCO Annual
Meeting - Proceedings 2002Abstract 1369
Dorval 1986
Dorval T Palangie T Jouve M Garcia-Giralt E Israel L
Falcoff E et alClinical phase II trial of recombinant DNA
interferon (interferon alpha 2b) in patients with metastatic
malignant melanoma Cancer 198658(2)215ndash8
Dutcher 1989
Dutcher JP Creekmore S Weiss GR Margolin K
Markowitz AB Roper M et alA phase II study of
interleukin-2 and lymphokine-activated killer cells in
patients with metastatic malignant melanoma Journal of
clinical oncology official journal of the American Society of
Clinical Oncology 19897(4)477ndash85
Falkson 1995
Falkson CI Experience with interferon alpha 2b combined
with dacarbazine in the treatment of metastatic malignant
melanoma Medical oncology (Northwood London England)
199512(1)35ndash40
Garbe 1990
Garbe C Krasagakis K Zouboulis CC Schroder K Kruger
S Stadler R et alAntitumor activities of interferon alpha
beta and gamma and their combinations on human
melanoma cells in vitro changes of proliferation melanin
synthesis and immunophenotype Journal of Investigative
Dermatology 199095 Suppl (6)231ndash7
Gershenwald 1999
Gershenwald JE Thompson W Mansfield PF Lee JE
Colome MI Tseng CH et alMulti-institutional melanoma
lymphatic mapping experience the prognostic value of
sentinel lymph node status in 612 stage I or II melanoma
patients Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199917(3)976ndash83
Hanninen 1991
Hanninen EL Korfer A Hadam M Schneekloth C
Dallmann I Menzel T et alBiological monitoring of
low-dose interleukin 2 in humans soluble interleukin 2
receptors cytokines and cell surface phenotypes Cancer
Research 199151(23 Pt 1)6312ndash6
Huncharek 2001
Huncharek M Caubet JF McGarry R Single-agent
DTIC versus combination chemotherapy with or without
immunotherapy in metastatic melanoma a meta-analysis
of 3273 patients from 20 randomized trials Melanoma
Research 200111(1)75ndash81
Juni 2001
Juni P Altman DG Egger M Assessing the quality of
controlled clinical trials BMJ 200132342ndash6
Kadison 2003
Kadison AS Morton DL Immunotherapy of malignant
melanoma The Surgical Clinics of North America 200383
(2)343ndash70
Keilholz 2002
Keilholz U Gore ME Biochemotherapy for advanced
melanoma Seminars in Oncology 200229(5)456ndash61
Khayat 2002
Khayat D Bernard-Marty C Meric JB Rixe O
Biochemotherapy for advanced melanoma maybe it is real
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Society of Clinical Oncology 200220(10)2411ndash4
Koh 1991
Koh HK Cutaneous melanoma New England Journal of
Medicine 1991325(3)171ndash82
La Vecchia 1999
La Vecchia C Lucchini F Negri E Levi F Recent declines
in worldwide mortality from cutaneous melanoma in youth
and middle age International Journal of Cancer 199981(1)
62ndash6
Lee 2000
Lee ML Tomsu K Von Eschen KB Duration of survival
for disseminated malignant melanoma results of a meta-
analysis Melanoma Research 200010(1)81ndash92
Legha 1998
Legha SS Ring S Eton O Bedikian A Buzaid AC Plager
C et alDevelopment of a biochemotherapy regimen
with concurrent administration of cisplatin vinblastine
dacarbazine interferon alfa and interleukin-2 for patients
with metastatic melanoma Journal of clinical oncology
official journal of the American Society of Clinical Oncology
199816(5)1752ndash9
Leong 2003
Leong SP Future perspectives on malignant melanoma
Surgical Clinics of North America 200383(2)453ndash6
Lokich 1979
Lokich JJ Garnick MB Legg M Intralesional immune
therapy methanol extraction residue of BCG or purified
protein derivative Oncology 197936(5)236ndash41
Nathan 1998
Nathan FE Mastrangelo MJ Systemic therapy in
melanoma Seminars in Surgical Oncology 199814(4)
319ndash27
Osborn 1977
Osborn DE Castro JE Immunological response in patients
receiving Corynebacterium parvum therapy Clinical
Oncology 19773(2)155ndash64
13Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Parmar 1998
Parmar MKB TV Stewart L Extracting summary statistics
to perform meta-analyses of the published literature for
survival endpoints Statistics in Medicine 1998172815ndash34
Richards 1992
Richards JM Mehta N Ramming K Skosey P Sequential
chemoimmunotherapy in the treatment of metastatic
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199210(8)1338ndash43
Rigel 1989
Rigel DS Rivers JK Kopf AW Friedman RJ Vinokur AF
Heilman ER et alDysplastic nevi Markers for increased
risk for melanoma Cancer 198963(2)386ndash9
Rosenberg 1989
Rosenberg SA Lotze MT Yang JC Aebersold PM Linehan
WM Seipp CA et alExperience with the use of high-
dose interleukin-2 in the treatment of 652 cancer patients
Annals of Surgery 1989210(4)474-84 discussion 484-5
Sertoli 1989
Sertoli MR Bernengo MG Ardizzoni A Brunetti I Falcone
A Vidili MG et alPhase II trial of recombinant alpha-2b
interferon in the treatment of metastatic skin melanoma
Oncology 198946(2)96ndash8
Smith 1993
Smith KA Lowest dose interleukin-2 immunotherapy
Blood 199381(6)1414ndash23
Stopeck 2001
Stopeck AT Jones A Hersh EM Thompson JA
Finucane DM Gutheil JC et alPhase II study of direct
intralesional gene transfer of allovectin-7 an HLA-B7
beta2-microglobulin DNA-liposome complex in patients
with metastatic melanoma Clinical Cancer Research 20017
(8)2285ndash91
Tsang 1983
Tsang KY Fudenberg HH Pan JF Gnagy MJ Bristow
CB An in vitro study on the effects of isoprinosine on
immune responses in cancer patients International Journal
of Immunopharmacology 19835(6)481ndash90
Wingo 1995
Wingo PA Tong T Bolden S Cancer statistics 1995 CA
a cancer journal for clinicians 199545(1)8ndash30
Yusuf 1985
Yusuf S Peto R Lewis J Collins R Sleight P Beta blockade
during and after myocardial infarction an overview of the
randomized trials Progress in Cardiovascular Diseases 1985
27(5)335ndash71lowast Indicates the major publication for the study
14Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Atkins 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding public
Participants PS lt= 1
Brain mets no info
Age 20 to 80 (median 50)
Number of cycles no info
Randomised 416 a 206 b 210
Evaluable 405 a 201 b 204
Interventions a (CT) cisplatin 20mgm2 D1 to 4 vinblastin 12 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1-4 vimblastin 12 mgm2 D1-4 DTIC 800 mgm2 D1
IFN-alpha 5 mIU D1-5 D8 D10 D12 IL-2 9 mIU D1-4
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
Notes Multicentric yes
Withdrawals a five b six
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
15Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Atzpodien 2002
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding both (pharmaceutic and public)
Participants PS lt= 1
Brain mets yes Age 28 to 77 (median 57)
Number of cycles no info
Randomised 124 a 60 b 64
Evaluable 124 a 60 b 64
Interventions a (CT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily
b (ICT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily IFN-alpha 5 mIUm2 D1 week4 and 5
mIUm2 D1 D3 D5 week 5 IL-2 10 mIUm2 D1 D3 D5
(each five weeks)
Outcomes 1 Response rates
2 Overall survival
3 Progression free survival
Notes Multicentric yes
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Bajetta 1994
Methods D parallel group (three groups)
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding pharmaceutic
Participants PS lt= 2
Brain mets no
16Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Bajetta 1994 (Continued)
Age 18 to 70 (median 53)
Number of cycles 8
Randomised 266 a 88 b 86 c 92
Evaluable 242 a 82 b 76 c 84
Interventions a (CT) DTIC 800 mgm2 D1
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU 3xweek
c (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU D1 to 3 6 mIU D4 to 6 9 mIU daily
(each 21 days)
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Overall survival
Notes Multicentric yes
Withdrawals a six b ten c eight
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Danson 2003
Methods D parallel group
AC independent allocation
RS permuted blocks
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets yes Age 16 to 88 (median 58)
Number of cycles six
Randomised 125 a 59 b 62
Evaluable 121 a 55 b 62
Interventions a (CT) temozolomide 200 mgm2 88 h (5 doses)
b (ICT) Temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIU 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
17Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Danson 2003 (Continued)
Notes Multicentric no
Withdrawals a 4 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Del Vecchio 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no Age 19 to 70 (median 50)
Number of cycles no info
Randomised 151 a 75 b 76
Evaluable 145 a 72 b 73
Interventions a (CT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250 mgm2 D1 to
3
b (ICT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250m gm2 D1 to
3 IFN-alpha 5 mIUm2 D1 to 5 IL-2 9 mIUday x 5 daysweek x 2 weeks with a week of
rest
(each 21 days)
Outcomes 1 Response rates
2 Time to Progression
2 Overall Survival
Notes Multicentric yes
Withdrawals a three b three
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
18Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Eton 2002
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding pharm
Participants PS lt= 3
Brain mets yes Age median 49
Number of cycles no info
Randomised 190
Evaluable 183 a 92 b 91
Interventions a (CT) cisplatin 20m gm2 D1 to 4 vimblastin 2 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1 to 4 vinblastin 15 mgm2 D1 to 4 DTIC 800 mgm2
D1 IFN-alpha 5mIUm2 D5 to 9 D17-21 IL-2 9 mIUm2 D5 to 8 D17 to 20
(each 21 days)
Outcomes 1 Response rates
2 Time to progression
3 Overall survival
Notes Multicentric no
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1991
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size no
ITT no
Placebo no
Funding both
Participants PS lt= 1
Brain mets no
Age 22 to 79
(median 57)
Number of cycles at least two
19Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1991 (Continued)
Randomised 73 Evaluable 68 a 34 b 34
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Time to treatment failure
3 Median survival
4 Toxicity
Notes Multicentric no
Withdrawals a three b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1998
Methods D 2 x 2 factorial design
AC independent allocation
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 18 to 84
Number of cycles no info
Randomised 271 Evaluable 263 a 68 b 65 c 63 d 67
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
c (CT) DTIC 200m gm2 D1 to 5 tamoxifen 20 mgdaily
d (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek tamoxifen 20 mgdaily
(each 28 days)
Outcomes 1 Response rates
2 Toxicity rates
20Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1998 (Continued)
3 Overall survival
4 Time to treatment failure
Notes Multicentric yes
Withdrawals a one b three c three d one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Gorbonova 2000
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no
Age 23 to 75
Number of cycles no info
Randomised 30 Evaluable 28 a 14 b 14
Interventions a (CT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2
b (ICT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2 IFN-alpha 3 mIU D5 7
9 11 13 15 17 19
(each 28 days)
Outcomes 1 Response rates
Notes Multicentric no
Withdrawals a two b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
21Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Johnston 1998
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age 18 to 70
(median 45)
Number of cycles no info
Randomised 65 Evaluable 65 a 30 b 35
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to 3
Tamoxifen 40 mg daily
b (ICT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to
3 Tamoxifen 40 mg daily IFN-alpha 9 mIU D1 to 3 IL-2 18 mIU D-2 IL-2 9 mIU D-
1 and 0
(each 28 days)
Outcomes 1 Response rates
2 Time to disease progression
3 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Kirkwood 1990
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding pharm
22Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Kirkwood 1990 (Continued)
Participants PS no info
Brain mets no info
Age no info
Number of cycles no info
Randomised 74 Evaluable 68 a 24 b 23 c 21
Interventions a (CT) DTIC 250 mgm2 D1 to 5 (each 21 days)
b (I) IFN-alpha 3 mIU d1 to 5 every week for 3 weeks than 3 mIUm2 3 xweek
c (ICT) DTIC 250 mgm2 D1 to 5 (each 21 days) IFN-alpha 3 mIU d1 to 5 every week
for 3 weeks than 3 mIUm2 3 xweek
Outcomes 1 Response rates
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Middleton 2000
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets no
Age 24 to 71
(median 51)
Number of cycles six
Randomised 105 Evaluable 96 a 46 b 50
Interventions a (CT) DTIC 800 mgm2 D1 cisplatin 25 mgm2 D1 to 3 BCNU 150 mgm2 D1
tamoxifen 20 mgdaily
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 9 mIU 3 xweek
(each 21 days)
Outcomes 1 Response rates
2 One year survival
3 Median survival
23Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Middleton 2000 (Continued)
4 Toxicity
4 Time spent in hospital
Notes Multicentric no
Withdrawals a seven b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Ridolfi 2002
Methods D parallel group
AC independent allocation by telephone
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 25 to 77
Number of cycles six
Randomised 178 Evaluable 176 a 89 b 87
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1
b (ICT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1 IFN-
alpha 3 mIU 3 xweek IL-2 45 mIU D3 to 5 D8 to 12
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
3 Time to progression
4 Toxicity
Notes Multicentric yes
Withdrawals a one b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
24Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
T A B L E O F C O N T E N T S
1HEADER
1ABSTRACT
2PLAIN LANGUAGE SUMMARY
2BACKGROUND
4OBJECTIVES
4METHODS
Figure 1 6
7RESULTS
9DISCUSSION
10AUTHORSrsquo CONCLUSIONS
10ACKNOWLEDGEMENTS
11REFERENCES
14CHARACTERISTICS OF STUDIES
30DATA AND ANALYSES
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival 31
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival 32
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival 34
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival 35
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate 36
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate 37
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate 38
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival 39
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3 40
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3 41
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality 42
42ADDITIONAL TABLES
45APPENDICES
46FEEDBACK
47WHATrsquoS NEW
47HISTORY
48CONTRIBUTIONS OF AUTHORS
48DECLARATIONS OF INTEREST
48NOTES
48INDEX TERMS
iChemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
[Intervention Review]
Chemoimmunotherapy versus chemotherapy for metastaticmalignant melanoma
Andre D Sasse1 Emma C Sasse1 Luciana GO Clark2 Luciana Ulloa3 Otavio Augusto Camara Clark4
1Internal Medicine UNICAMP (Universidade Estadual de Campinas) Campinas Brazil 2Oncology Hospital Celso PierroPUC-
Campinas e Instituto do Radium de Campinas Campinas Brazil 3Public Health Unit Blumenau-SC Brazil 4Evidecircncias Scientific
Solutions in Healthcare Satildeo Paulo Brazil
Contact address Andre D Sasse Internal Medicine UNICAMP (Universidade Estadual de Campinas) Av Dr Luiz de Tella 1515
Cidade Universitaria Campinas Sao Paulo 13083 000 Brazil andresassecom
Editorial group Cochrane Skin Group
Publication status and date Edited (no change to conclusions) published in Issue 8 2013
Review content assessed as up-to-date 15 November 2006
Citation Sasse AD Sasse EC Clark LGO Ulloa L Clark OAC Chemoimmunotherapy versus chemotherapy for metastatic malignant
melanoma Cochrane Database of Systematic Reviews 2007 Issue 1 Art No CD005413 DOI 10100214651858CD005413pub2
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
A B S T R A C T
Background
Malignant melanoma one of the most aggressive of all skin cancers is increasing in incidence throughout the world Surgery remains
the cornerstone of curative treatment in earlier stages Metastatic disease is incurable in most affected people because melanoma does
not respond to most systemic treatments A number of novel approaches are under evaluation and have shown promising results but
they are usually associated with increased toxicity and cost The combination of chemotherapy and immunotherapy has been reported
to improve treatment results but it is still unclear whether evidence exists to support this choice compared with chemotherapy alone
No language restrictions were imposed
Objectives
To compare the effects of therapy with chemotherapy and immunotherapy (chemoimmunotherapy) versus chemotherapy alone in
people with metastatic malignant melanoma
Search methods
We searched the Cochrane Skin Group Specialised Register (14 February 2006) the Cochrane Central Register of Controlled Trials
(The Cochrane Library Issue 3 2005) MEDLINE (2003 to 30 January 2006 ) EMBASE (2003 to 20 July 2005) and LILACS (1982
to 20 February 2006) References conference proceedings and databases of ongoing trials were also used to locate trials
Selection criteria
All randomised controlled trials that compared the use of chemotherapy versus chemoimmunotherapy on people of any age diagnosed
with metastatic melanoma
Data collection and analysis
Two authors independently assessed each study to determine whether it met the pre-defined selection criteria with differences being
resolved through discussion with the review team Two authors independently extracted the data from the articles using data extraction
forms Quality assessment included an evaluation of various components associated with biased estimates of treatment effect Whenever
possible a meta-analysis was performed on the extracted data in order to calculate a weighed treatment effect across trials
1Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Main results
Eighteen studies met our criteria and were included in the meta-analysis with a total of 2625 participants We found evidence of an
increase of objective response rates in people treated with chemoimmunotherapy in comparison with people treated with chemotherapy
Nevertheless the impact of these increased response rates was not translated into a survival benefit We found no difference in survival
to support the addition of immunotherapy to chemotherapy in the systemic treatment of metastatic melanoma with a hazard ratio
of 089 (95 CI 072 to 111 P = 031) Additionally we found increased hematological and non-hematological toxicities in people
treated with chemoimmunotherapy
Authorsrsquo conclusions
We failed to find any clear evidence that the addition of immunotherapy to chemotherapy increases survival of people with metastatic
melanoma Further use of combined immunotherapy and chemotherapy should only be done in the context of clinical trials
P L A I N L A N G U A G E S U M M A R Y
Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Malignant melanoma is one of the most aggressive of all skin cancers If it is confined to the skin it can often be cured by surgery
However if it has spread melanoma is usually incurable because it does not respond to most treatments Recently clinicians have been
trying a combination of chemotherapy and immunotherapy in the hope of improving the outcome The review of trials showed an
increased response to treatment when immunotherapy was added to chemotherapy but no difference was seen in survival rate and toxic
effects were increased
There is not enough evidence to support the use of a combination of combined immunotherapy and chemotherapy in treatment of
metastatic malignant melanoma
B A C K G R O U N D
Description of the condition
Epidemiology and progress of melanoma
Malignant melanomas develop due to changes in the melanocytes
cells that produce melanin pigment Melanomas are most com-
monly found in the skin but can also be found in the uveal tract
(back of the eye) upper digestive tract anal canal rectum and
vagina
Malignant melanoma of the skin accounts for 1 to 3 of all ma-
lignant tumors and there has been an increase in its incidence of
6 to 7 each year since 1985 (La Vecchia 1999 Wingo 1995)
However the overall mortality rate has only slightly increased
probably due to an increase in the early diagnosis of lesions that
have a better prognosis (Leong 2003)
As with other tumors the stage (progress) of the disease is still an
important determinant of survival In the earlier stages melanoma
is confined to the skin where the disease is curable in a high
percentage of cases through surgical removal of the tumor (Nathan
1998) The 5 year survival rate for melanoma that is confined to
the skin is 80 to 100 (Nathan 1998) depending on the thickness
of the primary tumor
In people where the cancer has spread to the lymph nodes (nodal
disease) three variables independently affect the prognosis
1 the number of positive lymph nodes
2 the presence of ulceration within the primary tumor
3 whether the nodal disease is macroscopic (an enlarged
lymph node can be felt by a doctor) or microscopic (the lymph
node cannot be felt but abnormal melanoma cells are present
and can be seen when viewed under a microscope) (Balch 2001)
In people with macroscopic disease more than one positive node
and an ulcerated primary tumor the 5 year survival rate is only
16 In people with one microscopically positive lymph node and
without ulceration in the primary lesion the 5 year survival rate
is 71 (Balch 2001)
The detection of lymph node metastases previously relied on crude
clinical or regional elective lymph node dissection (removal of a
2Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
whole group of lymph nodes responsible for draining a partic-
ular area of the body) but several large randomised controlled
trials have shown no improvement in survival using this tech-
nique Currently sentinel lymph node mapping and directed se-
lective lymphadenectomy (ie only removing those nodes that
show up as positive using the sentinel node imaging technique) has
been shown to identify lymph node metastases more precisely and
with less surgical morbidity than elective dissection (Gershenwald
1999)
Causes
Although the cause of melanoma is unknown major risk factors
have been identified (Koh 1991) Epidemiological studies suggest
that sunlight (ultraviolet radiation) is the most common environ-
mental factor Pale skin a tendency to sunburn fair or red hair
large numbers of melanocytic nevi (moles) and multiple dysplastic
nevi (atypical moles) have been shown to be independent risk fac-
tors for the development of melanoma Fair skin that does not tan
easily in combination with high sun exposure provides the largest
cumulative risk factor for melanoma development (Rigel 1989)
Impact
Malignant melanoma that has spread to distant sites by dissemi-
nation is associated with extremely poor survival median survival
is approximately 8 months and less than 5 of such people will
survive for more than 5 years (Lee 2000)
There are large prospective randomised multicenter trials that
have answered some basic management questions improved the
care of melanoma sufferers and expanded our understanding of
the disease However many aspects of treatment such as the thera-
peutic role of cytotoxic chemotherapy and biologic therapy alone
or in combination remain controversial and inconclusive (Crosby
2000 Leong 2003)
Description of the intervention
Systemic therapy
This has little or no impact on survival for advanced disease
There is no evidence derived from randomised controlled trials to
show superiority of systemic therapy over supportive care (Crosby
2000) The minority of people with metastatic melanoma who do
respond to systemic treatment have remissions which are generally
of short duration (Nathan 1998) Few agents have demonstrated
substantial anti-tumor activity against metastatic melanoma The
alkylating agent dacarbazine (DTIC) is considered to be the most
active drug for the treatment of this disease with a response rate of
20 and a median duration of response of 4 to 5 months (Khayat
2002 Nathan 1998) Other cytotoxic compounds such as temo-
zolomide (a dacarbazine analogue) (Middleton 2000) cisplatin
and carboplatin (Bajetta 2002) vinca alkaloids (Khayat 2002)
taxanes (Bafaloukos 2002) and nitrosoureas (Cure 1999) have not
improved these results All of these treatments are associated with
response rates of less than 15 and all are associated with signif-
icant adverse effects (Bafaloukos 2002 Bajetta 2002 Cure 1999
Khayat 2002 Middleton 2000)
Combination chemotherapy
The role of combination chemotherapy in advanced disease re-
mains unclear Prospective randomised studies have failed to
demonstrate any significant benefit for combination chemother-
apy when compared with single agents except for a slight increase
in response rates (Huncharek 2001)
Experimental treatments
Experimental treatments such as vaccines antibody treatments
and gene therapy are being developed and are of high scientific
interest However their efficacy in advanced melanoma has so
far been very limited with overall response rates of less than 5
(Keilholz 2002 Stopeck 2001) Since the 1970s immunostim-
ulating agents such as Bacillus Calmette-Guerin (BCG) (Lokich
1979 Osborn 1977) Corynebacterium parvum (Osborn 1977)
or isoprinosine (Tsang 1983) have been evaluated as local or sys-
temic treatments After some early hopes all these treatments have
also failed to demonstrate a significant and consistent effect in the
clinical management of advanced melanoma (Khayat 2002)
Immunotherapy
Two points have driven the attention of researchers in the im-
munology field to melanoma Firstly the spontaneous regression
of melanoma (ie the tumor occasionally appears to go away in
some people) Spontaneous regression is much more frequent than
in melanoma than with any other solid tumor and it is associated
with a specific cellular immune response (Kadison 2003) Sec-
ondly the fact that some people with melanoma also have tumor
rejection antigen recognized by CD4 and CD8 T cells (immune
cells that can help get rid of cancer cells) (Kadison 2003)
At least two types of immunotherapy have been used in advanced
melanoma interferon-alpha and interleukin-2
Interferon-alpha (IFN-α) belongs to a group of proteins known
to have antiproliferative and antitumor effects (Garbe 1990) In
addition IFN-α exhibits certain immunomodulatory effects - it
upregulates the expression of major histocompatibility complex
(MHC) class I antigens in melanoma cells and also the expres-
sion of co-stimulatory molecules rendering the cells more suscep-
tible to immunological defense mechanisms (Barth 1995) Phase
II studies of IFN-α as a single agent have demonstrated response
rates of approximately 20 with a slightly more durable response
3Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
than the one found with dacarbazine (DTIC) (Creagan 1984
Dorval 1986 Sertoli 1989)
Interleukin-2 (IL-2) is a major growth factor for lymphoid cells
including T cells and natural killer (NK) cells (Hanninen 1991
Smith 1993) Clinical trials have demonstrated modest anti-tumor
activity in people with metastatic melanoma (Rosenberg 1989)
responses were seen in approximately 15 of people with a
small proportion of complete responses (Dutcher 1989 Rosenberg
1989)
Chemoimmunotherapy
As chemotherapy and immunotherapy have different and per-
haps synergistic mechanisms of action their combination of im-
munotherapy with chemotherapy (chemoimmunotherapy) has
been studied since the early 1990s (Khayat 2002) Some reports
have suggested that chemotherapeutic agents administered in com-
bination with IL-2 or IFN or both can improve response rates
(Legha 1998 Richards 1992) with complete response rates in 10
to 20 of people as well as increases in median survival (Falkson
1991) Based on these results the use of chemoimmunotherapy is
currently preferred in some institutions as a first-line treatment in
advanced (stage IV) melanoma (Kadison 2003 Keilholz 2002)
although it is still considered an experimental therapy by oth-
ers(Crosby 2000)
Why it is important to do this review
There are substantial controversies about the real benefit of
chemoimmunotherapy some studies conclude that the combi-
nation of treatments did not improve survival (Rosenberg 1999
Young 2001) or even response rates (Falkson 1998 Gorbonova
2000 Johnston 1998 Thomson 1993) in people with metastatic
melanoma There is also concern that combined therapy may in-
crease treatment-related toxicity (Falkson 1998 Johnston 1998)
The lack of conclusive data coming from seemingly conflict-
ing studies about the impact of treatment demands a systematic
review This will provide the most reliable assessment for sup-
porting clinical decision-making with people who have advanced
melanoma
O B J E C T I V E S
To compare the effects of chemotherapy alone versus combined
therapy with chemotherapy and immunotherapy (chemoim-
munotherapy) in people with metastatic malignant melanoma
M E T H O D S
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs)
Types of participants
People of any age diagnosed with metastatic malignant melanoma
that has spread to distant sites by systemic dissemination
Types of interventions
1 Chemotherapy
2 Chemoimmunotherapy ie the combination of
chemotherapy and immunotherapy with interferon-alpha or
interleukin-2 or both
Types of outcome measures
Primary outcomes
Overall survival - number of participants alive at the end of the
trial
Secondary outcomes
1 One two and five-year survival rates - proportion of
participants alive at one two and five year follow-up
2 Response rates (partial and complete) - proportion of
participants that have achieved partial or complete responses as
defined by the trial authors
3 Progression-free survival - number of participants without
progression of disease at the end of the trial
4 Treatment morbidity (treatment-related toxicity) -
proportion of participants that have developed hematological or
non-hematological toxicities
5 Treatment related mortality - proportion of participants
that have died due to the treatment This outcome was not
described previously in the protocol and was added after
discussion between the reviewers that considered it relevant
Mortality related to treatment is a great concern in oncology
when comparing treatments with potential differences in toxicity
6 Quality of life measures
Search methods for identification of studies
We searched electronic databases and other resources to locate
reports of studies No language restrictions were imposed
4Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Electronic searches
Electronic databases
We searched the following electronic databases
1 MEDLINE (OVID) (Appendix 1)
2 The Cochrane Skin Group Specialised Register
3 The Cochrane Central Register of Controlled Trials
4 Medline (PubMed)
5 EMBASE
6 LILACS (Latin American and Caribbean Health Science
Information Database)
Search strategies for databases 2 to 6 are located in Appendix 2
Search of databases of ongoing trials (unpublished literature)
We asked trial authors and pharmaceutical companies about un-
published and ongoing trials Databases of major research groups
and registers of trials in the following databases were also searched
with the term rsquoMELANOMArsquo
bull Current Controlled Trials Register (httpwwwcontrolled-
trialscom) on 30th January 2006
bull European Organisation for Research and Treatment of
Cancer (httpwwweortcbe) on 20th February 2006
bull National Cancer Institute America (http
wwwcancergovclinicaltrials) on 16th November 2005
bull National Cancer Institute Canada (httphttp
wwwctgqueensucapublicClinical_Trialsclinical_trialshtml)
on 30th January 2006
bull Australian Clinical Trials Registry (httpwwwactrorgau)
on 30th January 2006
bull US Food and Drug Administration (httpwwwfdagov)
on 30th January 2006
bull ClinicalTrialsgov (httpwwwclinicaltrialsgov) on 16th
November 2005
Searching other resources
References from unpublished studies
All bibliographies of selected studies were scanned for possible
references to RCTs
Conference proceedings
We handsearched the abstracts from conference proceedings of
the ASCO (American Society of Clinical Oncology) and ESMO
(European Society of Medical Oncology)
Data collection and analysis
Where there was uncertainty we tried to contact trial authors for
clarification
A consumer (LU) was involved throughout the review process to
ensure the readability of the final review Updating will be done
every two years
Selection of studies
Two authors (ADS and ECS) checked the titles and abstracts iden-
tified from the searches If it was clear that the study did not refer
to a RCT on metastatic melanoma we excluded it Two authors
(ADS and OAC) independently assessed each remaining study to
determine whether it met the pre-defined selection criteria Any
differences were resolved through discussion with the review team
Excluded studies are listed in the Table of Excluded Studies
Data extraction and management
Two authors (ADS and ECS) independently extracted the data
from the studies All data were extracted directly from the text or
calculated according to the available information
Any differences were resolved by discussion with one author
(OAC) A data extraction form was developed and piloted in order
to summarize the trials One author (ADS) checked and entered
the data Two authors (ECS and LGC) independently checked the
data entry
Assessment of risk of bias in included studies
Assessment of methodological quality
The quality assessment included an evaluation of the following
components for each included study since there is some evidence
that these are associated with biased estimates of treatment effect
(Juni 2001)
(a) the method of generation of the randomisation sequence
(b) the method of allocation concealment - it was considered rsquoad-
equatersquo if the assignment could not be foreseen
(c) who was blindednot blinded (participants clinicians outcome
assessors)
(d) how many participants were lost to follow up in each arm and
whether participants were analysed in the groups to which they
were originally randomised (intention-to-treat)
In addition the quality assessment also included
(e) the source of funding
(f ) if the participant had a biopsy proven melanoma
(g) the baseline assessment of the participants for presence of liver
and brain metastases performance status
(h) whether the aims interventions (including drug doses and
duration of treatment) and outcome measures were clearly defined
5Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(i) the use and appropriateness of statistical analyses
We recorded all the information in a table of quality criteria and
gave a description of the quality of each study based on these
characteristics
Measures of treatment effect
Where possible we performed a meta-analysis for the outcomes
in order to calculate a weighted treatment effect across trials using
a random-effects model For binary endpoints we calculated the
risk ratio (RR) with 95 confidence intervals (Yusuf 1985) We
also expressed the results as a number needed to treat (NNT)
where appropriate for a range of plausible control event rates For
overall survival a time-to-event data we calculated the Hazard
Ratio (HR) When data were not available for direct extraction
we calculated indirectly (from different parameters using indirect
calculation of the variance and the number of observed minus
expected events) according to the method described by Parmar
(Parmar 1998) In the funnel plot (Figure 1) and comparison 1
rsquoPeto OR (IPD)rsquo is a Hazard Ratio For continuous data such as
quality of life we planned to use standardised mean differences
with 95 confidence intervals would have been used
Figure 1 Funnel plot using overall survival as the outcome
Assessment of heterogeneity
Heterogeneity was assessed using I2 Where the heterogeneity was
considerable (I2 gt 50) we explored possible reasons using the
type (interleukin-2 or interferon) and dose (high or low) of im-
munotherapy used as subgroups Where we were not able to find
an explanation we have recorded this along with appropriate cau-
tion in the interpretation of these data
Data synthesis
Analysis and presentation
Once studies had been selected critically appraised and the data
extracted we entered the data in the Characteristics of included
studies table
6Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Three studies (Bajetta 1994 Kirkwood 1990 Vorobiof 1994) eval-
uated three arms of treatment with one of them evaluating che-
motherapy alone and the two others using chemoimmunotherapy
One study (Falkson 1998) had four arms two using chemotherapy
and two using chemoimmunotherapy The data from the similar
arms were grouped considered as one and then compared to the
other arm
R E S U L T S
Description of studies
Results of the search
We scanned approximately 700 citations Initially 28 studies
were identified Four studies (Arance 2000 Chiarion-Sileni 2003
Danson 2002 Falkson 1995) had data that overlapped with three
included studies (Danson 2003 Falkson 1991 Ridolfi 2002)
Ongoing studies
No ongoing studies were available to be included in the meta-
analysis
Included studies
Eighteen studies with a total of 2625 participants met our criteria
and were included in the meta-analysis (please see Characteristics
of included studies) One study differed considerably from the oth-
ers because vindesine was used as the chemotherapy control a drug
without evidence of response in metastatic melanoma (Vorobiof
1994) Another study differed considerably as lower dose treat-
ment in the chemoimmunotherapy group was used (Middleton
2000) The first study was published in 1990 and the last studies
were published in 2003
Participants
The participants were between the ages of 16 and 88 years and
had an Eastern Cooperative Oncology Group performance status
from 0 to 3 Only three studies included participants with brain
metastasis (Atzpodien 2002 Danson 2003 Eton 2002)
Interventions
Seven studies compared chemotherapy to chemoimmunotherapy
with IFN plus IL-2 (Atkins 2003 Atzpodien 2002 Del Vecchio
2003 Eton 2002 Johnston 1998 Ridolfi 2002 Rosenberg 1999)
Eleven compared chemotherapy to chemoimmunotherapy with
IFN (Bajetta 1994 Danson 2003 Falkson 1991 Falkson 1998
Gorbonova 2000 Kirkwood 1990 Middleton 2000 Spieth 2003
Thomson 1993 Vorobiof 1994 Young 2001)
The drugs used in chemotherapeutic schemes varied between the
trials Seven trials evaluated DTIC combined with other drugs in
both arms (Atkins 2003 Atzpodien 2002 Del Vecchio 2003 Eton
2002 Johnston 1998 Ridolfi 2002 Rosenberg 1999) and six
evaluated DTIC alone as the control (Bajetta 1994 Falkson 1991
Falkson 1998 Kirkwood 1990 Thomson 1993 Young 2001)
Four studies evaluated other schemes without DTIC two trials
used temozolomide (Danson 2003 Spieth 2003) one trial used
vindesine (Vorobiof 1994) and one trial used combined drugs
based on cisplatin (Gorbonova 2000)
Only one study did not use the same scheme in both the arms
using combined drugs with DTIC as the chemotherapy control
and a lower dose for the chemoimmunotherapy group with DTIC
alone (Middleton 2000)
Setting
Ten studies were carried out in Europe four in the United States
two in South Africa and one was a multicentre worldwide trial
All trials were reported in the English language
Outcomes
Response rates were the primary outcome measures in most trials
and were described in all included studies Two studies did not
evaluate survival rates (Gorbonova 2000 Kirkwood 1990) Three
studies included quality of life analyses in the outcomes (Ridolfi
2002 Thomson 1993 Young 2001) The length of the follow-up
varied widely between the trials and sometimes it was not speci-
fied We did not find a reasonable definition about what could be
considered high or low doses of immunotherapy and the influence
of the immunotherapeutic doses on the outcomes could not be
assessed
Excluded studies
Six studies were excluded (see Characteristics of excluded studies)
The reasons for exclusion were that the study had immunotherapy
on both arms (Bajetta 2001 Richtig 2004 Sertoli 1999 Sparano
1993 Vuoristo 2005) or the study was not randomised (Legha
1996)
Risk of bias in included studies
The quality assessment consisted of a basic methodological eval-
uation of each included study and is shown in Table 1 Addi-
tional quality assessment is shown in Table 2 The criteria used for
methodological quality analysis of the studies are listed in Table 3
(Explanation of Quality Analysis Headings)
7Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Although blinding participants and clinicians is theoretically pos-
sible it is difficult to plan a double-blind study with immunother-
apy This is due to the substantial acute and late toxicities associ-
ated with immunotherapy in one group No study was described
as double-blinded The groups at baseline were in general similar
with a description of most prognostic factors related to metastatic
melanoma (gender performance status age prior therapy liver
metastasis)
In three studies almost all methodological aspects of the trials
were described poorly (Gorbonova 2000 Kirkwood 1990 Spieth
2003)
Allocation
All the included studies were described as randomised as this
was a selection criterion However most papers did not describe
the method of randomisation The method of generation of the
randomised sequence was described and considered adequate in
only 6 out of 18 studies Eleven of 18 studies provided information
on allocation concealment all of which were considered adequate
Blinding
Blinding of outcome assessment and detection bias
We did not find information about blinding of the outcome as-
sessors in any included study
Incomplete outcome data
Handling of losses and attrition bias
In general there were few participants lost to follow up in the
studies The highest number of people lost was 24 in a total of 262
participants (Bajetta 1994) Eleven studies included an intention-
to-treat analysis
Effects of interventions
Primary outcome
Overall survival (eight studies)
This was considered as the number of participants alive at the end
of the trial Sufficient data were available from 8 of the 18 studies
There was no statistically significant difference in survival between
chemoimmunotherapy and chemotherapy with a hazard ratio
(HR) of improved survival of 089 (95 CI 072 to 111 P = 031
Analysis 11) in favour of chemoimmunotherapy In other words
overall survival was slightly lower in the chemoimmunotherapy
group but this was not statistically significant There was no het-
erogeneity across trials (I2 = 0) The funnel plot method using
overall survival as the outcome is presented in Figure 1 It shows
that there was no evidence of substantial publication bias but in-
terpretation of the funnel plot is likely to be unreliable since only
eight relatively large studies were found
When we evaluated the influence of the type of immunotherapy
used in the chemoimmunotherapy group (IL-2 plus IFN-alpha
or IFN-alpha only) we found no statistically significant difference
between the groups with a HR of 096 (95 CI 074 to 124 P =
076 Analysis 11) for chemoimmunotherapy with IL-2 plus IFN-
alpha and a HR of 074 (95 CI 049 to 112 P = 015 Analysis
11) for chemoimmunotherapy associated with only IFN-alpha
Secondary outcomes
One two and five-year survival rates (13 studies)
The number of participants alive at one two and five year follow-
ups were analyzed Data from 13 trials evaluating one year survival
were pooled There was no statistically significant difference in one
year survival between the groups with a risk ratio (RR) of 106
(95 CI 091 to 124 P = 048 Analysis 12) and no significant
heterogeneity across trials (I2 = 363)
Data from 11 trials evaluating 2 year survival were extracted and
pooled Again there was no statistically significant difference be-
tween the groups with a RR of 108 (95 CI 086 to 136 P =
050 Analysis 13) without heterogeneity across trials (I2 = 0)
Only two trials reported data about five year survival The meta-
analysis showed no statistically significant difference in 5 year sur-
vival between the groups with a RR of survival of 234 (95
CI 097 to 565 P = 006 Analysis 14) favouring chemoim-
munotherapy There was no heterogeneity across trials (I2 = 0)
Response rates (17 studies)
Data regarding the number of participants with partial or com-
plete responses from 17 trials were used to evaluate objective re-
sponse rates The analysis detected a statistically significant differ-
ence in favor of chemoimmunotherapy in global response rates
with a RR of 140 (95 CI 120 to 163 P lt 00001 Analysis
21) There was no heterogeneity across trials (I2 = 42) We
tried to evaluate the influence of the type of immunotherapeutic
in the group of chemoimmunotherapy (IL-2 plus IFN-alpha or
IFN-alpha only) We found similar results with a RR of global
response of 146 (95 CI 119 to 179 p = 00002 Analysis 21)
in favor of chemoimmunotherapy with IL-2 plus IFN-alpha and
a RR of 132 (95 CI 102 to 171 p = 004 Analysis 21) in favor
of chemoimmunotherapy with IFN-alpha There was no hetero-
geneity across trials (I2 = 0)
8Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Data from 15 trials were used to evaluate partial and complete
response rates We found a statistically significant difference in
favour of chemoimmunotherapy in both analyses with an HR of
131 (95 CI 107 to 159 p = 0008 Analysis 23) for partial
response rates and an HR of 158 (95 CI 106 to 236 p = 003
Analysis 23) for complete response rates
Progression-free survival (3 studies)
Only three studies had extractable data about the number of par-
ticipants with no disease progression at the end of the trial When
pooled together there was no statistically significant difference be-
tween the groups with an HR of 076 (95 CI 057 to 102 p =
007 Analysis 31) There was no heterogeneity across these trials
(I2 = 0)
Treatment related toxicity (11 studies)
Data from 11 studies were collected with the number of partici-
pants developing clinically significant hematological toxicity (de-
fined as grade 3 or 4) Eight studies had estimated points that
showed enhanced toxicities in the chemoimmunotherapy group
The meta-analysis of the studies showed extreme heterogeneity
(I2 = 941) across the trials We performed a sensitivity anal-
ysis excluding the studies with relatively low doses of chemo-
therapeutic drugs in the chemoimmunotherapy group (Danson
2003 Middleton 2000) but we found similar heterogeneity (I2 =
978)
When we analyzed data from the four studies with similar rela-
tive doses of chemotherapeutics associated with interferon-alpha
without interleukin-2 we found an increase of clinically signifi-
cant hematological toxicities in the chemoimmunotherapy group
with a RR 454 (95 CI 235 to 879 p lt 000001) There was
no heterogeneity across these trials (I2 = 0) When we analyzed
data from studies with combination of interferon-alpha plus in-
terleukin-2 in the chemoimmunotherapy group we again found
extreme heterogeneity across the trials (I2 = 979)
Despite the heterogeneity in global meta-analysis we concluded
that it was not possible to quantify the differences in hematologi-
cal toxicity in such different trials In order to explore these differ-
ences we noted that one study referred to hematological toxicity
in 100 of participants treated with chemoimmunotherapy and
in 96 of participants treated with chemotherapy (Eton 2002)
Another study referred to hematological toxicity only in 2 and
1 respectively (Bajetta 1994)
Non-hematological toxicities were described in almost all stud-
ies and were mainly described as nausea vomiting flu-like syn-
drome asthenia hypotension and fever Data from six similar
studies were extractable and were pooled in the meta-analysis re-
sulting in a statistically significant difference against the chemoim-
munotherapy group with a RR of 274 (95 CI 206 to 364 p
lt 000001 Analysis 42) There was no heterogeneity across trials
(I2 = 0) These results must be treated with caution because of
similar difficulties in pooling these data on hematological toxici-
ties with different therapeutic schemes and several trials described
non-hematological toxicities but we were not able to extract the
data
Data about treatment-related mortality were available in 11 stud-
ies We found no significant difference between the groups with a
RR of 078 (95 CI 026 to 232 p = 065 Analysis 43) There
was no heterogeneity across the trials (I2 = 0)
Quality of life (three studies)
Only three studies reported data on quality of life (Ridolfi 2002
Thomson 1993 Young 2001) all using different methods One
trial described quality of life analysis in detail in an additional pub-
lication (Chiarion-Sileni 2003 Ridolfi 2002) This study found
a significant decrease of overall quality of life in the chemoim-
munotherapy group in comparison to the chemotherapy group
(p = 003) The other two studies did not find differences in global
quality of life between the groups (Thomson 1993 Young 2001)
Thomson did not report global quality of life (Thomson 1993)
Young found no significant differences in quality of life for the
change in scores over time (z = -129 p = 020) (Young 2001)
It was not possible to pool the data as all three studies did not
provide extractable data
Sensitivity analyses on the influence of source of funding baseline
assessment and allocation concealment on the survival analysis
and response rate analyses revealed that there was no relation be-
tween these methodological aspects and the outcome There was
no statistically significant difference in survival between the groups
in all analyses and the difference in response rates in favour of
chemoimmunotherapy was found to be significant
D I S C U S S I O N
Metastatic melanoma is reputed as refractory to most systemic
treatments and little progress has been made in treatment of
metastatic melanoma These concepts are supported by results
from previous systematic reviews One review concluded that there
is no evidence derived from RCTs that systemic treatment is better
than best supportive care (Crosby 2000) Another review of 20
randomised trials (involving 3273 participants) comparing single-
agent DTIC with DTIC in combination with other drugs with or
without immunotherapy concluded that combination of drugs in-
creased response rates but not overall survival (Huncharek 2001)
This systematic review summarises the evidence regarding the
use of chemoimmunotherapy compared to chemotherapy alone
to treat people with metastatic malignant melanoma There are
some important observations regarding the characteristics of the
included studies in this systematic review The ideal combination
9Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
of drugs for an investigation is not well established Seven studies
evaluated chemoimmunotherapy with interferon-alpha plus inter-
leukin-2 and 11 evaluated chemoimmunotherapy only with in-
terferon-alpha The treatment plans with drugs and dosages used
differed between studies
Most studies did not contribute in answering relevant questions
about the impact of chemoimmunotherapy in the treatment of
metastatic melanoma The outcomes were not clearly described in
several of the studies (Atkins 2003 Del Vecchio 2003 Gorbonova
2000 Kirkwood 1990 Spieth 2003 Thomson 1993) Two of
them did not report survival rates evaluating only response rates
(Gorbonova 2000 Kirkwood 1990) All these aspects influenced
the comparability of the trials and must be considered in the data
interpretation
On the basis of a meta-analysis of data coming from eight studies
this review showed no evidence of a difference in overall survival to
support the addition of immunotherapy to chemotherapy in the
systemic treatment of metastatic melanoma (Atkins 2003 Danson
2003 Eton 2002 Falkson 1991 Johnston 1998 Ridolfi 2002
Spieth 2003 Young 2001) Evaluation of one two and five-year
survival with data from other studies again showed no survival
advantage of the drug combination treatment
We found higher clinical response rates in people treated with
chemoimmunotherapy in comparison with people treated with
chemotherapy which was not translated into survival benefit
Additionally we found higher toxicity rates in people treated
with chemoimmunotherapy Despite the importance of evaluat-
ing quality of life there was no available data to perform the meta-
analysis in this systematic review Only three studies reported data
about quality of life all with different methods One trial described
poorer quality of life in people treated with chemoimmunother-
apy related to more intense side effects (Ridolfi 2002) Two trials
however showed no difference between groups (Thomson 1993
Young 2001) It is important that quality of life is included in all
future studies
Our meta-analysis did not find differences between treatment re-
lated mortality Subgroup analysis comparing combinations with
interferon-alpha and with interferon-alpha plus interleukin-2 did
not show different results in survival or response rates
The use of chemoimmunotherapy ie a combination of chemo-
therapy with interferon-alpha or interleukin-2 or both has not
been shown to be beneficial in this review Although short term
response rates were better overall in the chemoimmunotherapy
groups survival was not improved and drug-related toxicities were
higher in the combined chemoimmunotherapy group To date no
treatment regimen has shown efficiency in prolonging survival in
people with metastatic melanoma Little has changed in the sys-
temic management of metastatic melanoma in the last few years
The standard of care remains single-agent DTIC and the role of
immunotherapy remains in doubt
The use of chemoimmunotherapy in the treatment of melanoma
is justified only in the context of clinical trials
A U T H O R S rsquo C O N C L U S I O N S
Implications for practice
We failed to find any evidence to support the view that the
use of chemoimmunotherapy prolongs survival in people with
metastatic melanoma when compared to chemotherapy alone Al-
though short-term clinical responses were higher in the chemoim-
munotherapy group this was associated with a higher rate of
serious adverse events esp haematological toxicity Our review
does not support the use of a combination of immunother-
apy and chemotherapy in chemoimmunotherapy regimens out-
side of clinical trials The standard of care for people with
advanced melanoma remains chemotherapy with single-agent
DTIC Chemoimmunotherapy must not be recommended to peo-
ple in daily practice
Implications for research
Research related to the development of more effective treatments
for people with metastatic melanoma is urgently needed
For people with an incurable disease the primary outcome needs
to be overall survival and all studies should include a quality of life
analysis
Future trials should be designed to define the best systemic treat-
ment and should use chemotherapy with (DTIC) as a standard
control group in order to permit comparisons to be made
A C K N O W L E D G E M E N T S
The authors wish to thank Raquel Gebara Lima for her kind
support in grammar and style
The editorial base would like to thank the following people who
were external referees for this review Keith Wheatley and Pat
Lawton (content experts) and Kathie Godfrey (consumer)
10Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
R E F E R E N C E S
References to studies included in this review
Atkins 2003 published data only
Atkins MB Lee S Flaherty LE Sosman JA Sondak VK
Kirkwood JM A prospective randomized phase III trial
of concurrent biochemotherapy (BCT) with cisplatin
vinblastine dacarbazine (CVD) IL-2 and interferon alpha-
2b (IFN) versus CVD alone in patients with metastatic
melanoma (E3695) An ECOG-coordinated intergroup
trial In ASCO Annual Meeting 2003 2003 p ASCO
Annual Meeting - Proceedings 2003Abstract 2847
Atzpodien 2002 published data only
Atzpodien J Neuber K Kamanabrou D Fluck M Brocker
EB Neumann C et alCombination chemotherapy with or
without sc IL-2 and IFN-alpha results of a prospectively
randomized trial of the Cooperative Advanced Malignant
Melanoma Chemoimmunotherapy Group (ACIMM)
British journal of cancer 200286(2)179ndash84
Bajetta 1994 published data only
Bajetta E Di Leo A Zampino MG Sertoli MR Comella
G Barduagni M et alMulticenter randomized trial of
dacarbazine alone or in combination with two different
doses and schedules of interferon alfa-2a in the treatment
of advanced melanoma Journal of clinical oncology official
journal of the American Society of Clinical Oncology 199412
(4)806ndash11
Danson 2003 published data only
Danson S Lorigan P Arance A Clamp A Ranson
M Hodgetts J et alRandomized phase II study of
temozolomide given every 8 hours or daily with either
interferon alfa-2b or thalidomide in metastatic malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 200321(13)2551ndash7
Del Vecchio 2003 published data only
Del Vecchio M Bajetta E Vitali M Gattinoni L Santinami
M Daponte A et alMulticenter phase III randomized trial
of cisplatin vindesine and dacarbazine (CVD) versus CVD
plus subcutaneous (sc) interleukin-2 (IL-2) and interferon-
alpha-2b (IFN) in metastatic melanoma patients (pts) In
ASCO Annual Meeting 2003 2003 p ASCO Annual
Meeting - Proceedings 2003Abstract 2849
Eton 2002 published data only
Eton O Legha SS Bedikian AY Lee JJ Buzaid AC
Hodges C et alSequential biochemotherapy versus
chemotherapy for metastatic melanoma results from a
phase III randomized trial Journal of clinical oncology
official journal of the American Society of Clinical Oncology
200220(8)2045ndash52
Falkson 1991 published data only
Falkson CI Falkson G Falkson HC Improved results with
the addition of interferon alfa-2b to dacarbazine in the
treatment of patients with metastatic malignant melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 19919(8)1403ndash8
Falkson 1998 published data only
Falkson CI Ibrahim J Kirkwood JM Coates AS Atkins
MB Blum RH Phase III trial of dacarbazine versus
dacarbazine with interferon alpha-2b versus dacarbazine
with tamoxifen versus dacarbazine with interferon alpha-
2b and tamoxifen in patients with metastatic malignant
melanoma an Eastern Cooperative Oncology Group study
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199816(5)1743ndash51
Gorbonova 2000 published data only
Gorbonova VA Egorov GN Perevodchikova NI Orel
NF Combined chemotherapy with or without interferon
alpha N1 (IFN) for advanced malignant melanoma - a
randomized pilot phase III study Gan To Kagaku Ryoho
200027 Suppl (2)310ndash4
Johnston 1998 published data only
Johnston SR Constenla DO Moore J Atkinson H ArsquoHern
RP Dadian G et alRandomized phase II trial of BCDT
[carmustine (BCNU) cisplatin dacarbazine (DTIC)
and tamoxifen] with or without interferon alpha (IFN-
alpha) and interleukin (IL-2) in patients with metastatic
melanoma British Journal of Cancer 199877(8)1280ndash6
Kirkwood 1990 published data only
Kirkwood JM Ernstoff MS Giuliano A Gams R Robinson
WA Costanzi J et alInterferon alpha-2a and dacarbazine
in melanoma Journal of the National Cancer Institute 1990
82(12)1062ndash3
Middleton 2000 published data only
Middleton MR Grob JJ Aaronson N Fierlbeck G
Tilgen W Seiter S et alRandomized phase III study of
temozolomide versus dacarbazine in the treatment of
patients with advanced metastatic malignant melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200018(1)158ndash66
Ridolfi 2002 published data only
Ridolfi R Chiarion-Sileni V Guida M Romanini A
Labianca R Freschi A et alCisplatin dacarbazine with
or without subcutaneous interleukin-2 and interferon
alpha-2b in advanced melanoma outpatients results from
an Italian multicenter phase III randomized clinical trial
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200220(6)1600ndash7
Rosenberg 1999 published data only
Rosenberg SA Yang JC Schwartzentruber DJ Hwu P
Marincola FM Topalian SL et alProspective randomized
trial of the treatment of patients with metastatic melanoma
using chemotherapy with cisplatin dacarbazine and
tamoxifen alone or in combination with interleukin-2 and
interferon alfa-2b Journal of Clinical Oncology 199917(3)
968ndash75
Spieth 2003 published data only
Spieth K Dummer R Garbe C Mauch C Schuler G
Landthaler M et alTemozolomide in combination with
11Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
interferon alfa versus temozolomide alone in patients with
advanced metastatic melanoma A randomized phase
III multicenter study of the Dermatologic Cooperative
Oncology Group (DeCOG) In ASCO Annual Meeting
2003Abstract 2887
Thomson 1993 published data only
Thomson DB Adena M McLeod GR Hersey P Gill PG
Coates AS et alInterferon-alpha 2a does not improve
response or survival when combined with dacarbazine
in metastatic malignant melanoma results of a multi-
institutional Australian randomized trial Melanoma
Research 19933(2)133ndash8
Vorobiof 1994 published data only
Vorobiof DA Bezwoda WR A randomised trial of vindesine
plus interferon-alpha 2b compared with interferon-alpha 2b
or vindesine alone in the treatment of advanced malignant
melanoma European journal of cancer (Oxford England
1990) 199430A(6)797ndash800
Young 2001 published data only
Young AM Marsden J Goodman A Burton A Dunn
JA Prospective randomized comparison of dacarbazine
(DTIC) versus DTIC plus interferon-alpha (IFN-alpha) in
metastatic melanoma Clinical oncology (Royal College of
Radiologists (Great Britain)) 200113(6)458ndash65
References to studies excluded from this review
Bajetta 2001 published data only
Bajetta E Del Vecchio M Vitali M Martinetti A Ferrari L
Queirolo P et alA feasibility study using polychemotherapy
(cisplatin + vindesine + dacarbazine) plus interferon-alpha
or monochemotherapy with dacarbazine plus interferon-
alpha in metastatic melanoma Tumori 200187(4)219ndash22
Legha 1996 published data only
Legha SS Ring S Bedikian A Plager C Eton O Buzaid
AC et alTreatment of metastatic melanoma with combined
chemotherapy containing cisplatin vinblastine and
dacarbazine (CVD) and biotherapy using interleukin-2 and
interferon-alpha Annals of oncology official journal of the
European Society for Medical Oncology ESMO 19967(8)
827ndash35
Richtig 2004 published data only
Richtig E Hofmann-Wellenhof R Pehamberger H
Forstinger C Wolff K Mischer P et alTemozolomide and
interferon alpha 2b in metastatic melanoma stage IV British
Journal of Dermatology 2004151(1)91ndash8
Sertoli 1999 published data only
Sertoli MR Queirolo P Bajetta E DelVecchio M
Comella G Barduagni L et alMulti-institutional phase
II randomized trial of integrated therapy with cisplatin
dacarbazine vindesine subcutaneous interleukin-2
interferon alpha2a and tamoxifen in metastatic melanoma
BREMIM (Biological Response Modifiers in Melanoma)
Melanoma research 19999(5)503ndash9
Sparano 1993 published data only
Sparano JA Fisher RI Sunderland M Margolin K Ernest
ML Sznol M et alRandomized phase III trial of treatment
with high-dose interleukin-2 either alone or in combination
with interferon alfa-2a in patients with advanced melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199311(10)1969ndash77
Vuoristo 2005 published data only
Vuoristo MS Hahka-Kemppinen M Parvinen LM
Pyrhonen S Seppa H Korpela M et alRandomized trial of
dacarbazine versus bleomycin vincristine lomustine and
dacarbazine (BOLD) chemotherapy combined with natural
or recombinant interferon-alpha in patients with advanced
melanoma Melanoma research 200515(4)291ndash6
Additional references
Arance 2000
Arance A Middleton M Lorigan P Thatcher N Three-
arm phase II study of temozolomide (TMZ) in metastatic
melanoma (MM) In ASCO Annual Meeting 2000
Abstract 2257
Bafaloukos 2002
Bafaloukos D Aravantinos G Fountzilas G Stathopoulos
G Gogas H Samonis G et alDocetaxel in combination
with dacarbazine in patients with advanced melanoma
Oncology 200263(4)333ndash7
Bajetta 2002
Bajetta E Del Vecchio M Bernard-Marty C Vitali
M Buzzoni R Rixe O et alMetastatic melanoma
chemotherapy Seminars in Oncology 200229(5)427ndash45
Balch 2001
Balch CM Soong SJ Gershenwald JE Thompson JF
Reintgen DS Cascinelli N et alPrognostic factors analysis
of 17600 melanoma patients validation of the American
Joint Committee on Cancer melanoma staging system
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200119(16)3622ndash34
Barth 1995
Barth A Morton DL The role of adjuvant therapy in
melanoma management Cancer 199575 Suppl (2)
726ndash34
Chiarion-Sileni 2003
Chiarion-Sileni V Del Bianco P De Salvo GL Lo Re G
Romanini A Labianca R et alQuality of life evaluation in a
randomised trial of chemotherapy versus bio-chemotherapy
in advanced melanoma patients European journal of cancer
(Oxford England 1990) 200339(11)1577ndash85
Creagan 1984
Creagan ET Ahmann DL Green SJ Long HJ Frytak S
OrsquoFallon JR et alPhase II study of low-dose recombinant
leukocyte A interferon in disseminated malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 19842(9)1002ndash5
Crosby 2000
Crosby T Fish R Coles B Mason MD Systemic treatments
for metastatic cutaneous melanoma Cochrane Database
of Systematic Reviews 2000 Issue 2 [DOI 101002
14651858CD001215]
12Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Cure 1999
Cure H Souteyrand P Ouabdesselam R Roche H
Ravaud A DrsquoIncan M et alResults of a phase II trial
with cystemustine at 90 mgm(2) as a first- or second-line
treatment in advanced malignant melanoma a trial of the
EORTC Clinical Studies Group Melanoma Research 1999
9(6)607ndash10
Danson 2002
Danson S Arance A Lorigan P Clamp A Hodgetts J
Lomax L Thatcher N Middleton MR A randomized
study of temozolomide (TMZ) alone with interferon-
alpha (TMZ-IFN) or with thalidomide (TMZ-THAL) in
metastatic malignant melanoma (MMM) ASCO Annual
Meeting - Proceedings 2002Abstract 1369
Dorval 1986
Dorval T Palangie T Jouve M Garcia-Giralt E Israel L
Falcoff E et alClinical phase II trial of recombinant DNA
interferon (interferon alpha 2b) in patients with metastatic
malignant melanoma Cancer 198658(2)215ndash8
Dutcher 1989
Dutcher JP Creekmore S Weiss GR Margolin K
Markowitz AB Roper M et alA phase II study of
interleukin-2 and lymphokine-activated killer cells in
patients with metastatic malignant melanoma Journal of
clinical oncology official journal of the American Society of
Clinical Oncology 19897(4)477ndash85
Falkson 1995
Falkson CI Experience with interferon alpha 2b combined
with dacarbazine in the treatment of metastatic malignant
melanoma Medical oncology (Northwood London England)
199512(1)35ndash40
Garbe 1990
Garbe C Krasagakis K Zouboulis CC Schroder K Kruger
S Stadler R et alAntitumor activities of interferon alpha
beta and gamma and their combinations on human
melanoma cells in vitro changes of proliferation melanin
synthesis and immunophenotype Journal of Investigative
Dermatology 199095 Suppl (6)231ndash7
Gershenwald 1999
Gershenwald JE Thompson W Mansfield PF Lee JE
Colome MI Tseng CH et alMulti-institutional melanoma
lymphatic mapping experience the prognostic value of
sentinel lymph node status in 612 stage I or II melanoma
patients Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199917(3)976ndash83
Hanninen 1991
Hanninen EL Korfer A Hadam M Schneekloth C
Dallmann I Menzel T et alBiological monitoring of
low-dose interleukin 2 in humans soluble interleukin 2
receptors cytokines and cell surface phenotypes Cancer
Research 199151(23 Pt 1)6312ndash6
Huncharek 2001
Huncharek M Caubet JF McGarry R Single-agent
DTIC versus combination chemotherapy with or without
immunotherapy in metastatic melanoma a meta-analysis
of 3273 patients from 20 randomized trials Melanoma
Research 200111(1)75ndash81
Juni 2001
Juni P Altman DG Egger M Assessing the quality of
controlled clinical trials BMJ 200132342ndash6
Kadison 2003
Kadison AS Morton DL Immunotherapy of malignant
melanoma The Surgical Clinics of North America 200383
(2)343ndash70
Keilholz 2002
Keilholz U Gore ME Biochemotherapy for advanced
melanoma Seminars in Oncology 200229(5)456ndash61
Khayat 2002
Khayat D Bernard-Marty C Meric JB Rixe O
Biochemotherapy for advanced melanoma maybe it is real
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200220(10)2411ndash4
Koh 1991
Koh HK Cutaneous melanoma New England Journal of
Medicine 1991325(3)171ndash82
La Vecchia 1999
La Vecchia C Lucchini F Negri E Levi F Recent declines
in worldwide mortality from cutaneous melanoma in youth
and middle age International Journal of Cancer 199981(1)
62ndash6
Lee 2000
Lee ML Tomsu K Von Eschen KB Duration of survival
for disseminated malignant melanoma results of a meta-
analysis Melanoma Research 200010(1)81ndash92
Legha 1998
Legha SS Ring S Eton O Bedikian A Buzaid AC Plager
C et alDevelopment of a biochemotherapy regimen
with concurrent administration of cisplatin vinblastine
dacarbazine interferon alfa and interleukin-2 for patients
with metastatic melanoma Journal of clinical oncology
official journal of the American Society of Clinical Oncology
199816(5)1752ndash9
Leong 2003
Leong SP Future perspectives on malignant melanoma
Surgical Clinics of North America 200383(2)453ndash6
Lokich 1979
Lokich JJ Garnick MB Legg M Intralesional immune
therapy methanol extraction residue of BCG or purified
protein derivative Oncology 197936(5)236ndash41
Nathan 1998
Nathan FE Mastrangelo MJ Systemic therapy in
melanoma Seminars in Surgical Oncology 199814(4)
319ndash27
Osborn 1977
Osborn DE Castro JE Immunological response in patients
receiving Corynebacterium parvum therapy Clinical
Oncology 19773(2)155ndash64
13Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Parmar 1998
Parmar MKB TV Stewart L Extracting summary statistics
to perform meta-analyses of the published literature for
survival endpoints Statistics in Medicine 1998172815ndash34
Richards 1992
Richards JM Mehta N Ramming K Skosey P Sequential
chemoimmunotherapy in the treatment of metastatic
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199210(8)1338ndash43
Rigel 1989
Rigel DS Rivers JK Kopf AW Friedman RJ Vinokur AF
Heilman ER et alDysplastic nevi Markers for increased
risk for melanoma Cancer 198963(2)386ndash9
Rosenberg 1989
Rosenberg SA Lotze MT Yang JC Aebersold PM Linehan
WM Seipp CA et alExperience with the use of high-
dose interleukin-2 in the treatment of 652 cancer patients
Annals of Surgery 1989210(4)474-84 discussion 484-5
Sertoli 1989
Sertoli MR Bernengo MG Ardizzoni A Brunetti I Falcone
A Vidili MG et alPhase II trial of recombinant alpha-2b
interferon in the treatment of metastatic skin melanoma
Oncology 198946(2)96ndash8
Smith 1993
Smith KA Lowest dose interleukin-2 immunotherapy
Blood 199381(6)1414ndash23
Stopeck 2001
Stopeck AT Jones A Hersh EM Thompson JA
Finucane DM Gutheil JC et alPhase II study of direct
intralesional gene transfer of allovectin-7 an HLA-B7
beta2-microglobulin DNA-liposome complex in patients
with metastatic melanoma Clinical Cancer Research 20017
(8)2285ndash91
Tsang 1983
Tsang KY Fudenberg HH Pan JF Gnagy MJ Bristow
CB An in vitro study on the effects of isoprinosine on
immune responses in cancer patients International Journal
of Immunopharmacology 19835(6)481ndash90
Wingo 1995
Wingo PA Tong T Bolden S Cancer statistics 1995 CA
a cancer journal for clinicians 199545(1)8ndash30
Yusuf 1985
Yusuf S Peto R Lewis J Collins R Sleight P Beta blockade
during and after myocardial infarction an overview of the
randomized trials Progress in Cardiovascular Diseases 1985
27(5)335ndash71lowast Indicates the major publication for the study
14Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Atkins 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding public
Participants PS lt= 1
Brain mets no info
Age 20 to 80 (median 50)
Number of cycles no info
Randomised 416 a 206 b 210
Evaluable 405 a 201 b 204
Interventions a (CT) cisplatin 20mgm2 D1 to 4 vinblastin 12 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1-4 vimblastin 12 mgm2 D1-4 DTIC 800 mgm2 D1
IFN-alpha 5 mIU D1-5 D8 D10 D12 IL-2 9 mIU D1-4
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
Notes Multicentric yes
Withdrawals a five b six
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
15Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Atzpodien 2002
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding both (pharmaceutic and public)
Participants PS lt= 1
Brain mets yes Age 28 to 77 (median 57)
Number of cycles no info
Randomised 124 a 60 b 64
Evaluable 124 a 60 b 64
Interventions a (CT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily
b (ICT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily IFN-alpha 5 mIUm2 D1 week4 and 5
mIUm2 D1 D3 D5 week 5 IL-2 10 mIUm2 D1 D3 D5
(each five weeks)
Outcomes 1 Response rates
2 Overall survival
3 Progression free survival
Notes Multicentric yes
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Bajetta 1994
Methods D parallel group (three groups)
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding pharmaceutic
Participants PS lt= 2
Brain mets no
16Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Bajetta 1994 (Continued)
Age 18 to 70 (median 53)
Number of cycles 8
Randomised 266 a 88 b 86 c 92
Evaluable 242 a 82 b 76 c 84
Interventions a (CT) DTIC 800 mgm2 D1
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU 3xweek
c (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU D1 to 3 6 mIU D4 to 6 9 mIU daily
(each 21 days)
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Overall survival
Notes Multicentric yes
Withdrawals a six b ten c eight
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Danson 2003
Methods D parallel group
AC independent allocation
RS permuted blocks
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets yes Age 16 to 88 (median 58)
Number of cycles six
Randomised 125 a 59 b 62
Evaluable 121 a 55 b 62
Interventions a (CT) temozolomide 200 mgm2 88 h (5 doses)
b (ICT) Temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIU 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
17Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Danson 2003 (Continued)
Notes Multicentric no
Withdrawals a 4 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Del Vecchio 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no Age 19 to 70 (median 50)
Number of cycles no info
Randomised 151 a 75 b 76
Evaluable 145 a 72 b 73
Interventions a (CT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250 mgm2 D1 to
3
b (ICT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250m gm2 D1 to
3 IFN-alpha 5 mIUm2 D1 to 5 IL-2 9 mIUday x 5 daysweek x 2 weeks with a week of
rest
(each 21 days)
Outcomes 1 Response rates
2 Time to Progression
2 Overall Survival
Notes Multicentric yes
Withdrawals a three b three
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
18Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Eton 2002
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding pharm
Participants PS lt= 3
Brain mets yes Age median 49
Number of cycles no info
Randomised 190
Evaluable 183 a 92 b 91
Interventions a (CT) cisplatin 20m gm2 D1 to 4 vimblastin 2 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1 to 4 vinblastin 15 mgm2 D1 to 4 DTIC 800 mgm2
D1 IFN-alpha 5mIUm2 D5 to 9 D17-21 IL-2 9 mIUm2 D5 to 8 D17 to 20
(each 21 days)
Outcomes 1 Response rates
2 Time to progression
3 Overall survival
Notes Multicentric no
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1991
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size no
ITT no
Placebo no
Funding both
Participants PS lt= 1
Brain mets no
Age 22 to 79
(median 57)
Number of cycles at least two
19Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1991 (Continued)
Randomised 73 Evaluable 68 a 34 b 34
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Time to treatment failure
3 Median survival
4 Toxicity
Notes Multicentric no
Withdrawals a three b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1998
Methods D 2 x 2 factorial design
AC independent allocation
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 18 to 84
Number of cycles no info
Randomised 271 Evaluable 263 a 68 b 65 c 63 d 67
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
c (CT) DTIC 200m gm2 D1 to 5 tamoxifen 20 mgdaily
d (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek tamoxifen 20 mgdaily
(each 28 days)
Outcomes 1 Response rates
2 Toxicity rates
20Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1998 (Continued)
3 Overall survival
4 Time to treatment failure
Notes Multicentric yes
Withdrawals a one b three c three d one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Gorbonova 2000
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no
Age 23 to 75
Number of cycles no info
Randomised 30 Evaluable 28 a 14 b 14
Interventions a (CT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2
b (ICT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2 IFN-alpha 3 mIU D5 7
9 11 13 15 17 19
(each 28 days)
Outcomes 1 Response rates
Notes Multicentric no
Withdrawals a two b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
21Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Johnston 1998
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age 18 to 70
(median 45)
Number of cycles no info
Randomised 65 Evaluable 65 a 30 b 35
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to 3
Tamoxifen 40 mg daily
b (ICT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to
3 Tamoxifen 40 mg daily IFN-alpha 9 mIU D1 to 3 IL-2 18 mIU D-2 IL-2 9 mIU D-
1 and 0
(each 28 days)
Outcomes 1 Response rates
2 Time to disease progression
3 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Kirkwood 1990
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding pharm
22Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Kirkwood 1990 (Continued)
Participants PS no info
Brain mets no info
Age no info
Number of cycles no info
Randomised 74 Evaluable 68 a 24 b 23 c 21
Interventions a (CT) DTIC 250 mgm2 D1 to 5 (each 21 days)
b (I) IFN-alpha 3 mIU d1 to 5 every week for 3 weeks than 3 mIUm2 3 xweek
c (ICT) DTIC 250 mgm2 D1 to 5 (each 21 days) IFN-alpha 3 mIU d1 to 5 every week
for 3 weeks than 3 mIUm2 3 xweek
Outcomes 1 Response rates
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Middleton 2000
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets no
Age 24 to 71
(median 51)
Number of cycles six
Randomised 105 Evaluable 96 a 46 b 50
Interventions a (CT) DTIC 800 mgm2 D1 cisplatin 25 mgm2 D1 to 3 BCNU 150 mgm2 D1
tamoxifen 20 mgdaily
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 9 mIU 3 xweek
(each 21 days)
Outcomes 1 Response rates
2 One year survival
3 Median survival
23Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Middleton 2000 (Continued)
4 Toxicity
4 Time spent in hospital
Notes Multicentric no
Withdrawals a seven b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Ridolfi 2002
Methods D parallel group
AC independent allocation by telephone
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 25 to 77
Number of cycles six
Randomised 178 Evaluable 176 a 89 b 87
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1
b (ICT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1 IFN-
alpha 3 mIU 3 xweek IL-2 45 mIU D3 to 5 D8 to 12
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
3 Time to progression
4 Toxicity
Notes Multicentric yes
Withdrawals a one b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
24Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
[Intervention Review]
Chemoimmunotherapy versus chemotherapy for metastaticmalignant melanoma
Andre D Sasse1 Emma C Sasse1 Luciana GO Clark2 Luciana Ulloa3 Otavio Augusto Camara Clark4
1Internal Medicine UNICAMP (Universidade Estadual de Campinas) Campinas Brazil 2Oncology Hospital Celso PierroPUC-
Campinas e Instituto do Radium de Campinas Campinas Brazil 3Public Health Unit Blumenau-SC Brazil 4Evidecircncias Scientific
Solutions in Healthcare Satildeo Paulo Brazil
Contact address Andre D Sasse Internal Medicine UNICAMP (Universidade Estadual de Campinas) Av Dr Luiz de Tella 1515
Cidade Universitaria Campinas Sao Paulo 13083 000 Brazil andresassecom
Editorial group Cochrane Skin Group
Publication status and date Edited (no change to conclusions) published in Issue 8 2013
Review content assessed as up-to-date 15 November 2006
Citation Sasse AD Sasse EC Clark LGO Ulloa L Clark OAC Chemoimmunotherapy versus chemotherapy for metastatic malignant
melanoma Cochrane Database of Systematic Reviews 2007 Issue 1 Art No CD005413 DOI 10100214651858CD005413pub2
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
A B S T R A C T
Background
Malignant melanoma one of the most aggressive of all skin cancers is increasing in incidence throughout the world Surgery remains
the cornerstone of curative treatment in earlier stages Metastatic disease is incurable in most affected people because melanoma does
not respond to most systemic treatments A number of novel approaches are under evaluation and have shown promising results but
they are usually associated with increased toxicity and cost The combination of chemotherapy and immunotherapy has been reported
to improve treatment results but it is still unclear whether evidence exists to support this choice compared with chemotherapy alone
No language restrictions were imposed
Objectives
To compare the effects of therapy with chemotherapy and immunotherapy (chemoimmunotherapy) versus chemotherapy alone in
people with metastatic malignant melanoma
Search methods
We searched the Cochrane Skin Group Specialised Register (14 February 2006) the Cochrane Central Register of Controlled Trials
(The Cochrane Library Issue 3 2005) MEDLINE (2003 to 30 January 2006 ) EMBASE (2003 to 20 July 2005) and LILACS (1982
to 20 February 2006) References conference proceedings and databases of ongoing trials were also used to locate trials
Selection criteria
All randomised controlled trials that compared the use of chemotherapy versus chemoimmunotherapy on people of any age diagnosed
with metastatic melanoma
Data collection and analysis
Two authors independently assessed each study to determine whether it met the pre-defined selection criteria with differences being
resolved through discussion with the review team Two authors independently extracted the data from the articles using data extraction
forms Quality assessment included an evaluation of various components associated with biased estimates of treatment effect Whenever
possible a meta-analysis was performed on the extracted data in order to calculate a weighed treatment effect across trials
1Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Main results
Eighteen studies met our criteria and were included in the meta-analysis with a total of 2625 participants We found evidence of an
increase of objective response rates in people treated with chemoimmunotherapy in comparison with people treated with chemotherapy
Nevertheless the impact of these increased response rates was not translated into a survival benefit We found no difference in survival
to support the addition of immunotherapy to chemotherapy in the systemic treatment of metastatic melanoma with a hazard ratio
of 089 (95 CI 072 to 111 P = 031) Additionally we found increased hematological and non-hematological toxicities in people
treated with chemoimmunotherapy
Authorsrsquo conclusions
We failed to find any clear evidence that the addition of immunotherapy to chemotherapy increases survival of people with metastatic
melanoma Further use of combined immunotherapy and chemotherapy should only be done in the context of clinical trials
P L A I N L A N G U A G E S U M M A R Y
Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Malignant melanoma is one of the most aggressive of all skin cancers If it is confined to the skin it can often be cured by surgery
However if it has spread melanoma is usually incurable because it does not respond to most treatments Recently clinicians have been
trying a combination of chemotherapy and immunotherapy in the hope of improving the outcome The review of trials showed an
increased response to treatment when immunotherapy was added to chemotherapy but no difference was seen in survival rate and toxic
effects were increased
There is not enough evidence to support the use of a combination of combined immunotherapy and chemotherapy in treatment of
metastatic malignant melanoma
B A C K G R O U N D
Description of the condition
Epidemiology and progress of melanoma
Malignant melanomas develop due to changes in the melanocytes
cells that produce melanin pigment Melanomas are most com-
monly found in the skin but can also be found in the uveal tract
(back of the eye) upper digestive tract anal canal rectum and
vagina
Malignant melanoma of the skin accounts for 1 to 3 of all ma-
lignant tumors and there has been an increase in its incidence of
6 to 7 each year since 1985 (La Vecchia 1999 Wingo 1995)
However the overall mortality rate has only slightly increased
probably due to an increase in the early diagnosis of lesions that
have a better prognosis (Leong 2003)
As with other tumors the stage (progress) of the disease is still an
important determinant of survival In the earlier stages melanoma
is confined to the skin where the disease is curable in a high
percentage of cases through surgical removal of the tumor (Nathan
1998) The 5 year survival rate for melanoma that is confined to
the skin is 80 to 100 (Nathan 1998) depending on the thickness
of the primary tumor
In people where the cancer has spread to the lymph nodes (nodal
disease) three variables independently affect the prognosis
1 the number of positive lymph nodes
2 the presence of ulceration within the primary tumor
3 whether the nodal disease is macroscopic (an enlarged
lymph node can be felt by a doctor) or microscopic (the lymph
node cannot be felt but abnormal melanoma cells are present
and can be seen when viewed under a microscope) (Balch 2001)
In people with macroscopic disease more than one positive node
and an ulcerated primary tumor the 5 year survival rate is only
16 In people with one microscopically positive lymph node and
without ulceration in the primary lesion the 5 year survival rate
is 71 (Balch 2001)
The detection of lymph node metastases previously relied on crude
clinical or regional elective lymph node dissection (removal of a
2Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
whole group of lymph nodes responsible for draining a partic-
ular area of the body) but several large randomised controlled
trials have shown no improvement in survival using this tech-
nique Currently sentinel lymph node mapping and directed se-
lective lymphadenectomy (ie only removing those nodes that
show up as positive using the sentinel node imaging technique) has
been shown to identify lymph node metastases more precisely and
with less surgical morbidity than elective dissection (Gershenwald
1999)
Causes
Although the cause of melanoma is unknown major risk factors
have been identified (Koh 1991) Epidemiological studies suggest
that sunlight (ultraviolet radiation) is the most common environ-
mental factor Pale skin a tendency to sunburn fair or red hair
large numbers of melanocytic nevi (moles) and multiple dysplastic
nevi (atypical moles) have been shown to be independent risk fac-
tors for the development of melanoma Fair skin that does not tan
easily in combination with high sun exposure provides the largest
cumulative risk factor for melanoma development (Rigel 1989)
Impact
Malignant melanoma that has spread to distant sites by dissemi-
nation is associated with extremely poor survival median survival
is approximately 8 months and less than 5 of such people will
survive for more than 5 years (Lee 2000)
There are large prospective randomised multicenter trials that
have answered some basic management questions improved the
care of melanoma sufferers and expanded our understanding of
the disease However many aspects of treatment such as the thera-
peutic role of cytotoxic chemotherapy and biologic therapy alone
or in combination remain controversial and inconclusive (Crosby
2000 Leong 2003)
Description of the intervention
Systemic therapy
This has little or no impact on survival for advanced disease
There is no evidence derived from randomised controlled trials to
show superiority of systemic therapy over supportive care (Crosby
2000) The minority of people with metastatic melanoma who do
respond to systemic treatment have remissions which are generally
of short duration (Nathan 1998) Few agents have demonstrated
substantial anti-tumor activity against metastatic melanoma The
alkylating agent dacarbazine (DTIC) is considered to be the most
active drug for the treatment of this disease with a response rate of
20 and a median duration of response of 4 to 5 months (Khayat
2002 Nathan 1998) Other cytotoxic compounds such as temo-
zolomide (a dacarbazine analogue) (Middleton 2000) cisplatin
and carboplatin (Bajetta 2002) vinca alkaloids (Khayat 2002)
taxanes (Bafaloukos 2002) and nitrosoureas (Cure 1999) have not
improved these results All of these treatments are associated with
response rates of less than 15 and all are associated with signif-
icant adverse effects (Bafaloukos 2002 Bajetta 2002 Cure 1999
Khayat 2002 Middleton 2000)
Combination chemotherapy
The role of combination chemotherapy in advanced disease re-
mains unclear Prospective randomised studies have failed to
demonstrate any significant benefit for combination chemother-
apy when compared with single agents except for a slight increase
in response rates (Huncharek 2001)
Experimental treatments
Experimental treatments such as vaccines antibody treatments
and gene therapy are being developed and are of high scientific
interest However their efficacy in advanced melanoma has so
far been very limited with overall response rates of less than 5
(Keilholz 2002 Stopeck 2001) Since the 1970s immunostim-
ulating agents such as Bacillus Calmette-Guerin (BCG) (Lokich
1979 Osborn 1977) Corynebacterium parvum (Osborn 1977)
or isoprinosine (Tsang 1983) have been evaluated as local or sys-
temic treatments After some early hopes all these treatments have
also failed to demonstrate a significant and consistent effect in the
clinical management of advanced melanoma (Khayat 2002)
Immunotherapy
Two points have driven the attention of researchers in the im-
munology field to melanoma Firstly the spontaneous regression
of melanoma (ie the tumor occasionally appears to go away in
some people) Spontaneous regression is much more frequent than
in melanoma than with any other solid tumor and it is associated
with a specific cellular immune response (Kadison 2003) Sec-
ondly the fact that some people with melanoma also have tumor
rejection antigen recognized by CD4 and CD8 T cells (immune
cells that can help get rid of cancer cells) (Kadison 2003)
At least two types of immunotherapy have been used in advanced
melanoma interferon-alpha and interleukin-2
Interferon-alpha (IFN-α) belongs to a group of proteins known
to have antiproliferative and antitumor effects (Garbe 1990) In
addition IFN-α exhibits certain immunomodulatory effects - it
upregulates the expression of major histocompatibility complex
(MHC) class I antigens in melanoma cells and also the expres-
sion of co-stimulatory molecules rendering the cells more suscep-
tible to immunological defense mechanisms (Barth 1995) Phase
II studies of IFN-α as a single agent have demonstrated response
rates of approximately 20 with a slightly more durable response
3Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
than the one found with dacarbazine (DTIC) (Creagan 1984
Dorval 1986 Sertoli 1989)
Interleukin-2 (IL-2) is a major growth factor for lymphoid cells
including T cells and natural killer (NK) cells (Hanninen 1991
Smith 1993) Clinical trials have demonstrated modest anti-tumor
activity in people with metastatic melanoma (Rosenberg 1989)
responses were seen in approximately 15 of people with a
small proportion of complete responses (Dutcher 1989 Rosenberg
1989)
Chemoimmunotherapy
As chemotherapy and immunotherapy have different and per-
haps synergistic mechanisms of action their combination of im-
munotherapy with chemotherapy (chemoimmunotherapy) has
been studied since the early 1990s (Khayat 2002) Some reports
have suggested that chemotherapeutic agents administered in com-
bination with IL-2 or IFN or both can improve response rates
(Legha 1998 Richards 1992) with complete response rates in 10
to 20 of people as well as increases in median survival (Falkson
1991) Based on these results the use of chemoimmunotherapy is
currently preferred in some institutions as a first-line treatment in
advanced (stage IV) melanoma (Kadison 2003 Keilholz 2002)
although it is still considered an experimental therapy by oth-
ers(Crosby 2000)
Why it is important to do this review
There are substantial controversies about the real benefit of
chemoimmunotherapy some studies conclude that the combi-
nation of treatments did not improve survival (Rosenberg 1999
Young 2001) or even response rates (Falkson 1998 Gorbonova
2000 Johnston 1998 Thomson 1993) in people with metastatic
melanoma There is also concern that combined therapy may in-
crease treatment-related toxicity (Falkson 1998 Johnston 1998)
The lack of conclusive data coming from seemingly conflict-
ing studies about the impact of treatment demands a systematic
review This will provide the most reliable assessment for sup-
porting clinical decision-making with people who have advanced
melanoma
O B J E C T I V E S
To compare the effects of chemotherapy alone versus combined
therapy with chemotherapy and immunotherapy (chemoim-
munotherapy) in people with metastatic malignant melanoma
M E T H O D S
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs)
Types of participants
People of any age diagnosed with metastatic malignant melanoma
that has spread to distant sites by systemic dissemination
Types of interventions
1 Chemotherapy
2 Chemoimmunotherapy ie the combination of
chemotherapy and immunotherapy with interferon-alpha or
interleukin-2 or both
Types of outcome measures
Primary outcomes
Overall survival - number of participants alive at the end of the
trial
Secondary outcomes
1 One two and five-year survival rates - proportion of
participants alive at one two and five year follow-up
2 Response rates (partial and complete) - proportion of
participants that have achieved partial or complete responses as
defined by the trial authors
3 Progression-free survival - number of participants without
progression of disease at the end of the trial
4 Treatment morbidity (treatment-related toxicity) -
proportion of participants that have developed hematological or
non-hematological toxicities
5 Treatment related mortality - proportion of participants
that have died due to the treatment This outcome was not
described previously in the protocol and was added after
discussion between the reviewers that considered it relevant
Mortality related to treatment is a great concern in oncology
when comparing treatments with potential differences in toxicity
6 Quality of life measures
Search methods for identification of studies
We searched electronic databases and other resources to locate
reports of studies No language restrictions were imposed
4Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Electronic searches
Electronic databases
We searched the following electronic databases
1 MEDLINE (OVID) (Appendix 1)
2 The Cochrane Skin Group Specialised Register
3 The Cochrane Central Register of Controlled Trials
4 Medline (PubMed)
5 EMBASE
6 LILACS (Latin American and Caribbean Health Science
Information Database)
Search strategies for databases 2 to 6 are located in Appendix 2
Search of databases of ongoing trials (unpublished literature)
We asked trial authors and pharmaceutical companies about un-
published and ongoing trials Databases of major research groups
and registers of trials in the following databases were also searched
with the term rsquoMELANOMArsquo
bull Current Controlled Trials Register (httpwwwcontrolled-
trialscom) on 30th January 2006
bull European Organisation for Research and Treatment of
Cancer (httpwwweortcbe) on 20th February 2006
bull National Cancer Institute America (http
wwwcancergovclinicaltrials) on 16th November 2005
bull National Cancer Institute Canada (httphttp
wwwctgqueensucapublicClinical_Trialsclinical_trialshtml)
on 30th January 2006
bull Australian Clinical Trials Registry (httpwwwactrorgau)
on 30th January 2006
bull US Food and Drug Administration (httpwwwfdagov)
on 30th January 2006
bull ClinicalTrialsgov (httpwwwclinicaltrialsgov) on 16th
November 2005
Searching other resources
References from unpublished studies
All bibliographies of selected studies were scanned for possible
references to RCTs
Conference proceedings
We handsearched the abstracts from conference proceedings of
the ASCO (American Society of Clinical Oncology) and ESMO
(European Society of Medical Oncology)
Data collection and analysis
Where there was uncertainty we tried to contact trial authors for
clarification
A consumer (LU) was involved throughout the review process to
ensure the readability of the final review Updating will be done
every two years
Selection of studies
Two authors (ADS and ECS) checked the titles and abstracts iden-
tified from the searches If it was clear that the study did not refer
to a RCT on metastatic melanoma we excluded it Two authors
(ADS and OAC) independently assessed each remaining study to
determine whether it met the pre-defined selection criteria Any
differences were resolved through discussion with the review team
Excluded studies are listed in the Table of Excluded Studies
Data extraction and management
Two authors (ADS and ECS) independently extracted the data
from the studies All data were extracted directly from the text or
calculated according to the available information
Any differences were resolved by discussion with one author
(OAC) A data extraction form was developed and piloted in order
to summarize the trials One author (ADS) checked and entered
the data Two authors (ECS and LGC) independently checked the
data entry
Assessment of risk of bias in included studies
Assessment of methodological quality
The quality assessment included an evaluation of the following
components for each included study since there is some evidence
that these are associated with biased estimates of treatment effect
(Juni 2001)
(a) the method of generation of the randomisation sequence
(b) the method of allocation concealment - it was considered rsquoad-
equatersquo if the assignment could not be foreseen
(c) who was blindednot blinded (participants clinicians outcome
assessors)
(d) how many participants were lost to follow up in each arm and
whether participants were analysed in the groups to which they
were originally randomised (intention-to-treat)
In addition the quality assessment also included
(e) the source of funding
(f ) if the participant had a biopsy proven melanoma
(g) the baseline assessment of the participants for presence of liver
and brain metastases performance status
(h) whether the aims interventions (including drug doses and
duration of treatment) and outcome measures were clearly defined
5Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(i) the use and appropriateness of statistical analyses
We recorded all the information in a table of quality criteria and
gave a description of the quality of each study based on these
characteristics
Measures of treatment effect
Where possible we performed a meta-analysis for the outcomes
in order to calculate a weighted treatment effect across trials using
a random-effects model For binary endpoints we calculated the
risk ratio (RR) with 95 confidence intervals (Yusuf 1985) We
also expressed the results as a number needed to treat (NNT)
where appropriate for a range of plausible control event rates For
overall survival a time-to-event data we calculated the Hazard
Ratio (HR) When data were not available for direct extraction
we calculated indirectly (from different parameters using indirect
calculation of the variance and the number of observed minus
expected events) according to the method described by Parmar
(Parmar 1998) In the funnel plot (Figure 1) and comparison 1
rsquoPeto OR (IPD)rsquo is a Hazard Ratio For continuous data such as
quality of life we planned to use standardised mean differences
with 95 confidence intervals would have been used
Figure 1 Funnel plot using overall survival as the outcome
Assessment of heterogeneity
Heterogeneity was assessed using I2 Where the heterogeneity was
considerable (I2 gt 50) we explored possible reasons using the
type (interleukin-2 or interferon) and dose (high or low) of im-
munotherapy used as subgroups Where we were not able to find
an explanation we have recorded this along with appropriate cau-
tion in the interpretation of these data
Data synthesis
Analysis and presentation
Once studies had been selected critically appraised and the data
extracted we entered the data in the Characteristics of included
studies table
6Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Three studies (Bajetta 1994 Kirkwood 1990 Vorobiof 1994) eval-
uated three arms of treatment with one of them evaluating che-
motherapy alone and the two others using chemoimmunotherapy
One study (Falkson 1998) had four arms two using chemotherapy
and two using chemoimmunotherapy The data from the similar
arms were grouped considered as one and then compared to the
other arm
R E S U L T S
Description of studies
Results of the search
We scanned approximately 700 citations Initially 28 studies
were identified Four studies (Arance 2000 Chiarion-Sileni 2003
Danson 2002 Falkson 1995) had data that overlapped with three
included studies (Danson 2003 Falkson 1991 Ridolfi 2002)
Ongoing studies
No ongoing studies were available to be included in the meta-
analysis
Included studies
Eighteen studies with a total of 2625 participants met our criteria
and were included in the meta-analysis (please see Characteristics
of included studies) One study differed considerably from the oth-
ers because vindesine was used as the chemotherapy control a drug
without evidence of response in metastatic melanoma (Vorobiof
1994) Another study differed considerably as lower dose treat-
ment in the chemoimmunotherapy group was used (Middleton
2000) The first study was published in 1990 and the last studies
were published in 2003
Participants
The participants were between the ages of 16 and 88 years and
had an Eastern Cooperative Oncology Group performance status
from 0 to 3 Only three studies included participants with brain
metastasis (Atzpodien 2002 Danson 2003 Eton 2002)
Interventions
Seven studies compared chemotherapy to chemoimmunotherapy
with IFN plus IL-2 (Atkins 2003 Atzpodien 2002 Del Vecchio
2003 Eton 2002 Johnston 1998 Ridolfi 2002 Rosenberg 1999)
Eleven compared chemotherapy to chemoimmunotherapy with
IFN (Bajetta 1994 Danson 2003 Falkson 1991 Falkson 1998
Gorbonova 2000 Kirkwood 1990 Middleton 2000 Spieth 2003
Thomson 1993 Vorobiof 1994 Young 2001)
The drugs used in chemotherapeutic schemes varied between the
trials Seven trials evaluated DTIC combined with other drugs in
both arms (Atkins 2003 Atzpodien 2002 Del Vecchio 2003 Eton
2002 Johnston 1998 Ridolfi 2002 Rosenberg 1999) and six
evaluated DTIC alone as the control (Bajetta 1994 Falkson 1991
Falkson 1998 Kirkwood 1990 Thomson 1993 Young 2001)
Four studies evaluated other schemes without DTIC two trials
used temozolomide (Danson 2003 Spieth 2003) one trial used
vindesine (Vorobiof 1994) and one trial used combined drugs
based on cisplatin (Gorbonova 2000)
Only one study did not use the same scheme in both the arms
using combined drugs with DTIC as the chemotherapy control
and a lower dose for the chemoimmunotherapy group with DTIC
alone (Middleton 2000)
Setting
Ten studies were carried out in Europe four in the United States
two in South Africa and one was a multicentre worldwide trial
All trials were reported in the English language
Outcomes
Response rates were the primary outcome measures in most trials
and were described in all included studies Two studies did not
evaluate survival rates (Gorbonova 2000 Kirkwood 1990) Three
studies included quality of life analyses in the outcomes (Ridolfi
2002 Thomson 1993 Young 2001) The length of the follow-up
varied widely between the trials and sometimes it was not speci-
fied We did not find a reasonable definition about what could be
considered high or low doses of immunotherapy and the influence
of the immunotherapeutic doses on the outcomes could not be
assessed
Excluded studies
Six studies were excluded (see Characteristics of excluded studies)
The reasons for exclusion were that the study had immunotherapy
on both arms (Bajetta 2001 Richtig 2004 Sertoli 1999 Sparano
1993 Vuoristo 2005) or the study was not randomised (Legha
1996)
Risk of bias in included studies
The quality assessment consisted of a basic methodological eval-
uation of each included study and is shown in Table 1 Addi-
tional quality assessment is shown in Table 2 The criteria used for
methodological quality analysis of the studies are listed in Table 3
(Explanation of Quality Analysis Headings)
7Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Although blinding participants and clinicians is theoretically pos-
sible it is difficult to plan a double-blind study with immunother-
apy This is due to the substantial acute and late toxicities associ-
ated with immunotherapy in one group No study was described
as double-blinded The groups at baseline were in general similar
with a description of most prognostic factors related to metastatic
melanoma (gender performance status age prior therapy liver
metastasis)
In three studies almost all methodological aspects of the trials
were described poorly (Gorbonova 2000 Kirkwood 1990 Spieth
2003)
Allocation
All the included studies were described as randomised as this
was a selection criterion However most papers did not describe
the method of randomisation The method of generation of the
randomised sequence was described and considered adequate in
only 6 out of 18 studies Eleven of 18 studies provided information
on allocation concealment all of which were considered adequate
Blinding
Blinding of outcome assessment and detection bias
We did not find information about blinding of the outcome as-
sessors in any included study
Incomplete outcome data
Handling of losses and attrition bias
In general there were few participants lost to follow up in the
studies The highest number of people lost was 24 in a total of 262
participants (Bajetta 1994) Eleven studies included an intention-
to-treat analysis
Effects of interventions
Primary outcome
Overall survival (eight studies)
This was considered as the number of participants alive at the end
of the trial Sufficient data were available from 8 of the 18 studies
There was no statistically significant difference in survival between
chemoimmunotherapy and chemotherapy with a hazard ratio
(HR) of improved survival of 089 (95 CI 072 to 111 P = 031
Analysis 11) in favour of chemoimmunotherapy In other words
overall survival was slightly lower in the chemoimmunotherapy
group but this was not statistically significant There was no het-
erogeneity across trials (I2 = 0) The funnel plot method using
overall survival as the outcome is presented in Figure 1 It shows
that there was no evidence of substantial publication bias but in-
terpretation of the funnel plot is likely to be unreliable since only
eight relatively large studies were found
When we evaluated the influence of the type of immunotherapy
used in the chemoimmunotherapy group (IL-2 plus IFN-alpha
or IFN-alpha only) we found no statistically significant difference
between the groups with a HR of 096 (95 CI 074 to 124 P =
076 Analysis 11) for chemoimmunotherapy with IL-2 plus IFN-
alpha and a HR of 074 (95 CI 049 to 112 P = 015 Analysis
11) for chemoimmunotherapy associated with only IFN-alpha
Secondary outcomes
One two and five-year survival rates (13 studies)
The number of participants alive at one two and five year follow-
ups were analyzed Data from 13 trials evaluating one year survival
were pooled There was no statistically significant difference in one
year survival between the groups with a risk ratio (RR) of 106
(95 CI 091 to 124 P = 048 Analysis 12) and no significant
heterogeneity across trials (I2 = 363)
Data from 11 trials evaluating 2 year survival were extracted and
pooled Again there was no statistically significant difference be-
tween the groups with a RR of 108 (95 CI 086 to 136 P =
050 Analysis 13) without heterogeneity across trials (I2 = 0)
Only two trials reported data about five year survival The meta-
analysis showed no statistically significant difference in 5 year sur-
vival between the groups with a RR of survival of 234 (95
CI 097 to 565 P = 006 Analysis 14) favouring chemoim-
munotherapy There was no heterogeneity across trials (I2 = 0)
Response rates (17 studies)
Data regarding the number of participants with partial or com-
plete responses from 17 trials were used to evaluate objective re-
sponse rates The analysis detected a statistically significant differ-
ence in favor of chemoimmunotherapy in global response rates
with a RR of 140 (95 CI 120 to 163 P lt 00001 Analysis
21) There was no heterogeneity across trials (I2 = 42) We
tried to evaluate the influence of the type of immunotherapeutic
in the group of chemoimmunotherapy (IL-2 plus IFN-alpha or
IFN-alpha only) We found similar results with a RR of global
response of 146 (95 CI 119 to 179 p = 00002 Analysis 21)
in favor of chemoimmunotherapy with IL-2 plus IFN-alpha and
a RR of 132 (95 CI 102 to 171 p = 004 Analysis 21) in favor
of chemoimmunotherapy with IFN-alpha There was no hetero-
geneity across trials (I2 = 0)
8Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Data from 15 trials were used to evaluate partial and complete
response rates We found a statistically significant difference in
favour of chemoimmunotherapy in both analyses with an HR of
131 (95 CI 107 to 159 p = 0008 Analysis 23) for partial
response rates and an HR of 158 (95 CI 106 to 236 p = 003
Analysis 23) for complete response rates
Progression-free survival (3 studies)
Only three studies had extractable data about the number of par-
ticipants with no disease progression at the end of the trial When
pooled together there was no statistically significant difference be-
tween the groups with an HR of 076 (95 CI 057 to 102 p =
007 Analysis 31) There was no heterogeneity across these trials
(I2 = 0)
Treatment related toxicity (11 studies)
Data from 11 studies were collected with the number of partici-
pants developing clinically significant hematological toxicity (de-
fined as grade 3 or 4) Eight studies had estimated points that
showed enhanced toxicities in the chemoimmunotherapy group
The meta-analysis of the studies showed extreme heterogeneity
(I2 = 941) across the trials We performed a sensitivity anal-
ysis excluding the studies with relatively low doses of chemo-
therapeutic drugs in the chemoimmunotherapy group (Danson
2003 Middleton 2000) but we found similar heterogeneity (I2 =
978)
When we analyzed data from the four studies with similar rela-
tive doses of chemotherapeutics associated with interferon-alpha
without interleukin-2 we found an increase of clinically signifi-
cant hematological toxicities in the chemoimmunotherapy group
with a RR 454 (95 CI 235 to 879 p lt 000001) There was
no heterogeneity across these trials (I2 = 0) When we analyzed
data from studies with combination of interferon-alpha plus in-
terleukin-2 in the chemoimmunotherapy group we again found
extreme heterogeneity across the trials (I2 = 979)
Despite the heterogeneity in global meta-analysis we concluded
that it was not possible to quantify the differences in hematologi-
cal toxicity in such different trials In order to explore these differ-
ences we noted that one study referred to hematological toxicity
in 100 of participants treated with chemoimmunotherapy and
in 96 of participants treated with chemotherapy (Eton 2002)
Another study referred to hematological toxicity only in 2 and
1 respectively (Bajetta 1994)
Non-hematological toxicities were described in almost all stud-
ies and were mainly described as nausea vomiting flu-like syn-
drome asthenia hypotension and fever Data from six similar
studies were extractable and were pooled in the meta-analysis re-
sulting in a statistically significant difference against the chemoim-
munotherapy group with a RR of 274 (95 CI 206 to 364 p
lt 000001 Analysis 42) There was no heterogeneity across trials
(I2 = 0) These results must be treated with caution because of
similar difficulties in pooling these data on hematological toxici-
ties with different therapeutic schemes and several trials described
non-hematological toxicities but we were not able to extract the
data
Data about treatment-related mortality were available in 11 stud-
ies We found no significant difference between the groups with a
RR of 078 (95 CI 026 to 232 p = 065 Analysis 43) There
was no heterogeneity across the trials (I2 = 0)
Quality of life (three studies)
Only three studies reported data on quality of life (Ridolfi 2002
Thomson 1993 Young 2001) all using different methods One
trial described quality of life analysis in detail in an additional pub-
lication (Chiarion-Sileni 2003 Ridolfi 2002) This study found
a significant decrease of overall quality of life in the chemoim-
munotherapy group in comparison to the chemotherapy group
(p = 003) The other two studies did not find differences in global
quality of life between the groups (Thomson 1993 Young 2001)
Thomson did not report global quality of life (Thomson 1993)
Young found no significant differences in quality of life for the
change in scores over time (z = -129 p = 020) (Young 2001)
It was not possible to pool the data as all three studies did not
provide extractable data
Sensitivity analyses on the influence of source of funding baseline
assessment and allocation concealment on the survival analysis
and response rate analyses revealed that there was no relation be-
tween these methodological aspects and the outcome There was
no statistically significant difference in survival between the groups
in all analyses and the difference in response rates in favour of
chemoimmunotherapy was found to be significant
D I S C U S S I O N
Metastatic melanoma is reputed as refractory to most systemic
treatments and little progress has been made in treatment of
metastatic melanoma These concepts are supported by results
from previous systematic reviews One review concluded that there
is no evidence derived from RCTs that systemic treatment is better
than best supportive care (Crosby 2000) Another review of 20
randomised trials (involving 3273 participants) comparing single-
agent DTIC with DTIC in combination with other drugs with or
without immunotherapy concluded that combination of drugs in-
creased response rates but not overall survival (Huncharek 2001)
This systematic review summarises the evidence regarding the
use of chemoimmunotherapy compared to chemotherapy alone
to treat people with metastatic malignant melanoma There are
some important observations regarding the characteristics of the
included studies in this systematic review The ideal combination
9Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
of drugs for an investigation is not well established Seven studies
evaluated chemoimmunotherapy with interferon-alpha plus inter-
leukin-2 and 11 evaluated chemoimmunotherapy only with in-
terferon-alpha The treatment plans with drugs and dosages used
differed between studies
Most studies did not contribute in answering relevant questions
about the impact of chemoimmunotherapy in the treatment of
metastatic melanoma The outcomes were not clearly described in
several of the studies (Atkins 2003 Del Vecchio 2003 Gorbonova
2000 Kirkwood 1990 Spieth 2003 Thomson 1993) Two of
them did not report survival rates evaluating only response rates
(Gorbonova 2000 Kirkwood 1990) All these aspects influenced
the comparability of the trials and must be considered in the data
interpretation
On the basis of a meta-analysis of data coming from eight studies
this review showed no evidence of a difference in overall survival to
support the addition of immunotherapy to chemotherapy in the
systemic treatment of metastatic melanoma (Atkins 2003 Danson
2003 Eton 2002 Falkson 1991 Johnston 1998 Ridolfi 2002
Spieth 2003 Young 2001) Evaluation of one two and five-year
survival with data from other studies again showed no survival
advantage of the drug combination treatment
We found higher clinical response rates in people treated with
chemoimmunotherapy in comparison with people treated with
chemotherapy which was not translated into survival benefit
Additionally we found higher toxicity rates in people treated
with chemoimmunotherapy Despite the importance of evaluat-
ing quality of life there was no available data to perform the meta-
analysis in this systematic review Only three studies reported data
about quality of life all with different methods One trial described
poorer quality of life in people treated with chemoimmunother-
apy related to more intense side effects (Ridolfi 2002) Two trials
however showed no difference between groups (Thomson 1993
Young 2001) It is important that quality of life is included in all
future studies
Our meta-analysis did not find differences between treatment re-
lated mortality Subgroup analysis comparing combinations with
interferon-alpha and with interferon-alpha plus interleukin-2 did
not show different results in survival or response rates
The use of chemoimmunotherapy ie a combination of chemo-
therapy with interferon-alpha or interleukin-2 or both has not
been shown to be beneficial in this review Although short term
response rates were better overall in the chemoimmunotherapy
groups survival was not improved and drug-related toxicities were
higher in the combined chemoimmunotherapy group To date no
treatment regimen has shown efficiency in prolonging survival in
people with metastatic melanoma Little has changed in the sys-
temic management of metastatic melanoma in the last few years
The standard of care remains single-agent DTIC and the role of
immunotherapy remains in doubt
The use of chemoimmunotherapy in the treatment of melanoma
is justified only in the context of clinical trials
A U T H O R S rsquo C O N C L U S I O N S
Implications for practice
We failed to find any evidence to support the view that the
use of chemoimmunotherapy prolongs survival in people with
metastatic melanoma when compared to chemotherapy alone Al-
though short-term clinical responses were higher in the chemoim-
munotherapy group this was associated with a higher rate of
serious adverse events esp haematological toxicity Our review
does not support the use of a combination of immunother-
apy and chemotherapy in chemoimmunotherapy regimens out-
side of clinical trials The standard of care for people with
advanced melanoma remains chemotherapy with single-agent
DTIC Chemoimmunotherapy must not be recommended to peo-
ple in daily practice
Implications for research
Research related to the development of more effective treatments
for people with metastatic melanoma is urgently needed
For people with an incurable disease the primary outcome needs
to be overall survival and all studies should include a quality of life
analysis
Future trials should be designed to define the best systemic treat-
ment and should use chemotherapy with (DTIC) as a standard
control group in order to permit comparisons to be made
A C K N O W L E D G E M E N T S
The authors wish to thank Raquel Gebara Lima for her kind
support in grammar and style
The editorial base would like to thank the following people who
were external referees for this review Keith Wheatley and Pat
Lawton (content experts) and Kathie Godfrey (consumer)
10Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
R E F E R E N C E S
References to studies included in this review
Atkins 2003 published data only
Atkins MB Lee S Flaherty LE Sosman JA Sondak VK
Kirkwood JM A prospective randomized phase III trial
of concurrent biochemotherapy (BCT) with cisplatin
vinblastine dacarbazine (CVD) IL-2 and interferon alpha-
2b (IFN) versus CVD alone in patients with metastatic
melanoma (E3695) An ECOG-coordinated intergroup
trial In ASCO Annual Meeting 2003 2003 p ASCO
Annual Meeting - Proceedings 2003Abstract 2847
Atzpodien 2002 published data only
Atzpodien J Neuber K Kamanabrou D Fluck M Brocker
EB Neumann C et alCombination chemotherapy with or
without sc IL-2 and IFN-alpha results of a prospectively
randomized trial of the Cooperative Advanced Malignant
Melanoma Chemoimmunotherapy Group (ACIMM)
British journal of cancer 200286(2)179ndash84
Bajetta 1994 published data only
Bajetta E Di Leo A Zampino MG Sertoli MR Comella
G Barduagni M et alMulticenter randomized trial of
dacarbazine alone or in combination with two different
doses and schedules of interferon alfa-2a in the treatment
of advanced melanoma Journal of clinical oncology official
journal of the American Society of Clinical Oncology 199412
(4)806ndash11
Danson 2003 published data only
Danson S Lorigan P Arance A Clamp A Ranson
M Hodgetts J et alRandomized phase II study of
temozolomide given every 8 hours or daily with either
interferon alfa-2b or thalidomide in metastatic malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 200321(13)2551ndash7
Del Vecchio 2003 published data only
Del Vecchio M Bajetta E Vitali M Gattinoni L Santinami
M Daponte A et alMulticenter phase III randomized trial
of cisplatin vindesine and dacarbazine (CVD) versus CVD
plus subcutaneous (sc) interleukin-2 (IL-2) and interferon-
alpha-2b (IFN) in metastatic melanoma patients (pts) In
ASCO Annual Meeting 2003 2003 p ASCO Annual
Meeting - Proceedings 2003Abstract 2849
Eton 2002 published data only
Eton O Legha SS Bedikian AY Lee JJ Buzaid AC
Hodges C et alSequential biochemotherapy versus
chemotherapy for metastatic melanoma results from a
phase III randomized trial Journal of clinical oncology
official journal of the American Society of Clinical Oncology
200220(8)2045ndash52
Falkson 1991 published data only
Falkson CI Falkson G Falkson HC Improved results with
the addition of interferon alfa-2b to dacarbazine in the
treatment of patients with metastatic malignant melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 19919(8)1403ndash8
Falkson 1998 published data only
Falkson CI Ibrahim J Kirkwood JM Coates AS Atkins
MB Blum RH Phase III trial of dacarbazine versus
dacarbazine with interferon alpha-2b versus dacarbazine
with tamoxifen versus dacarbazine with interferon alpha-
2b and tamoxifen in patients with metastatic malignant
melanoma an Eastern Cooperative Oncology Group study
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199816(5)1743ndash51
Gorbonova 2000 published data only
Gorbonova VA Egorov GN Perevodchikova NI Orel
NF Combined chemotherapy with or without interferon
alpha N1 (IFN) for advanced malignant melanoma - a
randomized pilot phase III study Gan To Kagaku Ryoho
200027 Suppl (2)310ndash4
Johnston 1998 published data only
Johnston SR Constenla DO Moore J Atkinson H ArsquoHern
RP Dadian G et alRandomized phase II trial of BCDT
[carmustine (BCNU) cisplatin dacarbazine (DTIC)
and tamoxifen] with or without interferon alpha (IFN-
alpha) and interleukin (IL-2) in patients with metastatic
melanoma British Journal of Cancer 199877(8)1280ndash6
Kirkwood 1990 published data only
Kirkwood JM Ernstoff MS Giuliano A Gams R Robinson
WA Costanzi J et alInterferon alpha-2a and dacarbazine
in melanoma Journal of the National Cancer Institute 1990
82(12)1062ndash3
Middleton 2000 published data only
Middleton MR Grob JJ Aaronson N Fierlbeck G
Tilgen W Seiter S et alRandomized phase III study of
temozolomide versus dacarbazine in the treatment of
patients with advanced metastatic malignant melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200018(1)158ndash66
Ridolfi 2002 published data only
Ridolfi R Chiarion-Sileni V Guida M Romanini A
Labianca R Freschi A et alCisplatin dacarbazine with
or without subcutaneous interleukin-2 and interferon
alpha-2b in advanced melanoma outpatients results from
an Italian multicenter phase III randomized clinical trial
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200220(6)1600ndash7
Rosenberg 1999 published data only
Rosenberg SA Yang JC Schwartzentruber DJ Hwu P
Marincola FM Topalian SL et alProspective randomized
trial of the treatment of patients with metastatic melanoma
using chemotherapy with cisplatin dacarbazine and
tamoxifen alone or in combination with interleukin-2 and
interferon alfa-2b Journal of Clinical Oncology 199917(3)
968ndash75
Spieth 2003 published data only
Spieth K Dummer R Garbe C Mauch C Schuler G
Landthaler M et alTemozolomide in combination with
11Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
interferon alfa versus temozolomide alone in patients with
advanced metastatic melanoma A randomized phase
III multicenter study of the Dermatologic Cooperative
Oncology Group (DeCOG) In ASCO Annual Meeting
2003Abstract 2887
Thomson 1993 published data only
Thomson DB Adena M McLeod GR Hersey P Gill PG
Coates AS et alInterferon-alpha 2a does not improve
response or survival when combined with dacarbazine
in metastatic malignant melanoma results of a multi-
institutional Australian randomized trial Melanoma
Research 19933(2)133ndash8
Vorobiof 1994 published data only
Vorobiof DA Bezwoda WR A randomised trial of vindesine
plus interferon-alpha 2b compared with interferon-alpha 2b
or vindesine alone in the treatment of advanced malignant
melanoma European journal of cancer (Oxford England
1990) 199430A(6)797ndash800
Young 2001 published data only
Young AM Marsden J Goodman A Burton A Dunn
JA Prospective randomized comparison of dacarbazine
(DTIC) versus DTIC plus interferon-alpha (IFN-alpha) in
metastatic melanoma Clinical oncology (Royal College of
Radiologists (Great Britain)) 200113(6)458ndash65
References to studies excluded from this review
Bajetta 2001 published data only
Bajetta E Del Vecchio M Vitali M Martinetti A Ferrari L
Queirolo P et alA feasibility study using polychemotherapy
(cisplatin + vindesine + dacarbazine) plus interferon-alpha
or monochemotherapy with dacarbazine plus interferon-
alpha in metastatic melanoma Tumori 200187(4)219ndash22
Legha 1996 published data only
Legha SS Ring S Bedikian A Plager C Eton O Buzaid
AC et alTreatment of metastatic melanoma with combined
chemotherapy containing cisplatin vinblastine and
dacarbazine (CVD) and biotherapy using interleukin-2 and
interferon-alpha Annals of oncology official journal of the
European Society for Medical Oncology ESMO 19967(8)
827ndash35
Richtig 2004 published data only
Richtig E Hofmann-Wellenhof R Pehamberger H
Forstinger C Wolff K Mischer P et alTemozolomide and
interferon alpha 2b in metastatic melanoma stage IV British
Journal of Dermatology 2004151(1)91ndash8
Sertoli 1999 published data only
Sertoli MR Queirolo P Bajetta E DelVecchio M
Comella G Barduagni L et alMulti-institutional phase
II randomized trial of integrated therapy with cisplatin
dacarbazine vindesine subcutaneous interleukin-2
interferon alpha2a and tamoxifen in metastatic melanoma
BREMIM (Biological Response Modifiers in Melanoma)
Melanoma research 19999(5)503ndash9
Sparano 1993 published data only
Sparano JA Fisher RI Sunderland M Margolin K Ernest
ML Sznol M et alRandomized phase III trial of treatment
with high-dose interleukin-2 either alone or in combination
with interferon alfa-2a in patients with advanced melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199311(10)1969ndash77
Vuoristo 2005 published data only
Vuoristo MS Hahka-Kemppinen M Parvinen LM
Pyrhonen S Seppa H Korpela M et alRandomized trial of
dacarbazine versus bleomycin vincristine lomustine and
dacarbazine (BOLD) chemotherapy combined with natural
or recombinant interferon-alpha in patients with advanced
melanoma Melanoma research 200515(4)291ndash6
Additional references
Arance 2000
Arance A Middleton M Lorigan P Thatcher N Three-
arm phase II study of temozolomide (TMZ) in metastatic
melanoma (MM) In ASCO Annual Meeting 2000
Abstract 2257
Bafaloukos 2002
Bafaloukos D Aravantinos G Fountzilas G Stathopoulos
G Gogas H Samonis G et alDocetaxel in combination
with dacarbazine in patients with advanced melanoma
Oncology 200263(4)333ndash7
Bajetta 2002
Bajetta E Del Vecchio M Bernard-Marty C Vitali
M Buzzoni R Rixe O et alMetastatic melanoma
chemotherapy Seminars in Oncology 200229(5)427ndash45
Balch 2001
Balch CM Soong SJ Gershenwald JE Thompson JF
Reintgen DS Cascinelli N et alPrognostic factors analysis
of 17600 melanoma patients validation of the American
Joint Committee on Cancer melanoma staging system
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200119(16)3622ndash34
Barth 1995
Barth A Morton DL The role of adjuvant therapy in
melanoma management Cancer 199575 Suppl (2)
726ndash34
Chiarion-Sileni 2003
Chiarion-Sileni V Del Bianco P De Salvo GL Lo Re G
Romanini A Labianca R et alQuality of life evaluation in a
randomised trial of chemotherapy versus bio-chemotherapy
in advanced melanoma patients European journal of cancer
(Oxford England 1990) 200339(11)1577ndash85
Creagan 1984
Creagan ET Ahmann DL Green SJ Long HJ Frytak S
OrsquoFallon JR et alPhase II study of low-dose recombinant
leukocyte A interferon in disseminated malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 19842(9)1002ndash5
Crosby 2000
Crosby T Fish R Coles B Mason MD Systemic treatments
for metastatic cutaneous melanoma Cochrane Database
of Systematic Reviews 2000 Issue 2 [DOI 101002
14651858CD001215]
12Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Cure 1999
Cure H Souteyrand P Ouabdesselam R Roche H
Ravaud A DrsquoIncan M et alResults of a phase II trial
with cystemustine at 90 mgm(2) as a first- or second-line
treatment in advanced malignant melanoma a trial of the
EORTC Clinical Studies Group Melanoma Research 1999
9(6)607ndash10
Danson 2002
Danson S Arance A Lorigan P Clamp A Hodgetts J
Lomax L Thatcher N Middleton MR A randomized
study of temozolomide (TMZ) alone with interferon-
alpha (TMZ-IFN) or with thalidomide (TMZ-THAL) in
metastatic malignant melanoma (MMM) ASCO Annual
Meeting - Proceedings 2002Abstract 1369
Dorval 1986
Dorval T Palangie T Jouve M Garcia-Giralt E Israel L
Falcoff E et alClinical phase II trial of recombinant DNA
interferon (interferon alpha 2b) in patients with metastatic
malignant melanoma Cancer 198658(2)215ndash8
Dutcher 1989
Dutcher JP Creekmore S Weiss GR Margolin K
Markowitz AB Roper M et alA phase II study of
interleukin-2 and lymphokine-activated killer cells in
patients with metastatic malignant melanoma Journal of
clinical oncology official journal of the American Society of
Clinical Oncology 19897(4)477ndash85
Falkson 1995
Falkson CI Experience with interferon alpha 2b combined
with dacarbazine in the treatment of metastatic malignant
melanoma Medical oncology (Northwood London England)
199512(1)35ndash40
Garbe 1990
Garbe C Krasagakis K Zouboulis CC Schroder K Kruger
S Stadler R et alAntitumor activities of interferon alpha
beta and gamma and their combinations on human
melanoma cells in vitro changes of proliferation melanin
synthesis and immunophenotype Journal of Investigative
Dermatology 199095 Suppl (6)231ndash7
Gershenwald 1999
Gershenwald JE Thompson W Mansfield PF Lee JE
Colome MI Tseng CH et alMulti-institutional melanoma
lymphatic mapping experience the prognostic value of
sentinel lymph node status in 612 stage I or II melanoma
patients Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199917(3)976ndash83
Hanninen 1991
Hanninen EL Korfer A Hadam M Schneekloth C
Dallmann I Menzel T et alBiological monitoring of
low-dose interleukin 2 in humans soluble interleukin 2
receptors cytokines and cell surface phenotypes Cancer
Research 199151(23 Pt 1)6312ndash6
Huncharek 2001
Huncharek M Caubet JF McGarry R Single-agent
DTIC versus combination chemotherapy with or without
immunotherapy in metastatic melanoma a meta-analysis
of 3273 patients from 20 randomized trials Melanoma
Research 200111(1)75ndash81
Juni 2001
Juni P Altman DG Egger M Assessing the quality of
controlled clinical trials BMJ 200132342ndash6
Kadison 2003
Kadison AS Morton DL Immunotherapy of malignant
melanoma The Surgical Clinics of North America 200383
(2)343ndash70
Keilholz 2002
Keilholz U Gore ME Biochemotherapy for advanced
melanoma Seminars in Oncology 200229(5)456ndash61
Khayat 2002
Khayat D Bernard-Marty C Meric JB Rixe O
Biochemotherapy for advanced melanoma maybe it is real
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200220(10)2411ndash4
Koh 1991
Koh HK Cutaneous melanoma New England Journal of
Medicine 1991325(3)171ndash82
La Vecchia 1999
La Vecchia C Lucchini F Negri E Levi F Recent declines
in worldwide mortality from cutaneous melanoma in youth
and middle age International Journal of Cancer 199981(1)
62ndash6
Lee 2000
Lee ML Tomsu K Von Eschen KB Duration of survival
for disseminated malignant melanoma results of a meta-
analysis Melanoma Research 200010(1)81ndash92
Legha 1998
Legha SS Ring S Eton O Bedikian A Buzaid AC Plager
C et alDevelopment of a biochemotherapy regimen
with concurrent administration of cisplatin vinblastine
dacarbazine interferon alfa and interleukin-2 for patients
with metastatic melanoma Journal of clinical oncology
official journal of the American Society of Clinical Oncology
199816(5)1752ndash9
Leong 2003
Leong SP Future perspectives on malignant melanoma
Surgical Clinics of North America 200383(2)453ndash6
Lokich 1979
Lokich JJ Garnick MB Legg M Intralesional immune
therapy methanol extraction residue of BCG or purified
protein derivative Oncology 197936(5)236ndash41
Nathan 1998
Nathan FE Mastrangelo MJ Systemic therapy in
melanoma Seminars in Surgical Oncology 199814(4)
319ndash27
Osborn 1977
Osborn DE Castro JE Immunological response in patients
receiving Corynebacterium parvum therapy Clinical
Oncology 19773(2)155ndash64
13Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Parmar 1998
Parmar MKB TV Stewart L Extracting summary statistics
to perform meta-analyses of the published literature for
survival endpoints Statistics in Medicine 1998172815ndash34
Richards 1992
Richards JM Mehta N Ramming K Skosey P Sequential
chemoimmunotherapy in the treatment of metastatic
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199210(8)1338ndash43
Rigel 1989
Rigel DS Rivers JK Kopf AW Friedman RJ Vinokur AF
Heilman ER et alDysplastic nevi Markers for increased
risk for melanoma Cancer 198963(2)386ndash9
Rosenberg 1989
Rosenberg SA Lotze MT Yang JC Aebersold PM Linehan
WM Seipp CA et alExperience with the use of high-
dose interleukin-2 in the treatment of 652 cancer patients
Annals of Surgery 1989210(4)474-84 discussion 484-5
Sertoli 1989
Sertoli MR Bernengo MG Ardizzoni A Brunetti I Falcone
A Vidili MG et alPhase II trial of recombinant alpha-2b
interferon in the treatment of metastatic skin melanoma
Oncology 198946(2)96ndash8
Smith 1993
Smith KA Lowest dose interleukin-2 immunotherapy
Blood 199381(6)1414ndash23
Stopeck 2001
Stopeck AT Jones A Hersh EM Thompson JA
Finucane DM Gutheil JC et alPhase II study of direct
intralesional gene transfer of allovectin-7 an HLA-B7
beta2-microglobulin DNA-liposome complex in patients
with metastatic melanoma Clinical Cancer Research 20017
(8)2285ndash91
Tsang 1983
Tsang KY Fudenberg HH Pan JF Gnagy MJ Bristow
CB An in vitro study on the effects of isoprinosine on
immune responses in cancer patients International Journal
of Immunopharmacology 19835(6)481ndash90
Wingo 1995
Wingo PA Tong T Bolden S Cancer statistics 1995 CA
a cancer journal for clinicians 199545(1)8ndash30
Yusuf 1985
Yusuf S Peto R Lewis J Collins R Sleight P Beta blockade
during and after myocardial infarction an overview of the
randomized trials Progress in Cardiovascular Diseases 1985
27(5)335ndash71lowast Indicates the major publication for the study
14Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Atkins 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding public
Participants PS lt= 1
Brain mets no info
Age 20 to 80 (median 50)
Number of cycles no info
Randomised 416 a 206 b 210
Evaluable 405 a 201 b 204
Interventions a (CT) cisplatin 20mgm2 D1 to 4 vinblastin 12 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1-4 vimblastin 12 mgm2 D1-4 DTIC 800 mgm2 D1
IFN-alpha 5 mIU D1-5 D8 D10 D12 IL-2 9 mIU D1-4
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
Notes Multicentric yes
Withdrawals a five b six
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
15Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Atzpodien 2002
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding both (pharmaceutic and public)
Participants PS lt= 1
Brain mets yes Age 28 to 77 (median 57)
Number of cycles no info
Randomised 124 a 60 b 64
Evaluable 124 a 60 b 64
Interventions a (CT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily
b (ICT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily IFN-alpha 5 mIUm2 D1 week4 and 5
mIUm2 D1 D3 D5 week 5 IL-2 10 mIUm2 D1 D3 D5
(each five weeks)
Outcomes 1 Response rates
2 Overall survival
3 Progression free survival
Notes Multicentric yes
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Bajetta 1994
Methods D parallel group (three groups)
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding pharmaceutic
Participants PS lt= 2
Brain mets no
16Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Bajetta 1994 (Continued)
Age 18 to 70 (median 53)
Number of cycles 8
Randomised 266 a 88 b 86 c 92
Evaluable 242 a 82 b 76 c 84
Interventions a (CT) DTIC 800 mgm2 D1
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU 3xweek
c (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU D1 to 3 6 mIU D4 to 6 9 mIU daily
(each 21 days)
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Overall survival
Notes Multicentric yes
Withdrawals a six b ten c eight
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Danson 2003
Methods D parallel group
AC independent allocation
RS permuted blocks
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets yes Age 16 to 88 (median 58)
Number of cycles six
Randomised 125 a 59 b 62
Evaluable 121 a 55 b 62
Interventions a (CT) temozolomide 200 mgm2 88 h (5 doses)
b (ICT) Temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIU 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
17Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Danson 2003 (Continued)
Notes Multicentric no
Withdrawals a 4 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Del Vecchio 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no Age 19 to 70 (median 50)
Number of cycles no info
Randomised 151 a 75 b 76
Evaluable 145 a 72 b 73
Interventions a (CT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250 mgm2 D1 to
3
b (ICT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250m gm2 D1 to
3 IFN-alpha 5 mIUm2 D1 to 5 IL-2 9 mIUday x 5 daysweek x 2 weeks with a week of
rest
(each 21 days)
Outcomes 1 Response rates
2 Time to Progression
2 Overall Survival
Notes Multicentric yes
Withdrawals a three b three
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
18Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Eton 2002
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding pharm
Participants PS lt= 3
Brain mets yes Age median 49
Number of cycles no info
Randomised 190
Evaluable 183 a 92 b 91
Interventions a (CT) cisplatin 20m gm2 D1 to 4 vimblastin 2 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1 to 4 vinblastin 15 mgm2 D1 to 4 DTIC 800 mgm2
D1 IFN-alpha 5mIUm2 D5 to 9 D17-21 IL-2 9 mIUm2 D5 to 8 D17 to 20
(each 21 days)
Outcomes 1 Response rates
2 Time to progression
3 Overall survival
Notes Multicentric no
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1991
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size no
ITT no
Placebo no
Funding both
Participants PS lt= 1
Brain mets no
Age 22 to 79
(median 57)
Number of cycles at least two
19Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1991 (Continued)
Randomised 73 Evaluable 68 a 34 b 34
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Time to treatment failure
3 Median survival
4 Toxicity
Notes Multicentric no
Withdrawals a three b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1998
Methods D 2 x 2 factorial design
AC independent allocation
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 18 to 84
Number of cycles no info
Randomised 271 Evaluable 263 a 68 b 65 c 63 d 67
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
c (CT) DTIC 200m gm2 D1 to 5 tamoxifen 20 mgdaily
d (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek tamoxifen 20 mgdaily
(each 28 days)
Outcomes 1 Response rates
2 Toxicity rates
20Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1998 (Continued)
3 Overall survival
4 Time to treatment failure
Notes Multicentric yes
Withdrawals a one b three c three d one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Gorbonova 2000
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no
Age 23 to 75
Number of cycles no info
Randomised 30 Evaluable 28 a 14 b 14
Interventions a (CT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2
b (ICT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2 IFN-alpha 3 mIU D5 7
9 11 13 15 17 19
(each 28 days)
Outcomes 1 Response rates
Notes Multicentric no
Withdrawals a two b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
21Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Johnston 1998
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age 18 to 70
(median 45)
Number of cycles no info
Randomised 65 Evaluable 65 a 30 b 35
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to 3
Tamoxifen 40 mg daily
b (ICT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to
3 Tamoxifen 40 mg daily IFN-alpha 9 mIU D1 to 3 IL-2 18 mIU D-2 IL-2 9 mIU D-
1 and 0
(each 28 days)
Outcomes 1 Response rates
2 Time to disease progression
3 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Kirkwood 1990
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding pharm
22Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Kirkwood 1990 (Continued)
Participants PS no info
Brain mets no info
Age no info
Number of cycles no info
Randomised 74 Evaluable 68 a 24 b 23 c 21
Interventions a (CT) DTIC 250 mgm2 D1 to 5 (each 21 days)
b (I) IFN-alpha 3 mIU d1 to 5 every week for 3 weeks than 3 mIUm2 3 xweek
c (ICT) DTIC 250 mgm2 D1 to 5 (each 21 days) IFN-alpha 3 mIU d1 to 5 every week
for 3 weeks than 3 mIUm2 3 xweek
Outcomes 1 Response rates
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Middleton 2000
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets no
Age 24 to 71
(median 51)
Number of cycles six
Randomised 105 Evaluable 96 a 46 b 50
Interventions a (CT) DTIC 800 mgm2 D1 cisplatin 25 mgm2 D1 to 3 BCNU 150 mgm2 D1
tamoxifen 20 mgdaily
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 9 mIU 3 xweek
(each 21 days)
Outcomes 1 Response rates
2 One year survival
3 Median survival
23Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Middleton 2000 (Continued)
4 Toxicity
4 Time spent in hospital
Notes Multicentric no
Withdrawals a seven b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Ridolfi 2002
Methods D parallel group
AC independent allocation by telephone
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 25 to 77
Number of cycles six
Randomised 178 Evaluable 176 a 89 b 87
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1
b (ICT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1 IFN-
alpha 3 mIU 3 xweek IL-2 45 mIU D3 to 5 D8 to 12
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
3 Time to progression
4 Toxicity
Notes Multicentric yes
Withdrawals a one b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
24Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Main results
Eighteen studies met our criteria and were included in the meta-analysis with a total of 2625 participants We found evidence of an
increase of objective response rates in people treated with chemoimmunotherapy in comparison with people treated with chemotherapy
Nevertheless the impact of these increased response rates was not translated into a survival benefit We found no difference in survival
to support the addition of immunotherapy to chemotherapy in the systemic treatment of metastatic melanoma with a hazard ratio
of 089 (95 CI 072 to 111 P = 031) Additionally we found increased hematological and non-hematological toxicities in people
treated with chemoimmunotherapy
Authorsrsquo conclusions
We failed to find any clear evidence that the addition of immunotherapy to chemotherapy increases survival of people with metastatic
melanoma Further use of combined immunotherapy and chemotherapy should only be done in the context of clinical trials
P L A I N L A N G U A G E S U M M A R Y
Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Malignant melanoma is one of the most aggressive of all skin cancers If it is confined to the skin it can often be cured by surgery
However if it has spread melanoma is usually incurable because it does not respond to most treatments Recently clinicians have been
trying a combination of chemotherapy and immunotherapy in the hope of improving the outcome The review of trials showed an
increased response to treatment when immunotherapy was added to chemotherapy but no difference was seen in survival rate and toxic
effects were increased
There is not enough evidence to support the use of a combination of combined immunotherapy and chemotherapy in treatment of
metastatic malignant melanoma
B A C K G R O U N D
Description of the condition
Epidemiology and progress of melanoma
Malignant melanomas develop due to changes in the melanocytes
cells that produce melanin pigment Melanomas are most com-
monly found in the skin but can also be found in the uveal tract
(back of the eye) upper digestive tract anal canal rectum and
vagina
Malignant melanoma of the skin accounts for 1 to 3 of all ma-
lignant tumors and there has been an increase in its incidence of
6 to 7 each year since 1985 (La Vecchia 1999 Wingo 1995)
However the overall mortality rate has only slightly increased
probably due to an increase in the early diagnosis of lesions that
have a better prognosis (Leong 2003)
As with other tumors the stage (progress) of the disease is still an
important determinant of survival In the earlier stages melanoma
is confined to the skin where the disease is curable in a high
percentage of cases through surgical removal of the tumor (Nathan
1998) The 5 year survival rate for melanoma that is confined to
the skin is 80 to 100 (Nathan 1998) depending on the thickness
of the primary tumor
In people where the cancer has spread to the lymph nodes (nodal
disease) three variables independently affect the prognosis
1 the number of positive lymph nodes
2 the presence of ulceration within the primary tumor
3 whether the nodal disease is macroscopic (an enlarged
lymph node can be felt by a doctor) or microscopic (the lymph
node cannot be felt but abnormal melanoma cells are present
and can be seen when viewed under a microscope) (Balch 2001)
In people with macroscopic disease more than one positive node
and an ulcerated primary tumor the 5 year survival rate is only
16 In people with one microscopically positive lymph node and
without ulceration in the primary lesion the 5 year survival rate
is 71 (Balch 2001)
The detection of lymph node metastases previously relied on crude
clinical or regional elective lymph node dissection (removal of a
2Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
whole group of lymph nodes responsible for draining a partic-
ular area of the body) but several large randomised controlled
trials have shown no improvement in survival using this tech-
nique Currently sentinel lymph node mapping and directed se-
lective lymphadenectomy (ie only removing those nodes that
show up as positive using the sentinel node imaging technique) has
been shown to identify lymph node metastases more precisely and
with less surgical morbidity than elective dissection (Gershenwald
1999)
Causes
Although the cause of melanoma is unknown major risk factors
have been identified (Koh 1991) Epidemiological studies suggest
that sunlight (ultraviolet radiation) is the most common environ-
mental factor Pale skin a tendency to sunburn fair or red hair
large numbers of melanocytic nevi (moles) and multiple dysplastic
nevi (atypical moles) have been shown to be independent risk fac-
tors for the development of melanoma Fair skin that does not tan
easily in combination with high sun exposure provides the largest
cumulative risk factor for melanoma development (Rigel 1989)
Impact
Malignant melanoma that has spread to distant sites by dissemi-
nation is associated with extremely poor survival median survival
is approximately 8 months and less than 5 of such people will
survive for more than 5 years (Lee 2000)
There are large prospective randomised multicenter trials that
have answered some basic management questions improved the
care of melanoma sufferers and expanded our understanding of
the disease However many aspects of treatment such as the thera-
peutic role of cytotoxic chemotherapy and biologic therapy alone
or in combination remain controversial and inconclusive (Crosby
2000 Leong 2003)
Description of the intervention
Systemic therapy
This has little or no impact on survival for advanced disease
There is no evidence derived from randomised controlled trials to
show superiority of systemic therapy over supportive care (Crosby
2000) The minority of people with metastatic melanoma who do
respond to systemic treatment have remissions which are generally
of short duration (Nathan 1998) Few agents have demonstrated
substantial anti-tumor activity against metastatic melanoma The
alkylating agent dacarbazine (DTIC) is considered to be the most
active drug for the treatment of this disease with a response rate of
20 and a median duration of response of 4 to 5 months (Khayat
2002 Nathan 1998) Other cytotoxic compounds such as temo-
zolomide (a dacarbazine analogue) (Middleton 2000) cisplatin
and carboplatin (Bajetta 2002) vinca alkaloids (Khayat 2002)
taxanes (Bafaloukos 2002) and nitrosoureas (Cure 1999) have not
improved these results All of these treatments are associated with
response rates of less than 15 and all are associated with signif-
icant adverse effects (Bafaloukos 2002 Bajetta 2002 Cure 1999
Khayat 2002 Middleton 2000)
Combination chemotherapy
The role of combination chemotherapy in advanced disease re-
mains unclear Prospective randomised studies have failed to
demonstrate any significant benefit for combination chemother-
apy when compared with single agents except for a slight increase
in response rates (Huncharek 2001)
Experimental treatments
Experimental treatments such as vaccines antibody treatments
and gene therapy are being developed and are of high scientific
interest However their efficacy in advanced melanoma has so
far been very limited with overall response rates of less than 5
(Keilholz 2002 Stopeck 2001) Since the 1970s immunostim-
ulating agents such as Bacillus Calmette-Guerin (BCG) (Lokich
1979 Osborn 1977) Corynebacterium parvum (Osborn 1977)
or isoprinosine (Tsang 1983) have been evaluated as local or sys-
temic treatments After some early hopes all these treatments have
also failed to demonstrate a significant and consistent effect in the
clinical management of advanced melanoma (Khayat 2002)
Immunotherapy
Two points have driven the attention of researchers in the im-
munology field to melanoma Firstly the spontaneous regression
of melanoma (ie the tumor occasionally appears to go away in
some people) Spontaneous regression is much more frequent than
in melanoma than with any other solid tumor and it is associated
with a specific cellular immune response (Kadison 2003) Sec-
ondly the fact that some people with melanoma also have tumor
rejection antigen recognized by CD4 and CD8 T cells (immune
cells that can help get rid of cancer cells) (Kadison 2003)
At least two types of immunotherapy have been used in advanced
melanoma interferon-alpha and interleukin-2
Interferon-alpha (IFN-α) belongs to a group of proteins known
to have antiproliferative and antitumor effects (Garbe 1990) In
addition IFN-α exhibits certain immunomodulatory effects - it
upregulates the expression of major histocompatibility complex
(MHC) class I antigens in melanoma cells and also the expres-
sion of co-stimulatory molecules rendering the cells more suscep-
tible to immunological defense mechanisms (Barth 1995) Phase
II studies of IFN-α as a single agent have demonstrated response
rates of approximately 20 with a slightly more durable response
3Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
than the one found with dacarbazine (DTIC) (Creagan 1984
Dorval 1986 Sertoli 1989)
Interleukin-2 (IL-2) is a major growth factor for lymphoid cells
including T cells and natural killer (NK) cells (Hanninen 1991
Smith 1993) Clinical trials have demonstrated modest anti-tumor
activity in people with metastatic melanoma (Rosenberg 1989)
responses were seen in approximately 15 of people with a
small proportion of complete responses (Dutcher 1989 Rosenberg
1989)
Chemoimmunotherapy
As chemotherapy and immunotherapy have different and per-
haps synergistic mechanisms of action their combination of im-
munotherapy with chemotherapy (chemoimmunotherapy) has
been studied since the early 1990s (Khayat 2002) Some reports
have suggested that chemotherapeutic agents administered in com-
bination with IL-2 or IFN or both can improve response rates
(Legha 1998 Richards 1992) with complete response rates in 10
to 20 of people as well as increases in median survival (Falkson
1991) Based on these results the use of chemoimmunotherapy is
currently preferred in some institutions as a first-line treatment in
advanced (stage IV) melanoma (Kadison 2003 Keilholz 2002)
although it is still considered an experimental therapy by oth-
ers(Crosby 2000)
Why it is important to do this review
There are substantial controversies about the real benefit of
chemoimmunotherapy some studies conclude that the combi-
nation of treatments did not improve survival (Rosenberg 1999
Young 2001) or even response rates (Falkson 1998 Gorbonova
2000 Johnston 1998 Thomson 1993) in people with metastatic
melanoma There is also concern that combined therapy may in-
crease treatment-related toxicity (Falkson 1998 Johnston 1998)
The lack of conclusive data coming from seemingly conflict-
ing studies about the impact of treatment demands a systematic
review This will provide the most reliable assessment for sup-
porting clinical decision-making with people who have advanced
melanoma
O B J E C T I V E S
To compare the effects of chemotherapy alone versus combined
therapy with chemotherapy and immunotherapy (chemoim-
munotherapy) in people with metastatic malignant melanoma
M E T H O D S
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs)
Types of participants
People of any age diagnosed with metastatic malignant melanoma
that has spread to distant sites by systemic dissemination
Types of interventions
1 Chemotherapy
2 Chemoimmunotherapy ie the combination of
chemotherapy and immunotherapy with interferon-alpha or
interleukin-2 or both
Types of outcome measures
Primary outcomes
Overall survival - number of participants alive at the end of the
trial
Secondary outcomes
1 One two and five-year survival rates - proportion of
participants alive at one two and five year follow-up
2 Response rates (partial and complete) - proportion of
participants that have achieved partial or complete responses as
defined by the trial authors
3 Progression-free survival - number of participants without
progression of disease at the end of the trial
4 Treatment morbidity (treatment-related toxicity) -
proportion of participants that have developed hematological or
non-hematological toxicities
5 Treatment related mortality - proportion of participants
that have died due to the treatment This outcome was not
described previously in the protocol and was added after
discussion between the reviewers that considered it relevant
Mortality related to treatment is a great concern in oncology
when comparing treatments with potential differences in toxicity
6 Quality of life measures
Search methods for identification of studies
We searched electronic databases and other resources to locate
reports of studies No language restrictions were imposed
4Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Electronic searches
Electronic databases
We searched the following electronic databases
1 MEDLINE (OVID) (Appendix 1)
2 The Cochrane Skin Group Specialised Register
3 The Cochrane Central Register of Controlled Trials
4 Medline (PubMed)
5 EMBASE
6 LILACS (Latin American and Caribbean Health Science
Information Database)
Search strategies for databases 2 to 6 are located in Appendix 2
Search of databases of ongoing trials (unpublished literature)
We asked trial authors and pharmaceutical companies about un-
published and ongoing trials Databases of major research groups
and registers of trials in the following databases were also searched
with the term rsquoMELANOMArsquo
bull Current Controlled Trials Register (httpwwwcontrolled-
trialscom) on 30th January 2006
bull European Organisation for Research and Treatment of
Cancer (httpwwweortcbe) on 20th February 2006
bull National Cancer Institute America (http
wwwcancergovclinicaltrials) on 16th November 2005
bull National Cancer Institute Canada (httphttp
wwwctgqueensucapublicClinical_Trialsclinical_trialshtml)
on 30th January 2006
bull Australian Clinical Trials Registry (httpwwwactrorgau)
on 30th January 2006
bull US Food and Drug Administration (httpwwwfdagov)
on 30th January 2006
bull ClinicalTrialsgov (httpwwwclinicaltrialsgov) on 16th
November 2005
Searching other resources
References from unpublished studies
All bibliographies of selected studies were scanned for possible
references to RCTs
Conference proceedings
We handsearched the abstracts from conference proceedings of
the ASCO (American Society of Clinical Oncology) and ESMO
(European Society of Medical Oncology)
Data collection and analysis
Where there was uncertainty we tried to contact trial authors for
clarification
A consumer (LU) was involved throughout the review process to
ensure the readability of the final review Updating will be done
every two years
Selection of studies
Two authors (ADS and ECS) checked the titles and abstracts iden-
tified from the searches If it was clear that the study did not refer
to a RCT on metastatic melanoma we excluded it Two authors
(ADS and OAC) independently assessed each remaining study to
determine whether it met the pre-defined selection criteria Any
differences were resolved through discussion with the review team
Excluded studies are listed in the Table of Excluded Studies
Data extraction and management
Two authors (ADS and ECS) independently extracted the data
from the studies All data were extracted directly from the text or
calculated according to the available information
Any differences were resolved by discussion with one author
(OAC) A data extraction form was developed and piloted in order
to summarize the trials One author (ADS) checked and entered
the data Two authors (ECS and LGC) independently checked the
data entry
Assessment of risk of bias in included studies
Assessment of methodological quality
The quality assessment included an evaluation of the following
components for each included study since there is some evidence
that these are associated with biased estimates of treatment effect
(Juni 2001)
(a) the method of generation of the randomisation sequence
(b) the method of allocation concealment - it was considered rsquoad-
equatersquo if the assignment could not be foreseen
(c) who was blindednot blinded (participants clinicians outcome
assessors)
(d) how many participants were lost to follow up in each arm and
whether participants were analysed in the groups to which they
were originally randomised (intention-to-treat)
In addition the quality assessment also included
(e) the source of funding
(f ) if the participant had a biopsy proven melanoma
(g) the baseline assessment of the participants for presence of liver
and brain metastases performance status
(h) whether the aims interventions (including drug doses and
duration of treatment) and outcome measures were clearly defined
5Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(i) the use and appropriateness of statistical analyses
We recorded all the information in a table of quality criteria and
gave a description of the quality of each study based on these
characteristics
Measures of treatment effect
Where possible we performed a meta-analysis for the outcomes
in order to calculate a weighted treatment effect across trials using
a random-effects model For binary endpoints we calculated the
risk ratio (RR) with 95 confidence intervals (Yusuf 1985) We
also expressed the results as a number needed to treat (NNT)
where appropriate for a range of plausible control event rates For
overall survival a time-to-event data we calculated the Hazard
Ratio (HR) When data were not available for direct extraction
we calculated indirectly (from different parameters using indirect
calculation of the variance and the number of observed minus
expected events) according to the method described by Parmar
(Parmar 1998) In the funnel plot (Figure 1) and comparison 1
rsquoPeto OR (IPD)rsquo is a Hazard Ratio For continuous data such as
quality of life we planned to use standardised mean differences
with 95 confidence intervals would have been used
Figure 1 Funnel plot using overall survival as the outcome
Assessment of heterogeneity
Heterogeneity was assessed using I2 Where the heterogeneity was
considerable (I2 gt 50) we explored possible reasons using the
type (interleukin-2 or interferon) and dose (high or low) of im-
munotherapy used as subgroups Where we were not able to find
an explanation we have recorded this along with appropriate cau-
tion in the interpretation of these data
Data synthesis
Analysis and presentation
Once studies had been selected critically appraised and the data
extracted we entered the data in the Characteristics of included
studies table
6Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Three studies (Bajetta 1994 Kirkwood 1990 Vorobiof 1994) eval-
uated three arms of treatment with one of them evaluating che-
motherapy alone and the two others using chemoimmunotherapy
One study (Falkson 1998) had four arms two using chemotherapy
and two using chemoimmunotherapy The data from the similar
arms were grouped considered as one and then compared to the
other arm
R E S U L T S
Description of studies
Results of the search
We scanned approximately 700 citations Initially 28 studies
were identified Four studies (Arance 2000 Chiarion-Sileni 2003
Danson 2002 Falkson 1995) had data that overlapped with three
included studies (Danson 2003 Falkson 1991 Ridolfi 2002)
Ongoing studies
No ongoing studies were available to be included in the meta-
analysis
Included studies
Eighteen studies with a total of 2625 participants met our criteria
and were included in the meta-analysis (please see Characteristics
of included studies) One study differed considerably from the oth-
ers because vindesine was used as the chemotherapy control a drug
without evidence of response in metastatic melanoma (Vorobiof
1994) Another study differed considerably as lower dose treat-
ment in the chemoimmunotherapy group was used (Middleton
2000) The first study was published in 1990 and the last studies
were published in 2003
Participants
The participants were between the ages of 16 and 88 years and
had an Eastern Cooperative Oncology Group performance status
from 0 to 3 Only three studies included participants with brain
metastasis (Atzpodien 2002 Danson 2003 Eton 2002)
Interventions
Seven studies compared chemotherapy to chemoimmunotherapy
with IFN plus IL-2 (Atkins 2003 Atzpodien 2002 Del Vecchio
2003 Eton 2002 Johnston 1998 Ridolfi 2002 Rosenberg 1999)
Eleven compared chemotherapy to chemoimmunotherapy with
IFN (Bajetta 1994 Danson 2003 Falkson 1991 Falkson 1998
Gorbonova 2000 Kirkwood 1990 Middleton 2000 Spieth 2003
Thomson 1993 Vorobiof 1994 Young 2001)
The drugs used in chemotherapeutic schemes varied between the
trials Seven trials evaluated DTIC combined with other drugs in
both arms (Atkins 2003 Atzpodien 2002 Del Vecchio 2003 Eton
2002 Johnston 1998 Ridolfi 2002 Rosenberg 1999) and six
evaluated DTIC alone as the control (Bajetta 1994 Falkson 1991
Falkson 1998 Kirkwood 1990 Thomson 1993 Young 2001)
Four studies evaluated other schemes without DTIC two trials
used temozolomide (Danson 2003 Spieth 2003) one trial used
vindesine (Vorobiof 1994) and one trial used combined drugs
based on cisplatin (Gorbonova 2000)
Only one study did not use the same scheme in both the arms
using combined drugs with DTIC as the chemotherapy control
and a lower dose for the chemoimmunotherapy group with DTIC
alone (Middleton 2000)
Setting
Ten studies were carried out in Europe four in the United States
two in South Africa and one was a multicentre worldwide trial
All trials were reported in the English language
Outcomes
Response rates were the primary outcome measures in most trials
and were described in all included studies Two studies did not
evaluate survival rates (Gorbonova 2000 Kirkwood 1990) Three
studies included quality of life analyses in the outcomes (Ridolfi
2002 Thomson 1993 Young 2001) The length of the follow-up
varied widely between the trials and sometimes it was not speci-
fied We did not find a reasonable definition about what could be
considered high or low doses of immunotherapy and the influence
of the immunotherapeutic doses on the outcomes could not be
assessed
Excluded studies
Six studies were excluded (see Characteristics of excluded studies)
The reasons for exclusion were that the study had immunotherapy
on both arms (Bajetta 2001 Richtig 2004 Sertoli 1999 Sparano
1993 Vuoristo 2005) or the study was not randomised (Legha
1996)
Risk of bias in included studies
The quality assessment consisted of a basic methodological eval-
uation of each included study and is shown in Table 1 Addi-
tional quality assessment is shown in Table 2 The criteria used for
methodological quality analysis of the studies are listed in Table 3
(Explanation of Quality Analysis Headings)
7Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Although blinding participants and clinicians is theoretically pos-
sible it is difficult to plan a double-blind study with immunother-
apy This is due to the substantial acute and late toxicities associ-
ated with immunotherapy in one group No study was described
as double-blinded The groups at baseline were in general similar
with a description of most prognostic factors related to metastatic
melanoma (gender performance status age prior therapy liver
metastasis)
In three studies almost all methodological aspects of the trials
were described poorly (Gorbonova 2000 Kirkwood 1990 Spieth
2003)
Allocation
All the included studies were described as randomised as this
was a selection criterion However most papers did not describe
the method of randomisation The method of generation of the
randomised sequence was described and considered adequate in
only 6 out of 18 studies Eleven of 18 studies provided information
on allocation concealment all of which were considered adequate
Blinding
Blinding of outcome assessment and detection bias
We did not find information about blinding of the outcome as-
sessors in any included study
Incomplete outcome data
Handling of losses and attrition bias
In general there were few participants lost to follow up in the
studies The highest number of people lost was 24 in a total of 262
participants (Bajetta 1994) Eleven studies included an intention-
to-treat analysis
Effects of interventions
Primary outcome
Overall survival (eight studies)
This was considered as the number of participants alive at the end
of the trial Sufficient data were available from 8 of the 18 studies
There was no statistically significant difference in survival between
chemoimmunotherapy and chemotherapy with a hazard ratio
(HR) of improved survival of 089 (95 CI 072 to 111 P = 031
Analysis 11) in favour of chemoimmunotherapy In other words
overall survival was slightly lower in the chemoimmunotherapy
group but this was not statistically significant There was no het-
erogeneity across trials (I2 = 0) The funnel plot method using
overall survival as the outcome is presented in Figure 1 It shows
that there was no evidence of substantial publication bias but in-
terpretation of the funnel plot is likely to be unreliable since only
eight relatively large studies were found
When we evaluated the influence of the type of immunotherapy
used in the chemoimmunotherapy group (IL-2 plus IFN-alpha
or IFN-alpha only) we found no statistically significant difference
between the groups with a HR of 096 (95 CI 074 to 124 P =
076 Analysis 11) for chemoimmunotherapy with IL-2 plus IFN-
alpha and a HR of 074 (95 CI 049 to 112 P = 015 Analysis
11) for chemoimmunotherapy associated with only IFN-alpha
Secondary outcomes
One two and five-year survival rates (13 studies)
The number of participants alive at one two and five year follow-
ups were analyzed Data from 13 trials evaluating one year survival
were pooled There was no statistically significant difference in one
year survival between the groups with a risk ratio (RR) of 106
(95 CI 091 to 124 P = 048 Analysis 12) and no significant
heterogeneity across trials (I2 = 363)
Data from 11 trials evaluating 2 year survival were extracted and
pooled Again there was no statistically significant difference be-
tween the groups with a RR of 108 (95 CI 086 to 136 P =
050 Analysis 13) without heterogeneity across trials (I2 = 0)
Only two trials reported data about five year survival The meta-
analysis showed no statistically significant difference in 5 year sur-
vival between the groups with a RR of survival of 234 (95
CI 097 to 565 P = 006 Analysis 14) favouring chemoim-
munotherapy There was no heterogeneity across trials (I2 = 0)
Response rates (17 studies)
Data regarding the number of participants with partial or com-
plete responses from 17 trials were used to evaluate objective re-
sponse rates The analysis detected a statistically significant differ-
ence in favor of chemoimmunotherapy in global response rates
with a RR of 140 (95 CI 120 to 163 P lt 00001 Analysis
21) There was no heterogeneity across trials (I2 = 42) We
tried to evaluate the influence of the type of immunotherapeutic
in the group of chemoimmunotherapy (IL-2 plus IFN-alpha or
IFN-alpha only) We found similar results with a RR of global
response of 146 (95 CI 119 to 179 p = 00002 Analysis 21)
in favor of chemoimmunotherapy with IL-2 plus IFN-alpha and
a RR of 132 (95 CI 102 to 171 p = 004 Analysis 21) in favor
of chemoimmunotherapy with IFN-alpha There was no hetero-
geneity across trials (I2 = 0)
8Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Data from 15 trials were used to evaluate partial and complete
response rates We found a statistically significant difference in
favour of chemoimmunotherapy in both analyses with an HR of
131 (95 CI 107 to 159 p = 0008 Analysis 23) for partial
response rates and an HR of 158 (95 CI 106 to 236 p = 003
Analysis 23) for complete response rates
Progression-free survival (3 studies)
Only three studies had extractable data about the number of par-
ticipants with no disease progression at the end of the trial When
pooled together there was no statistically significant difference be-
tween the groups with an HR of 076 (95 CI 057 to 102 p =
007 Analysis 31) There was no heterogeneity across these trials
(I2 = 0)
Treatment related toxicity (11 studies)
Data from 11 studies were collected with the number of partici-
pants developing clinically significant hematological toxicity (de-
fined as grade 3 or 4) Eight studies had estimated points that
showed enhanced toxicities in the chemoimmunotherapy group
The meta-analysis of the studies showed extreme heterogeneity
(I2 = 941) across the trials We performed a sensitivity anal-
ysis excluding the studies with relatively low doses of chemo-
therapeutic drugs in the chemoimmunotherapy group (Danson
2003 Middleton 2000) but we found similar heterogeneity (I2 =
978)
When we analyzed data from the four studies with similar rela-
tive doses of chemotherapeutics associated with interferon-alpha
without interleukin-2 we found an increase of clinically signifi-
cant hematological toxicities in the chemoimmunotherapy group
with a RR 454 (95 CI 235 to 879 p lt 000001) There was
no heterogeneity across these trials (I2 = 0) When we analyzed
data from studies with combination of interferon-alpha plus in-
terleukin-2 in the chemoimmunotherapy group we again found
extreme heterogeneity across the trials (I2 = 979)
Despite the heterogeneity in global meta-analysis we concluded
that it was not possible to quantify the differences in hematologi-
cal toxicity in such different trials In order to explore these differ-
ences we noted that one study referred to hematological toxicity
in 100 of participants treated with chemoimmunotherapy and
in 96 of participants treated with chemotherapy (Eton 2002)
Another study referred to hematological toxicity only in 2 and
1 respectively (Bajetta 1994)
Non-hematological toxicities were described in almost all stud-
ies and were mainly described as nausea vomiting flu-like syn-
drome asthenia hypotension and fever Data from six similar
studies were extractable and were pooled in the meta-analysis re-
sulting in a statistically significant difference against the chemoim-
munotherapy group with a RR of 274 (95 CI 206 to 364 p
lt 000001 Analysis 42) There was no heterogeneity across trials
(I2 = 0) These results must be treated with caution because of
similar difficulties in pooling these data on hematological toxici-
ties with different therapeutic schemes and several trials described
non-hematological toxicities but we were not able to extract the
data
Data about treatment-related mortality were available in 11 stud-
ies We found no significant difference between the groups with a
RR of 078 (95 CI 026 to 232 p = 065 Analysis 43) There
was no heterogeneity across the trials (I2 = 0)
Quality of life (three studies)
Only three studies reported data on quality of life (Ridolfi 2002
Thomson 1993 Young 2001) all using different methods One
trial described quality of life analysis in detail in an additional pub-
lication (Chiarion-Sileni 2003 Ridolfi 2002) This study found
a significant decrease of overall quality of life in the chemoim-
munotherapy group in comparison to the chemotherapy group
(p = 003) The other two studies did not find differences in global
quality of life between the groups (Thomson 1993 Young 2001)
Thomson did not report global quality of life (Thomson 1993)
Young found no significant differences in quality of life for the
change in scores over time (z = -129 p = 020) (Young 2001)
It was not possible to pool the data as all three studies did not
provide extractable data
Sensitivity analyses on the influence of source of funding baseline
assessment and allocation concealment on the survival analysis
and response rate analyses revealed that there was no relation be-
tween these methodological aspects and the outcome There was
no statistically significant difference in survival between the groups
in all analyses and the difference in response rates in favour of
chemoimmunotherapy was found to be significant
D I S C U S S I O N
Metastatic melanoma is reputed as refractory to most systemic
treatments and little progress has been made in treatment of
metastatic melanoma These concepts are supported by results
from previous systematic reviews One review concluded that there
is no evidence derived from RCTs that systemic treatment is better
than best supportive care (Crosby 2000) Another review of 20
randomised trials (involving 3273 participants) comparing single-
agent DTIC with DTIC in combination with other drugs with or
without immunotherapy concluded that combination of drugs in-
creased response rates but not overall survival (Huncharek 2001)
This systematic review summarises the evidence regarding the
use of chemoimmunotherapy compared to chemotherapy alone
to treat people with metastatic malignant melanoma There are
some important observations regarding the characteristics of the
included studies in this systematic review The ideal combination
9Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
of drugs for an investigation is not well established Seven studies
evaluated chemoimmunotherapy with interferon-alpha plus inter-
leukin-2 and 11 evaluated chemoimmunotherapy only with in-
terferon-alpha The treatment plans with drugs and dosages used
differed between studies
Most studies did not contribute in answering relevant questions
about the impact of chemoimmunotherapy in the treatment of
metastatic melanoma The outcomes were not clearly described in
several of the studies (Atkins 2003 Del Vecchio 2003 Gorbonova
2000 Kirkwood 1990 Spieth 2003 Thomson 1993) Two of
them did not report survival rates evaluating only response rates
(Gorbonova 2000 Kirkwood 1990) All these aspects influenced
the comparability of the trials and must be considered in the data
interpretation
On the basis of a meta-analysis of data coming from eight studies
this review showed no evidence of a difference in overall survival to
support the addition of immunotherapy to chemotherapy in the
systemic treatment of metastatic melanoma (Atkins 2003 Danson
2003 Eton 2002 Falkson 1991 Johnston 1998 Ridolfi 2002
Spieth 2003 Young 2001) Evaluation of one two and five-year
survival with data from other studies again showed no survival
advantage of the drug combination treatment
We found higher clinical response rates in people treated with
chemoimmunotherapy in comparison with people treated with
chemotherapy which was not translated into survival benefit
Additionally we found higher toxicity rates in people treated
with chemoimmunotherapy Despite the importance of evaluat-
ing quality of life there was no available data to perform the meta-
analysis in this systematic review Only three studies reported data
about quality of life all with different methods One trial described
poorer quality of life in people treated with chemoimmunother-
apy related to more intense side effects (Ridolfi 2002) Two trials
however showed no difference between groups (Thomson 1993
Young 2001) It is important that quality of life is included in all
future studies
Our meta-analysis did not find differences between treatment re-
lated mortality Subgroup analysis comparing combinations with
interferon-alpha and with interferon-alpha plus interleukin-2 did
not show different results in survival or response rates
The use of chemoimmunotherapy ie a combination of chemo-
therapy with interferon-alpha or interleukin-2 or both has not
been shown to be beneficial in this review Although short term
response rates were better overall in the chemoimmunotherapy
groups survival was not improved and drug-related toxicities were
higher in the combined chemoimmunotherapy group To date no
treatment regimen has shown efficiency in prolonging survival in
people with metastatic melanoma Little has changed in the sys-
temic management of metastatic melanoma in the last few years
The standard of care remains single-agent DTIC and the role of
immunotherapy remains in doubt
The use of chemoimmunotherapy in the treatment of melanoma
is justified only in the context of clinical trials
A U T H O R S rsquo C O N C L U S I O N S
Implications for practice
We failed to find any evidence to support the view that the
use of chemoimmunotherapy prolongs survival in people with
metastatic melanoma when compared to chemotherapy alone Al-
though short-term clinical responses were higher in the chemoim-
munotherapy group this was associated with a higher rate of
serious adverse events esp haematological toxicity Our review
does not support the use of a combination of immunother-
apy and chemotherapy in chemoimmunotherapy regimens out-
side of clinical trials The standard of care for people with
advanced melanoma remains chemotherapy with single-agent
DTIC Chemoimmunotherapy must not be recommended to peo-
ple in daily practice
Implications for research
Research related to the development of more effective treatments
for people with metastatic melanoma is urgently needed
For people with an incurable disease the primary outcome needs
to be overall survival and all studies should include a quality of life
analysis
Future trials should be designed to define the best systemic treat-
ment and should use chemotherapy with (DTIC) as a standard
control group in order to permit comparisons to be made
A C K N O W L E D G E M E N T S
The authors wish to thank Raquel Gebara Lima for her kind
support in grammar and style
The editorial base would like to thank the following people who
were external referees for this review Keith Wheatley and Pat
Lawton (content experts) and Kathie Godfrey (consumer)
10Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
R E F E R E N C E S
References to studies included in this review
Atkins 2003 published data only
Atkins MB Lee S Flaherty LE Sosman JA Sondak VK
Kirkwood JM A prospective randomized phase III trial
of concurrent biochemotherapy (BCT) with cisplatin
vinblastine dacarbazine (CVD) IL-2 and interferon alpha-
2b (IFN) versus CVD alone in patients with metastatic
melanoma (E3695) An ECOG-coordinated intergroup
trial In ASCO Annual Meeting 2003 2003 p ASCO
Annual Meeting - Proceedings 2003Abstract 2847
Atzpodien 2002 published data only
Atzpodien J Neuber K Kamanabrou D Fluck M Brocker
EB Neumann C et alCombination chemotherapy with or
without sc IL-2 and IFN-alpha results of a prospectively
randomized trial of the Cooperative Advanced Malignant
Melanoma Chemoimmunotherapy Group (ACIMM)
British journal of cancer 200286(2)179ndash84
Bajetta 1994 published data only
Bajetta E Di Leo A Zampino MG Sertoli MR Comella
G Barduagni M et alMulticenter randomized trial of
dacarbazine alone or in combination with two different
doses and schedules of interferon alfa-2a in the treatment
of advanced melanoma Journal of clinical oncology official
journal of the American Society of Clinical Oncology 199412
(4)806ndash11
Danson 2003 published data only
Danson S Lorigan P Arance A Clamp A Ranson
M Hodgetts J et alRandomized phase II study of
temozolomide given every 8 hours or daily with either
interferon alfa-2b or thalidomide in metastatic malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 200321(13)2551ndash7
Del Vecchio 2003 published data only
Del Vecchio M Bajetta E Vitali M Gattinoni L Santinami
M Daponte A et alMulticenter phase III randomized trial
of cisplatin vindesine and dacarbazine (CVD) versus CVD
plus subcutaneous (sc) interleukin-2 (IL-2) and interferon-
alpha-2b (IFN) in metastatic melanoma patients (pts) In
ASCO Annual Meeting 2003 2003 p ASCO Annual
Meeting - Proceedings 2003Abstract 2849
Eton 2002 published data only
Eton O Legha SS Bedikian AY Lee JJ Buzaid AC
Hodges C et alSequential biochemotherapy versus
chemotherapy for metastatic melanoma results from a
phase III randomized trial Journal of clinical oncology
official journal of the American Society of Clinical Oncology
200220(8)2045ndash52
Falkson 1991 published data only
Falkson CI Falkson G Falkson HC Improved results with
the addition of interferon alfa-2b to dacarbazine in the
treatment of patients with metastatic malignant melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 19919(8)1403ndash8
Falkson 1998 published data only
Falkson CI Ibrahim J Kirkwood JM Coates AS Atkins
MB Blum RH Phase III trial of dacarbazine versus
dacarbazine with interferon alpha-2b versus dacarbazine
with tamoxifen versus dacarbazine with interferon alpha-
2b and tamoxifen in patients with metastatic malignant
melanoma an Eastern Cooperative Oncology Group study
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199816(5)1743ndash51
Gorbonova 2000 published data only
Gorbonova VA Egorov GN Perevodchikova NI Orel
NF Combined chemotherapy with or without interferon
alpha N1 (IFN) for advanced malignant melanoma - a
randomized pilot phase III study Gan To Kagaku Ryoho
200027 Suppl (2)310ndash4
Johnston 1998 published data only
Johnston SR Constenla DO Moore J Atkinson H ArsquoHern
RP Dadian G et alRandomized phase II trial of BCDT
[carmustine (BCNU) cisplatin dacarbazine (DTIC)
and tamoxifen] with or without interferon alpha (IFN-
alpha) and interleukin (IL-2) in patients with metastatic
melanoma British Journal of Cancer 199877(8)1280ndash6
Kirkwood 1990 published data only
Kirkwood JM Ernstoff MS Giuliano A Gams R Robinson
WA Costanzi J et alInterferon alpha-2a and dacarbazine
in melanoma Journal of the National Cancer Institute 1990
82(12)1062ndash3
Middleton 2000 published data only
Middleton MR Grob JJ Aaronson N Fierlbeck G
Tilgen W Seiter S et alRandomized phase III study of
temozolomide versus dacarbazine in the treatment of
patients with advanced metastatic malignant melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200018(1)158ndash66
Ridolfi 2002 published data only
Ridolfi R Chiarion-Sileni V Guida M Romanini A
Labianca R Freschi A et alCisplatin dacarbazine with
or without subcutaneous interleukin-2 and interferon
alpha-2b in advanced melanoma outpatients results from
an Italian multicenter phase III randomized clinical trial
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200220(6)1600ndash7
Rosenberg 1999 published data only
Rosenberg SA Yang JC Schwartzentruber DJ Hwu P
Marincola FM Topalian SL et alProspective randomized
trial of the treatment of patients with metastatic melanoma
using chemotherapy with cisplatin dacarbazine and
tamoxifen alone or in combination with interleukin-2 and
interferon alfa-2b Journal of Clinical Oncology 199917(3)
968ndash75
Spieth 2003 published data only
Spieth K Dummer R Garbe C Mauch C Schuler G
Landthaler M et alTemozolomide in combination with
11Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
interferon alfa versus temozolomide alone in patients with
advanced metastatic melanoma A randomized phase
III multicenter study of the Dermatologic Cooperative
Oncology Group (DeCOG) In ASCO Annual Meeting
2003Abstract 2887
Thomson 1993 published data only
Thomson DB Adena M McLeod GR Hersey P Gill PG
Coates AS et alInterferon-alpha 2a does not improve
response or survival when combined with dacarbazine
in metastatic malignant melanoma results of a multi-
institutional Australian randomized trial Melanoma
Research 19933(2)133ndash8
Vorobiof 1994 published data only
Vorobiof DA Bezwoda WR A randomised trial of vindesine
plus interferon-alpha 2b compared with interferon-alpha 2b
or vindesine alone in the treatment of advanced malignant
melanoma European journal of cancer (Oxford England
1990) 199430A(6)797ndash800
Young 2001 published data only
Young AM Marsden J Goodman A Burton A Dunn
JA Prospective randomized comparison of dacarbazine
(DTIC) versus DTIC plus interferon-alpha (IFN-alpha) in
metastatic melanoma Clinical oncology (Royal College of
Radiologists (Great Britain)) 200113(6)458ndash65
References to studies excluded from this review
Bajetta 2001 published data only
Bajetta E Del Vecchio M Vitali M Martinetti A Ferrari L
Queirolo P et alA feasibility study using polychemotherapy
(cisplatin + vindesine + dacarbazine) plus interferon-alpha
or monochemotherapy with dacarbazine plus interferon-
alpha in metastatic melanoma Tumori 200187(4)219ndash22
Legha 1996 published data only
Legha SS Ring S Bedikian A Plager C Eton O Buzaid
AC et alTreatment of metastatic melanoma with combined
chemotherapy containing cisplatin vinblastine and
dacarbazine (CVD) and biotherapy using interleukin-2 and
interferon-alpha Annals of oncology official journal of the
European Society for Medical Oncology ESMO 19967(8)
827ndash35
Richtig 2004 published data only
Richtig E Hofmann-Wellenhof R Pehamberger H
Forstinger C Wolff K Mischer P et alTemozolomide and
interferon alpha 2b in metastatic melanoma stage IV British
Journal of Dermatology 2004151(1)91ndash8
Sertoli 1999 published data only
Sertoli MR Queirolo P Bajetta E DelVecchio M
Comella G Barduagni L et alMulti-institutional phase
II randomized trial of integrated therapy with cisplatin
dacarbazine vindesine subcutaneous interleukin-2
interferon alpha2a and tamoxifen in metastatic melanoma
BREMIM (Biological Response Modifiers in Melanoma)
Melanoma research 19999(5)503ndash9
Sparano 1993 published data only
Sparano JA Fisher RI Sunderland M Margolin K Ernest
ML Sznol M et alRandomized phase III trial of treatment
with high-dose interleukin-2 either alone or in combination
with interferon alfa-2a in patients with advanced melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199311(10)1969ndash77
Vuoristo 2005 published data only
Vuoristo MS Hahka-Kemppinen M Parvinen LM
Pyrhonen S Seppa H Korpela M et alRandomized trial of
dacarbazine versus bleomycin vincristine lomustine and
dacarbazine (BOLD) chemotherapy combined with natural
or recombinant interferon-alpha in patients with advanced
melanoma Melanoma research 200515(4)291ndash6
Additional references
Arance 2000
Arance A Middleton M Lorigan P Thatcher N Three-
arm phase II study of temozolomide (TMZ) in metastatic
melanoma (MM) In ASCO Annual Meeting 2000
Abstract 2257
Bafaloukos 2002
Bafaloukos D Aravantinos G Fountzilas G Stathopoulos
G Gogas H Samonis G et alDocetaxel in combination
with dacarbazine in patients with advanced melanoma
Oncology 200263(4)333ndash7
Bajetta 2002
Bajetta E Del Vecchio M Bernard-Marty C Vitali
M Buzzoni R Rixe O et alMetastatic melanoma
chemotherapy Seminars in Oncology 200229(5)427ndash45
Balch 2001
Balch CM Soong SJ Gershenwald JE Thompson JF
Reintgen DS Cascinelli N et alPrognostic factors analysis
of 17600 melanoma patients validation of the American
Joint Committee on Cancer melanoma staging system
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200119(16)3622ndash34
Barth 1995
Barth A Morton DL The role of adjuvant therapy in
melanoma management Cancer 199575 Suppl (2)
726ndash34
Chiarion-Sileni 2003
Chiarion-Sileni V Del Bianco P De Salvo GL Lo Re G
Romanini A Labianca R et alQuality of life evaluation in a
randomised trial of chemotherapy versus bio-chemotherapy
in advanced melanoma patients European journal of cancer
(Oxford England 1990) 200339(11)1577ndash85
Creagan 1984
Creagan ET Ahmann DL Green SJ Long HJ Frytak S
OrsquoFallon JR et alPhase II study of low-dose recombinant
leukocyte A interferon in disseminated malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 19842(9)1002ndash5
Crosby 2000
Crosby T Fish R Coles B Mason MD Systemic treatments
for metastatic cutaneous melanoma Cochrane Database
of Systematic Reviews 2000 Issue 2 [DOI 101002
14651858CD001215]
12Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Cure 1999
Cure H Souteyrand P Ouabdesselam R Roche H
Ravaud A DrsquoIncan M et alResults of a phase II trial
with cystemustine at 90 mgm(2) as a first- or second-line
treatment in advanced malignant melanoma a trial of the
EORTC Clinical Studies Group Melanoma Research 1999
9(6)607ndash10
Danson 2002
Danson S Arance A Lorigan P Clamp A Hodgetts J
Lomax L Thatcher N Middleton MR A randomized
study of temozolomide (TMZ) alone with interferon-
alpha (TMZ-IFN) or with thalidomide (TMZ-THAL) in
metastatic malignant melanoma (MMM) ASCO Annual
Meeting - Proceedings 2002Abstract 1369
Dorval 1986
Dorval T Palangie T Jouve M Garcia-Giralt E Israel L
Falcoff E et alClinical phase II trial of recombinant DNA
interferon (interferon alpha 2b) in patients with metastatic
malignant melanoma Cancer 198658(2)215ndash8
Dutcher 1989
Dutcher JP Creekmore S Weiss GR Margolin K
Markowitz AB Roper M et alA phase II study of
interleukin-2 and lymphokine-activated killer cells in
patients with metastatic malignant melanoma Journal of
clinical oncology official journal of the American Society of
Clinical Oncology 19897(4)477ndash85
Falkson 1995
Falkson CI Experience with interferon alpha 2b combined
with dacarbazine in the treatment of metastatic malignant
melanoma Medical oncology (Northwood London England)
199512(1)35ndash40
Garbe 1990
Garbe C Krasagakis K Zouboulis CC Schroder K Kruger
S Stadler R et alAntitumor activities of interferon alpha
beta and gamma and their combinations on human
melanoma cells in vitro changes of proliferation melanin
synthesis and immunophenotype Journal of Investigative
Dermatology 199095 Suppl (6)231ndash7
Gershenwald 1999
Gershenwald JE Thompson W Mansfield PF Lee JE
Colome MI Tseng CH et alMulti-institutional melanoma
lymphatic mapping experience the prognostic value of
sentinel lymph node status in 612 stage I or II melanoma
patients Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199917(3)976ndash83
Hanninen 1991
Hanninen EL Korfer A Hadam M Schneekloth C
Dallmann I Menzel T et alBiological monitoring of
low-dose interleukin 2 in humans soluble interleukin 2
receptors cytokines and cell surface phenotypes Cancer
Research 199151(23 Pt 1)6312ndash6
Huncharek 2001
Huncharek M Caubet JF McGarry R Single-agent
DTIC versus combination chemotherapy with or without
immunotherapy in metastatic melanoma a meta-analysis
of 3273 patients from 20 randomized trials Melanoma
Research 200111(1)75ndash81
Juni 2001
Juni P Altman DG Egger M Assessing the quality of
controlled clinical trials BMJ 200132342ndash6
Kadison 2003
Kadison AS Morton DL Immunotherapy of malignant
melanoma The Surgical Clinics of North America 200383
(2)343ndash70
Keilholz 2002
Keilholz U Gore ME Biochemotherapy for advanced
melanoma Seminars in Oncology 200229(5)456ndash61
Khayat 2002
Khayat D Bernard-Marty C Meric JB Rixe O
Biochemotherapy for advanced melanoma maybe it is real
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200220(10)2411ndash4
Koh 1991
Koh HK Cutaneous melanoma New England Journal of
Medicine 1991325(3)171ndash82
La Vecchia 1999
La Vecchia C Lucchini F Negri E Levi F Recent declines
in worldwide mortality from cutaneous melanoma in youth
and middle age International Journal of Cancer 199981(1)
62ndash6
Lee 2000
Lee ML Tomsu K Von Eschen KB Duration of survival
for disseminated malignant melanoma results of a meta-
analysis Melanoma Research 200010(1)81ndash92
Legha 1998
Legha SS Ring S Eton O Bedikian A Buzaid AC Plager
C et alDevelopment of a biochemotherapy regimen
with concurrent administration of cisplatin vinblastine
dacarbazine interferon alfa and interleukin-2 for patients
with metastatic melanoma Journal of clinical oncology
official journal of the American Society of Clinical Oncology
199816(5)1752ndash9
Leong 2003
Leong SP Future perspectives on malignant melanoma
Surgical Clinics of North America 200383(2)453ndash6
Lokich 1979
Lokich JJ Garnick MB Legg M Intralesional immune
therapy methanol extraction residue of BCG or purified
protein derivative Oncology 197936(5)236ndash41
Nathan 1998
Nathan FE Mastrangelo MJ Systemic therapy in
melanoma Seminars in Surgical Oncology 199814(4)
319ndash27
Osborn 1977
Osborn DE Castro JE Immunological response in patients
receiving Corynebacterium parvum therapy Clinical
Oncology 19773(2)155ndash64
13Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Parmar 1998
Parmar MKB TV Stewart L Extracting summary statistics
to perform meta-analyses of the published literature for
survival endpoints Statistics in Medicine 1998172815ndash34
Richards 1992
Richards JM Mehta N Ramming K Skosey P Sequential
chemoimmunotherapy in the treatment of metastatic
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199210(8)1338ndash43
Rigel 1989
Rigel DS Rivers JK Kopf AW Friedman RJ Vinokur AF
Heilman ER et alDysplastic nevi Markers for increased
risk for melanoma Cancer 198963(2)386ndash9
Rosenberg 1989
Rosenberg SA Lotze MT Yang JC Aebersold PM Linehan
WM Seipp CA et alExperience with the use of high-
dose interleukin-2 in the treatment of 652 cancer patients
Annals of Surgery 1989210(4)474-84 discussion 484-5
Sertoli 1989
Sertoli MR Bernengo MG Ardizzoni A Brunetti I Falcone
A Vidili MG et alPhase II trial of recombinant alpha-2b
interferon in the treatment of metastatic skin melanoma
Oncology 198946(2)96ndash8
Smith 1993
Smith KA Lowest dose interleukin-2 immunotherapy
Blood 199381(6)1414ndash23
Stopeck 2001
Stopeck AT Jones A Hersh EM Thompson JA
Finucane DM Gutheil JC et alPhase II study of direct
intralesional gene transfer of allovectin-7 an HLA-B7
beta2-microglobulin DNA-liposome complex in patients
with metastatic melanoma Clinical Cancer Research 20017
(8)2285ndash91
Tsang 1983
Tsang KY Fudenberg HH Pan JF Gnagy MJ Bristow
CB An in vitro study on the effects of isoprinosine on
immune responses in cancer patients International Journal
of Immunopharmacology 19835(6)481ndash90
Wingo 1995
Wingo PA Tong T Bolden S Cancer statistics 1995 CA
a cancer journal for clinicians 199545(1)8ndash30
Yusuf 1985
Yusuf S Peto R Lewis J Collins R Sleight P Beta blockade
during and after myocardial infarction an overview of the
randomized trials Progress in Cardiovascular Diseases 1985
27(5)335ndash71lowast Indicates the major publication for the study
14Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Atkins 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding public
Participants PS lt= 1
Brain mets no info
Age 20 to 80 (median 50)
Number of cycles no info
Randomised 416 a 206 b 210
Evaluable 405 a 201 b 204
Interventions a (CT) cisplatin 20mgm2 D1 to 4 vinblastin 12 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1-4 vimblastin 12 mgm2 D1-4 DTIC 800 mgm2 D1
IFN-alpha 5 mIU D1-5 D8 D10 D12 IL-2 9 mIU D1-4
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
Notes Multicentric yes
Withdrawals a five b six
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
15Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Atzpodien 2002
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding both (pharmaceutic and public)
Participants PS lt= 1
Brain mets yes Age 28 to 77 (median 57)
Number of cycles no info
Randomised 124 a 60 b 64
Evaluable 124 a 60 b 64
Interventions a (CT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily
b (ICT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily IFN-alpha 5 mIUm2 D1 week4 and 5
mIUm2 D1 D3 D5 week 5 IL-2 10 mIUm2 D1 D3 D5
(each five weeks)
Outcomes 1 Response rates
2 Overall survival
3 Progression free survival
Notes Multicentric yes
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Bajetta 1994
Methods D parallel group (three groups)
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding pharmaceutic
Participants PS lt= 2
Brain mets no
16Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Bajetta 1994 (Continued)
Age 18 to 70 (median 53)
Number of cycles 8
Randomised 266 a 88 b 86 c 92
Evaluable 242 a 82 b 76 c 84
Interventions a (CT) DTIC 800 mgm2 D1
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU 3xweek
c (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU D1 to 3 6 mIU D4 to 6 9 mIU daily
(each 21 days)
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Overall survival
Notes Multicentric yes
Withdrawals a six b ten c eight
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Danson 2003
Methods D parallel group
AC independent allocation
RS permuted blocks
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets yes Age 16 to 88 (median 58)
Number of cycles six
Randomised 125 a 59 b 62
Evaluable 121 a 55 b 62
Interventions a (CT) temozolomide 200 mgm2 88 h (5 doses)
b (ICT) Temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIU 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
17Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Danson 2003 (Continued)
Notes Multicentric no
Withdrawals a 4 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Del Vecchio 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no Age 19 to 70 (median 50)
Number of cycles no info
Randomised 151 a 75 b 76
Evaluable 145 a 72 b 73
Interventions a (CT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250 mgm2 D1 to
3
b (ICT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250m gm2 D1 to
3 IFN-alpha 5 mIUm2 D1 to 5 IL-2 9 mIUday x 5 daysweek x 2 weeks with a week of
rest
(each 21 days)
Outcomes 1 Response rates
2 Time to Progression
2 Overall Survival
Notes Multicentric yes
Withdrawals a three b three
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
18Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Eton 2002
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding pharm
Participants PS lt= 3
Brain mets yes Age median 49
Number of cycles no info
Randomised 190
Evaluable 183 a 92 b 91
Interventions a (CT) cisplatin 20m gm2 D1 to 4 vimblastin 2 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1 to 4 vinblastin 15 mgm2 D1 to 4 DTIC 800 mgm2
D1 IFN-alpha 5mIUm2 D5 to 9 D17-21 IL-2 9 mIUm2 D5 to 8 D17 to 20
(each 21 days)
Outcomes 1 Response rates
2 Time to progression
3 Overall survival
Notes Multicentric no
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1991
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size no
ITT no
Placebo no
Funding both
Participants PS lt= 1
Brain mets no
Age 22 to 79
(median 57)
Number of cycles at least two
19Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1991 (Continued)
Randomised 73 Evaluable 68 a 34 b 34
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Time to treatment failure
3 Median survival
4 Toxicity
Notes Multicentric no
Withdrawals a three b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1998
Methods D 2 x 2 factorial design
AC independent allocation
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 18 to 84
Number of cycles no info
Randomised 271 Evaluable 263 a 68 b 65 c 63 d 67
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
c (CT) DTIC 200m gm2 D1 to 5 tamoxifen 20 mgdaily
d (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek tamoxifen 20 mgdaily
(each 28 days)
Outcomes 1 Response rates
2 Toxicity rates
20Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1998 (Continued)
3 Overall survival
4 Time to treatment failure
Notes Multicentric yes
Withdrawals a one b three c three d one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Gorbonova 2000
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no
Age 23 to 75
Number of cycles no info
Randomised 30 Evaluable 28 a 14 b 14
Interventions a (CT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2
b (ICT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2 IFN-alpha 3 mIU D5 7
9 11 13 15 17 19
(each 28 days)
Outcomes 1 Response rates
Notes Multicentric no
Withdrawals a two b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
21Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Johnston 1998
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age 18 to 70
(median 45)
Number of cycles no info
Randomised 65 Evaluable 65 a 30 b 35
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to 3
Tamoxifen 40 mg daily
b (ICT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to
3 Tamoxifen 40 mg daily IFN-alpha 9 mIU D1 to 3 IL-2 18 mIU D-2 IL-2 9 mIU D-
1 and 0
(each 28 days)
Outcomes 1 Response rates
2 Time to disease progression
3 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Kirkwood 1990
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding pharm
22Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Kirkwood 1990 (Continued)
Participants PS no info
Brain mets no info
Age no info
Number of cycles no info
Randomised 74 Evaluable 68 a 24 b 23 c 21
Interventions a (CT) DTIC 250 mgm2 D1 to 5 (each 21 days)
b (I) IFN-alpha 3 mIU d1 to 5 every week for 3 weeks than 3 mIUm2 3 xweek
c (ICT) DTIC 250 mgm2 D1 to 5 (each 21 days) IFN-alpha 3 mIU d1 to 5 every week
for 3 weeks than 3 mIUm2 3 xweek
Outcomes 1 Response rates
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Middleton 2000
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets no
Age 24 to 71
(median 51)
Number of cycles six
Randomised 105 Evaluable 96 a 46 b 50
Interventions a (CT) DTIC 800 mgm2 D1 cisplatin 25 mgm2 D1 to 3 BCNU 150 mgm2 D1
tamoxifen 20 mgdaily
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 9 mIU 3 xweek
(each 21 days)
Outcomes 1 Response rates
2 One year survival
3 Median survival
23Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Middleton 2000 (Continued)
4 Toxicity
4 Time spent in hospital
Notes Multicentric no
Withdrawals a seven b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Ridolfi 2002
Methods D parallel group
AC independent allocation by telephone
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 25 to 77
Number of cycles six
Randomised 178 Evaluable 176 a 89 b 87
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1
b (ICT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1 IFN-
alpha 3 mIU 3 xweek IL-2 45 mIU D3 to 5 D8 to 12
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
3 Time to progression
4 Toxicity
Notes Multicentric yes
Withdrawals a one b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
24Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
whole group of lymph nodes responsible for draining a partic-
ular area of the body) but several large randomised controlled
trials have shown no improvement in survival using this tech-
nique Currently sentinel lymph node mapping and directed se-
lective lymphadenectomy (ie only removing those nodes that
show up as positive using the sentinel node imaging technique) has
been shown to identify lymph node metastases more precisely and
with less surgical morbidity than elective dissection (Gershenwald
1999)
Causes
Although the cause of melanoma is unknown major risk factors
have been identified (Koh 1991) Epidemiological studies suggest
that sunlight (ultraviolet radiation) is the most common environ-
mental factor Pale skin a tendency to sunburn fair or red hair
large numbers of melanocytic nevi (moles) and multiple dysplastic
nevi (atypical moles) have been shown to be independent risk fac-
tors for the development of melanoma Fair skin that does not tan
easily in combination with high sun exposure provides the largest
cumulative risk factor for melanoma development (Rigel 1989)
Impact
Malignant melanoma that has spread to distant sites by dissemi-
nation is associated with extremely poor survival median survival
is approximately 8 months and less than 5 of such people will
survive for more than 5 years (Lee 2000)
There are large prospective randomised multicenter trials that
have answered some basic management questions improved the
care of melanoma sufferers and expanded our understanding of
the disease However many aspects of treatment such as the thera-
peutic role of cytotoxic chemotherapy and biologic therapy alone
or in combination remain controversial and inconclusive (Crosby
2000 Leong 2003)
Description of the intervention
Systemic therapy
This has little or no impact on survival for advanced disease
There is no evidence derived from randomised controlled trials to
show superiority of systemic therapy over supportive care (Crosby
2000) The minority of people with metastatic melanoma who do
respond to systemic treatment have remissions which are generally
of short duration (Nathan 1998) Few agents have demonstrated
substantial anti-tumor activity against metastatic melanoma The
alkylating agent dacarbazine (DTIC) is considered to be the most
active drug for the treatment of this disease with a response rate of
20 and a median duration of response of 4 to 5 months (Khayat
2002 Nathan 1998) Other cytotoxic compounds such as temo-
zolomide (a dacarbazine analogue) (Middleton 2000) cisplatin
and carboplatin (Bajetta 2002) vinca alkaloids (Khayat 2002)
taxanes (Bafaloukos 2002) and nitrosoureas (Cure 1999) have not
improved these results All of these treatments are associated with
response rates of less than 15 and all are associated with signif-
icant adverse effects (Bafaloukos 2002 Bajetta 2002 Cure 1999
Khayat 2002 Middleton 2000)
Combination chemotherapy
The role of combination chemotherapy in advanced disease re-
mains unclear Prospective randomised studies have failed to
demonstrate any significant benefit for combination chemother-
apy when compared with single agents except for a slight increase
in response rates (Huncharek 2001)
Experimental treatments
Experimental treatments such as vaccines antibody treatments
and gene therapy are being developed and are of high scientific
interest However their efficacy in advanced melanoma has so
far been very limited with overall response rates of less than 5
(Keilholz 2002 Stopeck 2001) Since the 1970s immunostim-
ulating agents such as Bacillus Calmette-Guerin (BCG) (Lokich
1979 Osborn 1977) Corynebacterium parvum (Osborn 1977)
or isoprinosine (Tsang 1983) have been evaluated as local or sys-
temic treatments After some early hopes all these treatments have
also failed to demonstrate a significant and consistent effect in the
clinical management of advanced melanoma (Khayat 2002)
Immunotherapy
Two points have driven the attention of researchers in the im-
munology field to melanoma Firstly the spontaneous regression
of melanoma (ie the tumor occasionally appears to go away in
some people) Spontaneous regression is much more frequent than
in melanoma than with any other solid tumor and it is associated
with a specific cellular immune response (Kadison 2003) Sec-
ondly the fact that some people with melanoma also have tumor
rejection antigen recognized by CD4 and CD8 T cells (immune
cells that can help get rid of cancer cells) (Kadison 2003)
At least two types of immunotherapy have been used in advanced
melanoma interferon-alpha and interleukin-2
Interferon-alpha (IFN-α) belongs to a group of proteins known
to have antiproliferative and antitumor effects (Garbe 1990) In
addition IFN-α exhibits certain immunomodulatory effects - it
upregulates the expression of major histocompatibility complex
(MHC) class I antigens in melanoma cells and also the expres-
sion of co-stimulatory molecules rendering the cells more suscep-
tible to immunological defense mechanisms (Barth 1995) Phase
II studies of IFN-α as a single agent have demonstrated response
rates of approximately 20 with a slightly more durable response
3Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
than the one found with dacarbazine (DTIC) (Creagan 1984
Dorval 1986 Sertoli 1989)
Interleukin-2 (IL-2) is a major growth factor for lymphoid cells
including T cells and natural killer (NK) cells (Hanninen 1991
Smith 1993) Clinical trials have demonstrated modest anti-tumor
activity in people with metastatic melanoma (Rosenberg 1989)
responses were seen in approximately 15 of people with a
small proportion of complete responses (Dutcher 1989 Rosenberg
1989)
Chemoimmunotherapy
As chemotherapy and immunotherapy have different and per-
haps synergistic mechanisms of action their combination of im-
munotherapy with chemotherapy (chemoimmunotherapy) has
been studied since the early 1990s (Khayat 2002) Some reports
have suggested that chemotherapeutic agents administered in com-
bination with IL-2 or IFN or both can improve response rates
(Legha 1998 Richards 1992) with complete response rates in 10
to 20 of people as well as increases in median survival (Falkson
1991) Based on these results the use of chemoimmunotherapy is
currently preferred in some institutions as a first-line treatment in
advanced (stage IV) melanoma (Kadison 2003 Keilholz 2002)
although it is still considered an experimental therapy by oth-
ers(Crosby 2000)
Why it is important to do this review
There are substantial controversies about the real benefit of
chemoimmunotherapy some studies conclude that the combi-
nation of treatments did not improve survival (Rosenberg 1999
Young 2001) or even response rates (Falkson 1998 Gorbonova
2000 Johnston 1998 Thomson 1993) in people with metastatic
melanoma There is also concern that combined therapy may in-
crease treatment-related toxicity (Falkson 1998 Johnston 1998)
The lack of conclusive data coming from seemingly conflict-
ing studies about the impact of treatment demands a systematic
review This will provide the most reliable assessment for sup-
porting clinical decision-making with people who have advanced
melanoma
O B J E C T I V E S
To compare the effects of chemotherapy alone versus combined
therapy with chemotherapy and immunotherapy (chemoim-
munotherapy) in people with metastatic malignant melanoma
M E T H O D S
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs)
Types of participants
People of any age diagnosed with metastatic malignant melanoma
that has spread to distant sites by systemic dissemination
Types of interventions
1 Chemotherapy
2 Chemoimmunotherapy ie the combination of
chemotherapy and immunotherapy with interferon-alpha or
interleukin-2 or both
Types of outcome measures
Primary outcomes
Overall survival - number of participants alive at the end of the
trial
Secondary outcomes
1 One two and five-year survival rates - proportion of
participants alive at one two and five year follow-up
2 Response rates (partial and complete) - proportion of
participants that have achieved partial or complete responses as
defined by the trial authors
3 Progression-free survival - number of participants without
progression of disease at the end of the trial
4 Treatment morbidity (treatment-related toxicity) -
proportion of participants that have developed hematological or
non-hematological toxicities
5 Treatment related mortality - proportion of participants
that have died due to the treatment This outcome was not
described previously in the protocol and was added after
discussion between the reviewers that considered it relevant
Mortality related to treatment is a great concern in oncology
when comparing treatments with potential differences in toxicity
6 Quality of life measures
Search methods for identification of studies
We searched electronic databases and other resources to locate
reports of studies No language restrictions were imposed
4Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Electronic searches
Electronic databases
We searched the following electronic databases
1 MEDLINE (OVID) (Appendix 1)
2 The Cochrane Skin Group Specialised Register
3 The Cochrane Central Register of Controlled Trials
4 Medline (PubMed)
5 EMBASE
6 LILACS (Latin American and Caribbean Health Science
Information Database)
Search strategies for databases 2 to 6 are located in Appendix 2
Search of databases of ongoing trials (unpublished literature)
We asked trial authors and pharmaceutical companies about un-
published and ongoing trials Databases of major research groups
and registers of trials in the following databases were also searched
with the term rsquoMELANOMArsquo
bull Current Controlled Trials Register (httpwwwcontrolled-
trialscom) on 30th January 2006
bull European Organisation for Research and Treatment of
Cancer (httpwwweortcbe) on 20th February 2006
bull National Cancer Institute America (http
wwwcancergovclinicaltrials) on 16th November 2005
bull National Cancer Institute Canada (httphttp
wwwctgqueensucapublicClinical_Trialsclinical_trialshtml)
on 30th January 2006
bull Australian Clinical Trials Registry (httpwwwactrorgau)
on 30th January 2006
bull US Food and Drug Administration (httpwwwfdagov)
on 30th January 2006
bull ClinicalTrialsgov (httpwwwclinicaltrialsgov) on 16th
November 2005
Searching other resources
References from unpublished studies
All bibliographies of selected studies were scanned for possible
references to RCTs
Conference proceedings
We handsearched the abstracts from conference proceedings of
the ASCO (American Society of Clinical Oncology) and ESMO
(European Society of Medical Oncology)
Data collection and analysis
Where there was uncertainty we tried to contact trial authors for
clarification
A consumer (LU) was involved throughout the review process to
ensure the readability of the final review Updating will be done
every two years
Selection of studies
Two authors (ADS and ECS) checked the titles and abstracts iden-
tified from the searches If it was clear that the study did not refer
to a RCT on metastatic melanoma we excluded it Two authors
(ADS and OAC) independently assessed each remaining study to
determine whether it met the pre-defined selection criteria Any
differences were resolved through discussion with the review team
Excluded studies are listed in the Table of Excluded Studies
Data extraction and management
Two authors (ADS and ECS) independently extracted the data
from the studies All data were extracted directly from the text or
calculated according to the available information
Any differences were resolved by discussion with one author
(OAC) A data extraction form was developed and piloted in order
to summarize the trials One author (ADS) checked and entered
the data Two authors (ECS and LGC) independently checked the
data entry
Assessment of risk of bias in included studies
Assessment of methodological quality
The quality assessment included an evaluation of the following
components for each included study since there is some evidence
that these are associated with biased estimates of treatment effect
(Juni 2001)
(a) the method of generation of the randomisation sequence
(b) the method of allocation concealment - it was considered rsquoad-
equatersquo if the assignment could not be foreseen
(c) who was blindednot blinded (participants clinicians outcome
assessors)
(d) how many participants were lost to follow up in each arm and
whether participants were analysed in the groups to which they
were originally randomised (intention-to-treat)
In addition the quality assessment also included
(e) the source of funding
(f ) if the participant had a biopsy proven melanoma
(g) the baseline assessment of the participants for presence of liver
and brain metastases performance status
(h) whether the aims interventions (including drug doses and
duration of treatment) and outcome measures were clearly defined
5Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(i) the use and appropriateness of statistical analyses
We recorded all the information in a table of quality criteria and
gave a description of the quality of each study based on these
characteristics
Measures of treatment effect
Where possible we performed a meta-analysis for the outcomes
in order to calculate a weighted treatment effect across trials using
a random-effects model For binary endpoints we calculated the
risk ratio (RR) with 95 confidence intervals (Yusuf 1985) We
also expressed the results as a number needed to treat (NNT)
where appropriate for a range of plausible control event rates For
overall survival a time-to-event data we calculated the Hazard
Ratio (HR) When data were not available for direct extraction
we calculated indirectly (from different parameters using indirect
calculation of the variance and the number of observed minus
expected events) according to the method described by Parmar
(Parmar 1998) In the funnel plot (Figure 1) and comparison 1
rsquoPeto OR (IPD)rsquo is a Hazard Ratio For continuous data such as
quality of life we planned to use standardised mean differences
with 95 confidence intervals would have been used
Figure 1 Funnel plot using overall survival as the outcome
Assessment of heterogeneity
Heterogeneity was assessed using I2 Where the heterogeneity was
considerable (I2 gt 50) we explored possible reasons using the
type (interleukin-2 or interferon) and dose (high or low) of im-
munotherapy used as subgroups Where we were not able to find
an explanation we have recorded this along with appropriate cau-
tion in the interpretation of these data
Data synthesis
Analysis and presentation
Once studies had been selected critically appraised and the data
extracted we entered the data in the Characteristics of included
studies table
6Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Three studies (Bajetta 1994 Kirkwood 1990 Vorobiof 1994) eval-
uated three arms of treatment with one of them evaluating che-
motherapy alone and the two others using chemoimmunotherapy
One study (Falkson 1998) had four arms two using chemotherapy
and two using chemoimmunotherapy The data from the similar
arms were grouped considered as one and then compared to the
other arm
R E S U L T S
Description of studies
Results of the search
We scanned approximately 700 citations Initially 28 studies
were identified Four studies (Arance 2000 Chiarion-Sileni 2003
Danson 2002 Falkson 1995) had data that overlapped with three
included studies (Danson 2003 Falkson 1991 Ridolfi 2002)
Ongoing studies
No ongoing studies were available to be included in the meta-
analysis
Included studies
Eighteen studies with a total of 2625 participants met our criteria
and were included in the meta-analysis (please see Characteristics
of included studies) One study differed considerably from the oth-
ers because vindesine was used as the chemotherapy control a drug
without evidence of response in metastatic melanoma (Vorobiof
1994) Another study differed considerably as lower dose treat-
ment in the chemoimmunotherapy group was used (Middleton
2000) The first study was published in 1990 and the last studies
were published in 2003
Participants
The participants were between the ages of 16 and 88 years and
had an Eastern Cooperative Oncology Group performance status
from 0 to 3 Only three studies included participants with brain
metastasis (Atzpodien 2002 Danson 2003 Eton 2002)
Interventions
Seven studies compared chemotherapy to chemoimmunotherapy
with IFN plus IL-2 (Atkins 2003 Atzpodien 2002 Del Vecchio
2003 Eton 2002 Johnston 1998 Ridolfi 2002 Rosenberg 1999)
Eleven compared chemotherapy to chemoimmunotherapy with
IFN (Bajetta 1994 Danson 2003 Falkson 1991 Falkson 1998
Gorbonova 2000 Kirkwood 1990 Middleton 2000 Spieth 2003
Thomson 1993 Vorobiof 1994 Young 2001)
The drugs used in chemotherapeutic schemes varied between the
trials Seven trials evaluated DTIC combined with other drugs in
both arms (Atkins 2003 Atzpodien 2002 Del Vecchio 2003 Eton
2002 Johnston 1998 Ridolfi 2002 Rosenberg 1999) and six
evaluated DTIC alone as the control (Bajetta 1994 Falkson 1991
Falkson 1998 Kirkwood 1990 Thomson 1993 Young 2001)
Four studies evaluated other schemes without DTIC two trials
used temozolomide (Danson 2003 Spieth 2003) one trial used
vindesine (Vorobiof 1994) and one trial used combined drugs
based on cisplatin (Gorbonova 2000)
Only one study did not use the same scheme in both the arms
using combined drugs with DTIC as the chemotherapy control
and a lower dose for the chemoimmunotherapy group with DTIC
alone (Middleton 2000)
Setting
Ten studies were carried out in Europe four in the United States
two in South Africa and one was a multicentre worldwide trial
All trials were reported in the English language
Outcomes
Response rates were the primary outcome measures in most trials
and were described in all included studies Two studies did not
evaluate survival rates (Gorbonova 2000 Kirkwood 1990) Three
studies included quality of life analyses in the outcomes (Ridolfi
2002 Thomson 1993 Young 2001) The length of the follow-up
varied widely between the trials and sometimes it was not speci-
fied We did not find a reasonable definition about what could be
considered high or low doses of immunotherapy and the influence
of the immunotherapeutic doses on the outcomes could not be
assessed
Excluded studies
Six studies were excluded (see Characteristics of excluded studies)
The reasons for exclusion were that the study had immunotherapy
on both arms (Bajetta 2001 Richtig 2004 Sertoli 1999 Sparano
1993 Vuoristo 2005) or the study was not randomised (Legha
1996)
Risk of bias in included studies
The quality assessment consisted of a basic methodological eval-
uation of each included study and is shown in Table 1 Addi-
tional quality assessment is shown in Table 2 The criteria used for
methodological quality analysis of the studies are listed in Table 3
(Explanation of Quality Analysis Headings)
7Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Although blinding participants and clinicians is theoretically pos-
sible it is difficult to plan a double-blind study with immunother-
apy This is due to the substantial acute and late toxicities associ-
ated with immunotherapy in one group No study was described
as double-blinded The groups at baseline were in general similar
with a description of most prognostic factors related to metastatic
melanoma (gender performance status age prior therapy liver
metastasis)
In three studies almost all methodological aspects of the trials
were described poorly (Gorbonova 2000 Kirkwood 1990 Spieth
2003)
Allocation
All the included studies were described as randomised as this
was a selection criterion However most papers did not describe
the method of randomisation The method of generation of the
randomised sequence was described and considered adequate in
only 6 out of 18 studies Eleven of 18 studies provided information
on allocation concealment all of which were considered adequate
Blinding
Blinding of outcome assessment and detection bias
We did not find information about blinding of the outcome as-
sessors in any included study
Incomplete outcome data
Handling of losses and attrition bias
In general there were few participants lost to follow up in the
studies The highest number of people lost was 24 in a total of 262
participants (Bajetta 1994) Eleven studies included an intention-
to-treat analysis
Effects of interventions
Primary outcome
Overall survival (eight studies)
This was considered as the number of participants alive at the end
of the trial Sufficient data were available from 8 of the 18 studies
There was no statistically significant difference in survival between
chemoimmunotherapy and chemotherapy with a hazard ratio
(HR) of improved survival of 089 (95 CI 072 to 111 P = 031
Analysis 11) in favour of chemoimmunotherapy In other words
overall survival was slightly lower in the chemoimmunotherapy
group but this was not statistically significant There was no het-
erogeneity across trials (I2 = 0) The funnel plot method using
overall survival as the outcome is presented in Figure 1 It shows
that there was no evidence of substantial publication bias but in-
terpretation of the funnel plot is likely to be unreliable since only
eight relatively large studies were found
When we evaluated the influence of the type of immunotherapy
used in the chemoimmunotherapy group (IL-2 plus IFN-alpha
or IFN-alpha only) we found no statistically significant difference
between the groups with a HR of 096 (95 CI 074 to 124 P =
076 Analysis 11) for chemoimmunotherapy with IL-2 plus IFN-
alpha and a HR of 074 (95 CI 049 to 112 P = 015 Analysis
11) for chemoimmunotherapy associated with only IFN-alpha
Secondary outcomes
One two and five-year survival rates (13 studies)
The number of participants alive at one two and five year follow-
ups were analyzed Data from 13 trials evaluating one year survival
were pooled There was no statistically significant difference in one
year survival between the groups with a risk ratio (RR) of 106
(95 CI 091 to 124 P = 048 Analysis 12) and no significant
heterogeneity across trials (I2 = 363)
Data from 11 trials evaluating 2 year survival were extracted and
pooled Again there was no statistically significant difference be-
tween the groups with a RR of 108 (95 CI 086 to 136 P =
050 Analysis 13) without heterogeneity across trials (I2 = 0)
Only two trials reported data about five year survival The meta-
analysis showed no statistically significant difference in 5 year sur-
vival between the groups with a RR of survival of 234 (95
CI 097 to 565 P = 006 Analysis 14) favouring chemoim-
munotherapy There was no heterogeneity across trials (I2 = 0)
Response rates (17 studies)
Data regarding the number of participants with partial or com-
plete responses from 17 trials were used to evaluate objective re-
sponse rates The analysis detected a statistically significant differ-
ence in favor of chemoimmunotherapy in global response rates
with a RR of 140 (95 CI 120 to 163 P lt 00001 Analysis
21) There was no heterogeneity across trials (I2 = 42) We
tried to evaluate the influence of the type of immunotherapeutic
in the group of chemoimmunotherapy (IL-2 plus IFN-alpha or
IFN-alpha only) We found similar results with a RR of global
response of 146 (95 CI 119 to 179 p = 00002 Analysis 21)
in favor of chemoimmunotherapy with IL-2 plus IFN-alpha and
a RR of 132 (95 CI 102 to 171 p = 004 Analysis 21) in favor
of chemoimmunotherapy with IFN-alpha There was no hetero-
geneity across trials (I2 = 0)
8Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Data from 15 trials were used to evaluate partial and complete
response rates We found a statistically significant difference in
favour of chemoimmunotherapy in both analyses with an HR of
131 (95 CI 107 to 159 p = 0008 Analysis 23) for partial
response rates and an HR of 158 (95 CI 106 to 236 p = 003
Analysis 23) for complete response rates
Progression-free survival (3 studies)
Only three studies had extractable data about the number of par-
ticipants with no disease progression at the end of the trial When
pooled together there was no statistically significant difference be-
tween the groups with an HR of 076 (95 CI 057 to 102 p =
007 Analysis 31) There was no heterogeneity across these trials
(I2 = 0)
Treatment related toxicity (11 studies)
Data from 11 studies were collected with the number of partici-
pants developing clinically significant hematological toxicity (de-
fined as grade 3 or 4) Eight studies had estimated points that
showed enhanced toxicities in the chemoimmunotherapy group
The meta-analysis of the studies showed extreme heterogeneity
(I2 = 941) across the trials We performed a sensitivity anal-
ysis excluding the studies with relatively low doses of chemo-
therapeutic drugs in the chemoimmunotherapy group (Danson
2003 Middleton 2000) but we found similar heterogeneity (I2 =
978)
When we analyzed data from the four studies with similar rela-
tive doses of chemotherapeutics associated with interferon-alpha
without interleukin-2 we found an increase of clinically signifi-
cant hematological toxicities in the chemoimmunotherapy group
with a RR 454 (95 CI 235 to 879 p lt 000001) There was
no heterogeneity across these trials (I2 = 0) When we analyzed
data from studies with combination of interferon-alpha plus in-
terleukin-2 in the chemoimmunotherapy group we again found
extreme heterogeneity across the trials (I2 = 979)
Despite the heterogeneity in global meta-analysis we concluded
that it was not possible to quantify the differences in hematologi-
cal toxicity in such different trials In order to explore these differ-
ences we noted that one study referred to hematological toxicity
in 100 of participants treated with chemoimmunotherapy and
in 96 of participants treated with chemotherapy (Eton 2002)
Another study referred to hematological toxicity only in 2 and
1 respectively (Bajetta 1994)
Non-hematological toxicities were described in almost all stud-
ies and were mainly described as nausea vomiting flu-like syn-
drome asthenia hypotension and fever Data from six similar
studies were extractable and were pooled in the meta-analysis re-
sulting in a statistically significant difference against the chemoim-
munotherapy group with a RR of 274 (95 CI 206 to 364 p
lt 000001 Analysis 42) There was no heterogeneity across trials
(I2 = 0) These results must be treated with caution because of
similar difficulties in pooling these data on hematological toxici-
ties with different therapeutic schemes and several trials described
non-hematological toxicities but we were not able to extract the
data
Data about treatment-related mortality were available in 11 stud-
ies We found no significant difference between the groups with a
RR of 078 (95 CI 026 to 232 p = 065 Analysis 43) There
was no heterogeneity across the trials (I2 = 0)
Quality of life (three studies)
Only three studies reported data on quality of life (Ridolfi 2002
Thomson 1993 Young 2001) all using different methods One
trial described quality of life analysis in detail in an additional pub-
lication (Chiarion-Sileni 2003 Ridolfi 2002) This study found
a significant decrease of overall quality of life in the chemoim-
munotherapy group in comparison to the chemotherapy group
(p = 003) The other two studies did not find differences in global
quality of life between the groups (Thomson 1993 Young 2001)
Thomson did not report global quality of life (Thomson 1993)
Young found no significant differences in quality of life for the
change in scores over time (z = -129 p = 020) (Young 2001)
It was not possible to pool the data as all three studies did not
provide extractable data
Sensitivity analyses on the influence of source of funding baseline
assessment and allocation concealment on the survival analysis
and response rate analyses revealed that there was no relation be-
tween these methodological aspects and the outcome There was
no statistically significant difference in survival between the groups
in all analyses and the difference in response rates in favour of
chemoimmunotherapy was found to be significant
D I S C U S S I O N
Metastatic melanoma is reputed as refractory to most systemic
treatments and little progress has been made in treatment of
metastatic melanoma These concepts are supported by results
from previous systematic reviews One review concluded that there
is no evidence derived from RCTs that systemic treatment is better
than best supportive care (Crosby 2000) Another review of 20
randomised trials (involving 3273 participants) comparing single-
agent DTIC with DTIC in combination with other drugs with or
without immunotherapy concluded that combination of drugs in-
creased response rates but not overall survival (Huncharek 2001)
This systematic review summarises the evidence regarding the
use of chemoimmunotherapy compared to chemotherapy alone
to treat people with metastatic malignant melanoma There are
some important observations regarding the characteristics of the
included studies in this systematic review The ideal combination
9Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
of drugs for an investigation is not well established Seven studies
evaluated chemoimmunotherapy with interferon-alpha plus inter-
leukin-2 and 11 evaluated chemoimmunotherapy only with in-
terferon-alpha The treatment plans with drugs and dosages used
differed between studies
Most studies did not contribute in answering relevant questions
about the impact of chemoimmunotherapy in the treatment of
metastatic melanoma The outcomes were not clearly described in
several of the studies (Atkins 2003 Del Vecchio 2003 Gorbonova
2000 Kirkwood 1990 Spieth 2003 Thomson 1993) Two of
them did not report survival rates evaluating only response rates
(Gorbonova 2000 Kirkwood 1990) All these aspects influenced
the comparability of the trials and must be considered in the data
interpretation
On the basis of a meta-analysis of data coming from eight studies
this review showed no evidence of a difference in overall survival to
support the addition of immunotherapy to chemotherapy in the
systemic treatment of metastatic melanoma (Atkins 2003 Danson
2003 Eton 2002 Falkson 1991 Johnston 1998 Ridolfi 2002
Spieth 2003 Young 2001) Evaluation of one two and five-year
survival with data from other studies again showed no survival
advantage of the drug combination treatment
We found higher clinical response rates in people treated with
chemoimmunotherapy in comparison with people treated with
chemotherapy which was not translated into survival benefit
Additionally we found higher toxicity rates in people treated
with chemoimmunotherapy Despite the importance of evaluat-
ing quality of life there was no available data to perform the meta-
analysis in this systematic review Only three studies reported data
about quality of life all with different methods One trial described
poorer quality of life in people treated with chemoimmunother-
apy related to more intense side effects (Ridolfi 2002) Two trials
however showed no difference between groups (Thomson 1993
Young 2001) It is important that quality of life is included in all
future studies
Our meta-analysis did not find differences between treatment re-
lated mortality Subgroup analysis comparing combinations with
interferon-alpha and with interferon-alpha plus interleukin-2 did
not show different results in survival or response rates
The use of chemoimmunotherapy ie a combination of chemo-
therapy with interferon-alpha or interleukin-2 or both has not
been shown to be beneficial in this review Although short term
response rates were better overall in the chemoimmunotherapy
groups survival was not improved and drug-related toxicities were
higher in the combined chemoimmunotherapy group To date no
treatment regimen has shown efficiency in prolonging survival in
people with metastatic melanoma Little has changed in the sys-
temic management of metastatic melanoma in the last few years
The standard of care remains single-agent DTIC and the role of
immunotherapy remains in doubt
The use of chemoimmunotherapy in the treatment of melanoma
is justified only in the context of clinical trials
A U T H O R S rsquo C O N C L U S I O N S
Implications for practice
We failed to find any evidence to support the view that the
use of chemoimmunotherapy prolongs survival in people with
metastatic melanoma when compared to chemotherapy alone Al-
though short-term clinical responses were higher in the chemoim-
munotherapy group this was associated with a higher rate of
serious adverse events esp haematological toxicity Our review
does not support the use of a combination of immunother-
apy and chemotherapy in chemoimmunotherapy regimens out-
side of clinical trials The standard of care for people with
advanced melanoma remains chemotherapy with single-agent
DTIC Chemoimmunotherapy must not be recommended to peo-
ple in daily practice
Implications for research
Research related to the development of more effective treatments
for people with metastatic melanoma is urgently needed
For people with an incurable disease the primary outcome needs
to be overall survival and all studies should include a quality of life
analysis
Future trials should be designed to define the best systemic treat-
ment and should use chemotherapy with (DTIC) as a standard
control group in order to permit comparisons to be made
A C K N O W L E D G E M E N T S
The authors wish to thank Raquel Gebara Lima for her kind
support in grammar and style
The editorial base would like to thank the following people who
were external referees for this review Keith Wheatley and Pat
Lawton (content experts) and Kathie Godfrey (consumer)
10Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
R E F E R E N C E S
References to studies included in this review
Atkins 2003 published data only
Atkins MB Lee S Flaherty LE Sosman JA Sondak VK
Kirkwood JM A prospective randomized phase III trial
of concurrent biochemotherapy (BCT) with cisplatin
vinblastine dacarbazine (CVD) IL-2 and interferon alpha-
2b (IFN) versus CVD alone in patients with metastatic
melanoma (E3695) An ECOG-coordinated intergroup
trial In ASCO Annual Meeting 2003 2003 p ASCO
Annual Meeting - Proceedings 2003Abstract 2847
Atzpodien 2002 published data only
Atzpodien J Neuber K Kamanabrou D Fluck M Brocker
EB Neumann C et alCombination chemotherapy with or
without sc IL-2 and IFN-alpha results of a prospectively
randomized trial of the Cooperative Advanced Malignant
Melanoma Chemoimmunotherapy Group (ACIMM)
British journal of cancer 200286(2)179ndash84
Bajetta 1994 published data only
Bajetta E Di Leo A Zampino MG Sertoli MR Comella
G Barduagni M et alMulticenter randomized trial of
dacarbazine alone or in combination with two different
doses and schedules of interferon alfa-2a in the treatment
of advanced melanoma Journal of clinical oncology official
journal of the American Society of Clinical Oncology 199412
(4)806ndash11
Danson 2003 published data only
Danson S Lorigan P Arance A Clamp A Ranson
M Hodgetts J et alRandomized phase II study of
temozolomide given every 8 hours or daily with either
interferon alfa-2b or thalidomide in metastatic malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 200321(13)2551ndash7
Del Vecchio 2003 published data only
Del Vecchio M Bajetta E Vitali M Gattinoni L Santinami
M Daponte A et alMulticenter phase III randomized trial
of cisplatin vindesine and dacarbazine (CVD) versus CVD
plus subcutaneous (sc) interleukin-2 (IL-2) and interferon-
alpha-2b (IFN) in metastatic melanoma patients (pts) In
ASCO Annual Meeting 2003 2003 p ASCO Annual
Meeting - Proceedings 2003Abstract 2849
Eton 2002 published data only
Eton O Legha SS Bedikian AY Lee JJ Buzaid AC
Hodges C et alSequential biochemotherapy versus
chemotherapy for metastatic melanoma results from a
phase III randomized trial Journal of clinical oncology
official journal of the American Society of Clinical Oncology
200220(8)2045ndash52
Falkson 1991 published data only
Falkson CI Falkson G Falkson HC Improved results with
the addition of interferon alfa-2b to dacarbazine in the
treatment of patients with metastatic malignant melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 19919(8)1403ndash8
Falkson 1998 published data only
Falkson CI Ibrahim J Kirkwood JM Coates AS Atkins
MB Blum RH Phase III trial of dacarbazine versus
dacarbazine with interferon alpha-2b versus dacarbazine
with tamoxifen versus dacarbazine with interferon alpha-
2b and tamoxifen in patients with metastatic malignant
melanoma an Eastern Cooperative Oncology Group study
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199816(5)1743ndash51
Gorbonova 2000 published data only
Gorbonova VA Egorov GN Perevodchikova NI Orel
NF Combined chemotherapy with or without interferon
alpha N1 (IFN) for advanced malignant melanoma - a
randomized pilot phase III study Gan To Kagaku Ryoho
200027 Suppl (2)310ndash4
Johnston 1998 published data only
Johnston SR Constenla DO Moore J Atkinson H ArsquoHern
RP Dadian G et alRandomized phase II trial of BCDT
[carmustine (BCNU) cisplatin dacarbazine (DTIC)
and tamoxifen] with or without interferon alpha (IFN-
alpha) and interleukin (IL-2) in patients with metastatic
melanoma British Journal of Cancer 199877(8)1280ndash6
Kirkwood 1990 published data only
Kirkwood JM Ernstoff MS Giuliano A Gams R Robinson
WA Costanzi J et alInterferon alpha-2a and dacarbazine
in melanoma Journal of the National Cancer Institute 1990
82(12)1062ndash3
Middleton 2000 published data only
Middleton MR Grob JJ Aaronson N Fierlbeck G
Tilgen W Seiter S et alRandomized phase III study of
temozolomide versus dacarbazine in the treatment of
patients with advanced metastatic malignant melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200018(1)158ndash66
Ridolfi 2002 published data only
Ridolfi R Chiarion-Sileni V Guida M Romanini A
Labianca R Freschi A et alCisplatin dacarbazine with
or without subcutaneous interleukin-2 and interferon
alpha-2b in advanced melanoma outpatients results from
an Italian multicenter phase III randomized clinical trial
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200220(6)1600ndash7
Rosenberg 1999 published data only
Rosenberg SA Yang JC Schwartzentruber DJ Hwu P
Marincola FM Topalian SL et alProspective randomized
trial of the treatment of patients with metastatic melanoma
using chemotherapy with cisplatin dacarbazine and
tamoxifen alone or in combination with interleukin-2 and
interferon alfa-2b Journal of Clinical Oncology 199917(3)
968ndash75
Spieth 2003 published data only
Spieth K Dummer R Garbe C Mauch C Schuler G
Landthaler M et alTemozolomide in combination with
11Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
interferon alfa versus temozolomide alone in patients with
advanced metastatic melanoma A randomized phase
III multicenter study of the Dermatologic Cooperative
Oncology Group (DeCOG) In ASCO Annual Meeting
2003Abstract 2887
Thomson 1993 published data only
Thomson DB Adena M McLeod GR Hersey P Gill PG
Coates AS et alInterferon-alpha 2a does not improve
response or survival when combined with dacarbazine
in metastatic malignant melanoma results of a multi-
institutional Australian randomized trial Melanoma
Research 19933(2)133ndash8
Vorobiof 1994 published data only
Vorobiof DA Bezwoda WR A randomised trial of vindesine
plus interferon-alpha 2b compared with interferon-alpha 2b
or vindesine alone in the treatment of advanced malignant
melanoma European journal of cancer (Oxford England
1990) 199430A(6)797ndash800
Young 2001 published data only
Young AM Marsden J Goodman A Burton A Dunn
JA Prospective randomized comparison of dacarbazine
(DTIC) versus DTIC plus interferon-alpha (IFN-alpha) in
metastatic melanoma Clinical oncology (Royal College of
Radiologists (Great Britain)) 200113(6)458ndash65
References to studies excluded from this review
Bajetta 2001 published data only
Bajetta E Del Vecchio M Vitali M Martinetti A Ferrari L
Queirolo P et alA feasibility study using polychemotherapy
(cisplatin + vindesine + dacarbazine) plus interferon-alpha
or monochemotherapy with dacarbazine plus interferon-
alpha in metastatic melanoma Tumori 200187(4)219ndash22
Legha 1996 published data only
Legha SS Ring S Bedikian A Plager C Eton O Buzaid
AC et alTreatment of metastatic melanoma with combined
chemotherapy containing cisplatin vinblastine and
dacarbazine (CVD) and biotherapy using interleukin-2 and
interferon-alpha Annals of oncology official journal of the
European Society for Medical Oncology ESMO 19967(8)
827ndash35
Richtig 2004 published data only
Richtig E Hofmann-Wellenhof R Pehamberger H
Forstinger C Wolff K Mischer P et alTemozolomide and
interferon alpha 2b in metastatic melanoma stage IV British
Journal of Dermatology 2004151(1)91ndash8
Sertoli 1999 published data only
Sertoli MR Queirolo P Bajetta E DelVecchio M
Comella G Barduagni L et alMulti-institutional phase
II randomized trial of integrated therapy with cisplatin
dacarbazine vindesine subcutaneous interleukin-2
interferon alpha2a and tamoxifen in metastatic melanoma
BREMIM (Biological Response Modifiers in Melanoma)
Melanoma research 19999(5)503ndash9
Sparano 1993 published data only
Sparano JA Fisher RI Sunderland M Margolin K Ernest
ML Sznol M et alRandomized phase III trial of treatment
with high-dose interleukin-2 either alone or in combination
with interferon alfa-2a in patients with advanced melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199311(10)1969ndash77
Vuoristo 2005 published data only
Vuoristo MS Hahka-Kemppinen M Parvinen LM
Pyrhonen S Seppa H Korpela M et alRandomized trial of
dacarbazine versus bleomycin vincristine lomustine and
dacarbazine (BOLD) chemotherapy combined with natural
or recombinant interferon-alpha in patients with advanced
melanoma Melanoma research 200515(4)291ndash6
Additional references
Arance 2000
Arance A Middleton M Lorigan P Thatcher N Three-
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melanoma (MM) In ASCO Annual Meeting 2000
Abstract 2257
Bafaloukos 2002
Bafaloukos D Aravantinos G Fountzilas G Stathopoulos
G Gogas H Samonis G et alDocetaxel in combination
with dacarbazine in patients with advanced melanoma
Oncology 200263(4)333ndash7
Bajetta 2002
Bajetta E Del Vecchio M Bernard-Marty C Vitali
M Buzzoni R Rixe O et alMetastatic melanoma
chemotherapy Seminars in Oncology 200229(5)427ndash45
Balch 2001
Balch CM Soong SJ Gershenwald JE Thompson JF
Reintgen DS Cascinelli N et alPrognostic factors analysis
of 17600 melanoma patients validation of the American
Joint Committee on Cancer melanoma staging system
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200119(16)3622ndash34
Barth 1995
Barth A Morton DL The role of adjuvant therapy in
melanoma management Cancer 199575 Suppl (2)
726ndash34
Chiarion-Sileni 2003
Chiarion-Sileni V Del Bianco P De Salvo GL Lo Re G
Romanini A Labianca R et alQuality of life evaluation in a
randomised trial of chemotherapy versus bio-chemotherapy
in advanced melanoma patients European journal of cancer
(Oxford England 1990) 200339(11)1577ndash85
Creagan 1984
Creagan ET Ahmann DL Green SJ Long HJ Frytak S
OrsquoFallon JR et alPhase II study of low-dose recombinant
leukocyte A interferon in disseminated malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 19842(9)1002ndash5
Crosby 2000
Crosby T Fish R Coles B Mason MD Systemic treatments
for metastatic cutaneous melanoma Cochrane Database
of Systematic Reviews 2000 Issue 2 [DOI 101002
14651858CD001215]
12Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Cure 1999
Cure H Souteyrand P Ouabdesselam R Roche H
Ravaud A DrsquoIncan M et alResults of a phase II trial
with cystemustine at 90 mgm(2) as a first- or second-line
treatment in advanced malignant melanoma a trial of the
EORTC Clinical Studies Group Melanoma Research 1999
9(6)607ndash10
Danson 2002
Danson S Arance A Lorigan P Clamp A Hodgetts J
Lomax L Thatcher N Middleton MR A randomized
study of temozolomide (TMZ) alone with interferon-
alpha (TMZ-IFN) or with thalidomide (TMZ-THAL) in
metastatic malignant melanoma (MMM) ASCO Annual
Meeting - Proceedings 2002Abstract 1369
Dorval 1986
Dorval T Palangie T Jouve M Garcia-Giralt E Israel L
Falcoff E et alClinical phase II trial of recombinant DNA
interferon (interferon alpha 2b) in patients with metastatic
malignant melanoma Cancer 198658(2)215ndash8
Dutcher 1989
Dutcher JP Creekmore S Weiss GR Margolin K
Markowitz AB Roper M et alA phase II study of
interleukin-2 and lymphokine-activated killer cells in
patients with metastatic malignant melanoma Journal of
clinical oncology official journal of the American Society of
Clinical Oncology 19897(4)477ndash85
Falkson 1995
Falkson CI Experience with interferon alpha 2b combined
with dacarbazine in the treatment of metastatic malignant
melanoma Medical oncology (Northwood London England)
199512(1)35ndash40
Garbe 1990
Garbe C Krasagakis K Zouboulis CC Schroder K Kruger
S Stadler R et alAntitumor activities of interferon alpha
beta and gamma and their combinations on human
melanoma cells in vitro changes of proliferation melanin
synthesis and immunophenotype Journal of Investigative
Dermatology 199095 Suppl (6)231ndash7
Gershenwald 1999
Gershenwald JE Thompson W Mansfield PF Lee JE
Colome MI Tseng CH et alMulti-institutional melanoma
lymphatic mapping experience the prognostic value of
sentinel lymph node status in 612 stage I or II melanoma
patients Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199917(3)976ndash83
Hanninen 1991
Hanninen EL Korfer A Hadam M Schneekloth C
Dallmann I Menzel T et alBiological monitoring of
low-dose interleukin 2 in humans soluble interleukin 2
receptors cytokines and cell surface phenotypes Cancer
Research 199151(23 Pt 1)6312ndash6
Huncharek 2001
Huncharek M Caubet JF McGarry R Single-agent
DTIC versus combination chemotherapy with or without
immunotherapy in metastatic melanoma a meta-analysis
of 3273 patients from 20 randomized trials Melanoma
Research 200111(1)75ndash81
Juni 2001
Juni P Altman DG Egger M Assessing the quality of
controlled clinical trials BMJ 200132342ndash6
Kadison 2003
Kadison AS Morton DL Immunotherapy of malignant
melanoma The Surgical Clinics of North America 200383
(2)343ndash70
Keilholz 2002
Keilholz U Gore ME Biochemotherapy for advanced
melanoma Seminars in Oncology 200229(5)456ndash61
Khayat 2002
Khayat D Bernard-Marty C Meric JB Rixe O
Biochemotherapy for advanced melanoma maybe it is real
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Koh 1991
Koh HK Cutaneous melanoma New England Journal of
Medicine 1991325(3)171ndash82
La Vecchia 1999
La Vecchia C Lucchini F Negri E Levi F Recent declines
in worldwide mortality from cutaneous melanoma in youth
and middle age International Journal of Cancer 199981(1)
62ndash6
Lee 2000
Lee ML Tomsu K Von Eschen KB Duration of survival
for disseminated malignant melanoma results of a meta-
analysis Melanoma Research 200010(1)81ndash92
Legha 1998
Legha SS Ring S Eton O Bedikian A Buzaid AC Plager
C et alDevelopment of a biochemotherapy regimen
with concurrent administration of cisplatin vinblastine
dacarbazine interferon alfa and interleukin-2 for patients
with metastatic melanoma Journal of clinical oncology
official journal of the American Society of Clinical Oncology
199816(5)1752ndash9
Leong 2003
Leong SP Future perspectives on malignant melanoma
Surgical Clinics of North America 200383(2)453ndash6
Lokich 1979
Lokich JJ Garnick MB Legg M Intralesional immune
therapy methanol extraction residue of BCG or purified
protein derivative Oncology 197936(5)236ndash41
Nathan 1998
Nathan FE Mastrangelo MJ Systemic therapy in
melanoma Seminars in Surgical Oncology 199814(4)
319ndash27
Osborn 1977
Osborn DE Castro JE Immunological response in patients
receiving Corynebacterium parvum therapy Clinical
Oncology 19773(2)155ndash64
13Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Parmar 1998
Parmar MKB TV Stewart L Extracting summary statistics
to perform meta-analyses of the published literature for
survival endpoints Statistics in Medicine 1998172815ndash34
Richards 1992
Richards JM Mehta N Ramming K Skosey P Sequential
chemoimmunotherapy in the treatment of metastatic
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199210(8)1338ndash43
Rigel 1989
Rigel DS Rivers JK Kopf AW Friedman RJ Vinokur AF
Heilman ER et alDysplastic nevi Markers for increased
risk for melanoma Cancer 198963(2)386ndash9
Rosenberg 1989
Rosenberg SA Lotze MT Yang JC Aebersold PM Linehan
WM Seipp CA et alExperience with the use of high-
dose interleukin-2 in the treatment of 652 cancer patients
Annals of Surgery 1989210(4)474-84 discussion 484-5
Sertoli 1989
Sertoli MR Bernengo MG Ardizzoni A Brunetti I Falcone
A Vidili MG et alPhase II trial of recombinant alpha-2b
interferon in the treatment of metastatic skin melanoma
Oncology 198946(2)96ndash8
Smith 1993
Smith KA Lowest dose interleukin-2 immunotherapy
Blood 199381(6)1414ndash23
Stopeck 2001
Stopeck AT Jones A Hersh EM Thompson JA
Finucane DM Gutheil JC et alPhase II study of direct
intralesional gene transfer of allovectin-7 an HLA-B7
beta2-microglobulin DNA-liposome complex in patients
with metastatic melanoma Clinical Cancer Research 20017
(8)2285ndash91
Tsang 1983
Tsang KY Fudenberg HH Pan JF Gnagy MJ Bristow
CB An in vitro study on the effects of isoprinosine on
immune responses in cancer patients International Journal
of Immunopharmacology 19835(6)481ndash90
Wingo 1995
Wingo PA Tong T Bolden S Cancer statistics 1995 CA
a cancer journal for clinicians 199545(1)8ndash30
Yusuf 1985
Yusuf S Peto R Lewis J Collins R Sleight P Beta blockade
during and after myocardial infarction an overview of the
randomized trials Progress in Cardiovascular Diseases 1985
27(5)335ndash71lowast Indicates the major publication for the study
14Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Atkins 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding public
Participants PS lt= 1
Brain mets no info
Age 20 to 80 (median 50)
Number of cycles no info
Randomised 416 a 206 b 210
Evaluable 405 a 201 b 204
Interventions a (CT) cisplatin 20mgm2 D1 to 4 vinblastin 12 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1-4 vimblastin 12 mgm2 D1-4 DTIC 800 mgm2 D1
IFN-alpha 5 mIU D1-5 D8 D10 D12 IL-2 9 mIU D1-4
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
Notes Multicentric yes
Withdrawals a five b six
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
15Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Atzpodien 2002
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding both (pharmaceutic and public)
Participants PS lt= 1
Brain mets yes Age 28 to 77 (median 57)
Number of cycles no info
Randomised 124 a 60 b 64
Evaluable 124 a 60 b 64
Interventions a (CT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily
b (ICT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily IFN-alpha 5 mIUm2 D1 week4 and 5
mIUm2 D1 D3 D5 week 5 IL-2 10 mIUm2 D1 D3 D5
(each five weeks)
Outcomes 1 Response rates
2 Overall survival
3 Progression free survival
Notes Multicentric yes
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Bajetta 1994
Methods D parallel group (three groups)
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding pharmaceutic
Participants PS lt= 2
Brain mets no
16Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Bajetta 1994 (Continued)
Age 18 to 70 (median 53)
Number of cycles 8
Randomised 266 a 88 b 86 c 92
Evaluable 242 a 82 b 76 c 84
Interventions a (CT) DTIC 800 mgm2 D1
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU 3xweek
c (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU D1 to 3 6 mIU D4 to 6 9 mIU daily
(each 21 days)
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Overall survival
Notes Multicentric yes
Withdrawals a six b ten c eight
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Danson 2003
Methods D parallel group
AC independent allocation
RS permuted blocks
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets yes Age 16 to 88 (median 58)
Number of cycles six
Randomised 125 a 59 b 62
Evaluable 121 a 55 b 62
Interventions a (CT) temozolomide 200 mgm2 88 h (5 doses)
b (ICT) Temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIU 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
17Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Danson 2003 (Continued)
Notes Multicentric no
Withdrawals a 4 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Del Vecchio 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no Age 19 to 70 (median 50)
Number of cycles no info
Randomised 151 a 75 b 76
Evaluable 145 a 72 b 73
Interventions a (CT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250 mgm2 D1 to
3
b (ICT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250m gm2 D1 to
3 IFN-alpha 5 mIUm2 D1 to 5 IL-2 9 mIUday x 5 daysweek x 2 weeks with a week of
rest
(each 21 days)
Outcomes 1 Response rates
2 Time to Progression
2 Overall Survival
Notes Multicentric yes
Withdrawals a three b three
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
18Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Eton 2002
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding pharm
Participants PS lt= 3
Brain mets yes Age median 49
Number of cycles no info
Randomised 190
Evaluable 183 a 92 b 91
Interventions a (CT) cisplatin 20m gm2 D1 to 4 vimblastin 2 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1 to 4 vinblastin 15 mgm2 D1 to 4 DTIC 800 mgm2
D1 IFN-alpha 5mIUm2 D5 to 9 D17-21 IL-2 9 mIUm2 D5 to 8 D17 to 20
(each 21 days)
Outcomes 1 Response rates
2 Time to progression
3 Overall survival
Notes Multicentric no
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1991
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size no
ITT no
Placebo no
Funding both
Participants PS lt= 1
Brain mets no
Age 22 to 79
(median 57)
Number of cycles at least two
19Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1991 (Continued)
Randomised 73 Evaluable 68 a 34 b 34
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Time to treatment failure
3 Median survival
4 Toxicity
Notes Multicentric no
Withdrawals a three b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1998
Methods D 2 x 2 factorial design
AC independent allocation
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 18 to 84
Number of cycles no info
Randomised 271 Evaluable 263 a 68 b 65 c 63 d 67
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
c (CT) DTIC 200m gm2 D1 to 5 tamoxifen 20 mgdaily
d (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek tamoxifen 20 mgdaily
(each 28 days)
Outcomes 1 Response rates
2 Toxicity rates
20Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1998 (Continued)
3 Overall survival
4 Time to treatment failure
Notes Multicentric yes
Withdrawals a one b three c three d one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Gorbonova 2000
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no
Age 23 to 75
Number of cycles no info
Randomised 30 Evaluable 28 a 14 b 14
Interventions a (CT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2
b (ICT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2 IFN-alpha 3 mIU D5 7
9 11 13 15 17 19
(each 28 days)
Outcomes 1 Response rates
Notes Multicentric no
Withdrawals a two b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
21Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Johnston 1998
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age 18 to 70
(median 45)
Number of cycles no info
Randomised 65 Evaluable 65 a 30 b 35
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to 3
Tamoxifen 40 mg daily
b (ICT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to
3 Tamoxifen 40 mg daily IFN-alpha 9 mIU D1 to 3 IL-2 18 mIU D-2 IL-2 9 mIU D-
1 and 0
(each 28 days)
Outcomes 1 Response rates
2 Time to disease progression
3 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Kirkwood 1990
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding pharm
22Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Kirkwood 1990 (Continued)
Participants PS no info
Brain mets no info
Age no info
Number of cycles no info
Randomised 74 Evaluable 68 a 24 b 23 c 21
Interventions a (CT) DTIC 250 mgm2 D1 to 5 (each 21 days)
b (I) IFN-alpha 3 mIU d1 to 5 every week for 3 weeks than 3 mIUm2 3 xweek
c (ICT) DTIC 250 mgm2 D1 to 5 (each 21 days) IFN-alpha 3 mIU d1 to 5 every week
for 3 weeks than 3 mIUm2 3 xweek
Outcomes 1 Response rates
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Middleton 2000
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets no
Age 24 to 71
(median 51)
Number of cycles six
Randomised 105 Evaluable 96 a 46 b 50
Interventions a (CT) DTIC 800 mgm2 D1 cisplatin 25 mgm2 D1 to 3 BCNU 150 mgm2 D1
tamoxifen 20 mgdaily
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 9 mIU 3 xweek
(each 21 days)
Outcomes 1 Response rates
2 One year survival
3 Median survival
23Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Middleton 2000 (Continued)
4 Toxicity
4 Time spent in hospital
Notes Multicentric no
Withdrawals a seven b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Ridolfi 2002
Methods D parallel group
AC independent allocation by telephone
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 25 to 77
Number of cycles six
Randomised 178 Evaluable 176 a 89 b 87
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1
b (ICT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1 IFN-
alpha 3 mIU 3 xweek IL-2 45 mIU D3 to 5 D8 to 12
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
3 Time to progression
4 Toxicity
Notes Multicentric yes
Withdrawals a one b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
24Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
than the one found with dacarbazine (DTIC) (Creagan 1984
Dorval 1986 Sertoli 1989)
Interleukin-2 (IL-2) is a major growth factor for lymphoid cells
including T cells and natural killer (NK) cells (Hanninen 1991
Smith 1993) Clinical trials have demonstrated modest anti-tumor
activity in people with metastatic melanoma (Rosenberg 1989)
responses were seen in approximately 15 of people with a
small proportion of complete responses (Dutcher 1989 Rosenberg
1989)
Chemoimmunotherapy
As chemotherapy and immunotherapy have different and per-
haps synergistic mechanisms of action their combination of im-
munotherapy with chemotherapy (chemoimmunotherapy) has
been studied since the early 1990s (Khayat 2002) Some reports
have suggested that chemotherapeutic agents administered in com-
bination with IL-2 or IFN or both can improve response rates
(Legha 1998 Richards 1992) with complete response rates in 10
to 20 of people as well as increases in median survival (Falkson
1991) Based on these results the use of chemoimmunotherapy is
currently preferred in some institutions as a first-line treatment in
advanced (stage IV) melanoma (Kadison 2003 Keilholz 2002)
although it is still considered an experimental therapy by oth-
ers(Crosby 2000)
Why it is important to do this review
There are substantial controversies about the real benefit of
chemoimmunotherapy some studies conclude that the combi-
nation of treatments did not improve survival (Rosenberg 1999
Young 2001) or even response rates (Falkson 1998 Gorbonova
2000 Johnston 1998 Thomson 1993) in people with metastatic
melanoma There is also concern that combined therapy may in-
crease treatment-related toxicity (Falkson 1998 Johnston 1998)
The lack of conclusive data coming from seemingly conflict-
ing studies about the impact of treatment demands a systematic
review This will provide the most reliable assessment for sup-
porting clinical decision-making with people who have advanced
melanoma
O B J E C T I V E S
To compare the effects of chemotherapy alone versus combined
therapy with chemotherapy and immunotherapy (chemoim-
munotherapy) in people with metastatic malignant melanoma
M E T H O D S
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs)
Types of participants
People of any age diagnosed with metastatic malignant melanoma
that has spread to distant sites by systemic dissemination
Types of interventions
1 Chemotherapy
2 Chemoimmunotherapy ie the combination of
chemotherapy and immunotherapy with interferon-alpha or
interleukin-2 or both
Types of outcome measures
Primary outcomes
Overall survival - number of participants alive at the end of the
trial
Secondary outcomes
1 One two and five-year survival rates - proportion of
participants alive at one two and five year follow-up
2 Response rates (partial and complete) - proportion of
participants that have achieved partial or complete responses as
defined by the trial authors
3 Progression-free survival - number of participants without
progression of disease at the end of the trial
4 Treatment morbidity (treatment-related toxicity) -
proportion of participants that have developed hematological or
non-hematological toxicities
5 Treatment related mortality - proportion of participants
that have died due to the treatment This outcome was not
described previously in the protocol and was added after
discussion between the reviewers that considered it relevant
Mortality related to treatment is a great concern in oncology
when comparing treatments with potential differences in toxicity
6 Quality of life measures
Search methods for identification of studies
We searched electronic databases and other resources to locate
reports of studies No language restrictions were imposed
4Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Electronic searches
Electronic databases
We searched the following electronic databases
1 MEDLINE (OVID) (Appendix 1)
2 The Cochrane Skin Group Specialised Register
3 The Cochrane Central Register of Controlled Trials
4 Medline (PubMed)
5 EMBASE
6 LILACS (Latin American and Caribbean Health Science
Information Database)
Search strategies for databases 2 to 6 are located in Appendix 2
Search of databases of ongoing trials (unpublished literature)
We asked trial authors and pharmaceutical companies about un-
published and ongoing trials Databases of major research groups
and registers of trials in the following databases were also searched
with the term rsquoMELANOMArsquo
bull Current Controlled Trials Register (httpwwwcontrolled-
trialscom) on 30th January 2006
bull European Organisation for Research and Treatment of
Cancer (httpwwweortcbe) on 20th February 2006
bull National Cancer Institute America (http
wwwcancergovclinicaltrials) on 16th November 2005
bull National Cancer Institute Canada (httphttp
wwwctgqueensucapublicClinical_Trialsclinical_trialshtml)
on 30th January 2006
bull Australian Clinical Trials Registry (httpwwwactrorgau)
on 30th January 2006
bull US Food and Drug Administration (httpwwwfdagov)
on 30th January 2006
bull ClinicalTrialsgov (httpwwwclinicaltrialsgov) on 16th
November 2005
Searching other resources
References from unpublished studies
All bibliographies of selected studies were scanned for possible
references to RCTs
Conference proceedings
We handsearched the abstracts from conference proceedings of
the ASCO (American Society of Clinical Oncology) and ESMO
(European Society of Medical Oncology)
Data collection and analysis
Where there was uncertainty we tried to contact trial authors for
clarification
A consumer (LU) was involved throughout the review process to
ensure the readability of the final review Updating will be done
every two years
Selection of studies
Two authors (ADS and ECS) checked the titles and abstracts iden-
tified from the searches If it was clear that the study did not refer
to a RCT on metastatic melanoma we excluded it Two authors
(ADS and OAC) independently assessed each remaining study to
determine whether it met the pre-defined selection criteria Any
differences were resolved through discussion with the review team
Excluded studies are listed in the Table of Excluded Studies
Data extraction and management
Two authors (ADS and ECS) independently extracted the data
from the studies All data were extracted directly from the text or
calculated according to the available information
Any differences were resolved by discussion with one author
(OAC) A data extraction form was developed and piloted in order
to summarize the trials One author (ADS) checked and entered
the data Two authors (ECS and LGC) independently checked the
data entry
Assessment of risk of bias in included studies
Assessment of methodological quality
The quality assessment included an evaluation of the following
components for each included study since there is some evidence
that these are associated with biased estimates of treatment effect
(Juni 2001)
(a) the method of generation of the randomisation sequence
(b) the method of allocation concealment - it was considered rsquoad-
equatersquo if the assignment could not be foreseen
(c) who was blindednot blinded (participants clinicians outcome
assessors)
(d) how many participants were lost to follow up in each arm and
whether participants were analysed in the groups to which they
were originally randomised (intention-to-treat)
In addition the quality assessment also included
(e) the source of funding
(f ) if the participant had a biopsy proven melanoma
(g) the baseline assessment of the participants for presence of liver
and brain metastases performance status
(h) whether the aims interventions (including drug doses and
duration of treatment) and outcome measures were clearly defined
5Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(i) the use and appropriateness of statistical analyses
We recorded all the information in a table of quality criteria and
gave a description of the quality of each study based on these
characteristics
Measures of treatment effect
Where possible we performed a meta-analysis for the outcomes
in order to calculate a weighted treatment effect across trials using
a random-effects model For binary endpoints we calculated the
risk ratio (RR) with 95 confidence intervals (Yusuf 1985) We
also expressed the results as a number needed to treat (NNT)
where appropriate for a range of plausible control event rates For
overall survival a time-to-event data we calculated the Hazard
Ratio (HR) When data were not available for direct extraction
we calculated indirectly (from different parameters using indirect
calculation of the variance and the number of observed minus
expected events) according to the method described by Parmar
(Parmar 1998) In the funnel plot (Figure 1) and comparison 1
rsquoPeto OR (IPD)rsquo is a Hazard Ratio For continuous data such as
quality of life we planned to use standardised mean differences
with 95 confidence intervals would have been used
Figure 1 Funnel plot using overall survival as the outcome
Assessment of heterogeneity
Heterogeneity was assessed using I2 Where the heterogeneity was
considerable (I2 gt 50) we explored possible reasons using the
type (interleukin-2 or interferon) and dose (high or low) of im-
munotherapy used as subgroups Where we were not able to find
an explanation we have recorded this along with appropriate cau-
tion in the interpretation of these data
Data synthesis
Analysis and presentation
Once studies had been selected critically appraised and the data
extracted we entered the data in the Characteristics of included
studies table
6Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Three studies (Bajetta 1994 Kirkwood 1990 Vorobiof 1994) eval-
uated three arms of treatment with one of them evaluating che-
motherapy alone and the two others using chemoimmunotherapy
One study (Falkson 1998) had four arms two using chemotherapy
and two using chemoimmunotherapy The data from the similar
arms were grouped considered as one and then compared to the
other arm
R E S U L T S
Description of studies
Results of the search
We scanned approximately 700 citations Initially 28 studies
were identified Four studies (Arance 2000 Chiarion-Sileni 2003
Danson 2002 Falkson 1995) had data that overlapped with three
included studies (Danson 2003 Falkson 1991 Ridolfi 2002)
Ongoing studies
No ongoing studies were available to be included in the meta-
analysis
Included studies
Eighteen studies with a total of 2625 participants met our criteria
and were included in the meta-analysis (please see Characteristics
of included studies) One study differed considerably from the oth-
ers because vindesine was used as the chemotherapy control a drug
without evidence of response in metastatic melanoma (Vorobiof
1994) Another study differed considerably as lower dose treat-
ment in the chemoimmunotherapy group was used (Middleton
2000) The first study was published in 1990 and the last studies
were published in 2003
Participants
The participants were between the ages of 16 and 88 years and
had an Eastern Cooperative Oncology Group performance status
from 0 to 3 Only three studies included participants with brain
metastasis (Atzpodien 2002 Danson 2003 Eton 2002)
Interventions
Seven studies compared chemotherapy to chemoimmunotherapy
with IFN plus IL-2 (Atkins 2003 Atzpodien 2002 Del Vecchio
2003 Eton 2002 Johnston 1998 Ridolfi 2002 Rosenberg 1999)
Eleven compared chemotherapy to chemoimmunotherapy with
IFN (Bajetta 1994 Danson 2003 Falkson 1991 Falkson 1998
Gorbonova 2000 Kirkwood 1990 Middleton 2000 Spieth 2003
Thomson 1993 Vorobiof 1994 Young 2001)
The drugs used in chemotherapeutic schemes varied between the
trials Seven trials evaluated DTIC combined with other drugs in
both arms (Atkins 2003 Atzpodien 2002 Del Vecchio 2003 Eton
2002 Johnston 1998 Ridolfi 2002 Rosenberg 1999) and six
evaluated DTIC alone as the control (Bajetta 1994 Falkson 1991
Falkson 1998 Kirkwood 1990 Thomson 1993 Young 2001)
Four studies evaluated other schemes without DTIC two trials
used temozolomide (Danson 2003 Spieth 2003) one trial used
vindesine (Vorobiof 1994) and one trial used combined drugs
based on cisplatin (Gorbonova 2000)
Only one study did not use the same scheme in both the arms
using combined drugs with DTIC as the chemotherapy control
and a lower dose for the chemoimmunotherapy group with DTIC
alone (Middleton 2000)
Setting
Ten studies were carried out in Europe four in the United States
two in South Africa and one was a multicentre worldwide trial
All trials were reported in the English language
Outcomes
Response rates were the primary outcome measures in most trials
and were described in all included studies Two studies did not
evaluate survival rates (Gorbonova 2000 Kirkwood 1990) Three
studies included quality of life analyses in the outcomes (Ridolfi
2002 Thomson 1993 Young 2001) The length of the follow-up
varied widely between the trials and sometimes it was not speci-
fied We did not find a reasonable definition about what could be
considered high or low doses of immunotherapy and the influence
of the immunotherapeutic doses on the outcomes could not be
assessed
Excluded studies
Six studies were excluded (see Characteristics of excluded studies)
The reasons for exclusion were that the study had immunotherapy
on both arms (Bajetta 2001 Richtig 2004 Sertoli 1999 Sparano
1993 Vuoristo 2005) or the study was not randomised (Legha
1996)
Risk of bias in included studies
The quality assessment consisted of a basic methodological eval-
uation of each included study and is shown in Table 1 Addi-
tional quality assessment is shown in Table 2 The criteria used for
methodological quality analysis of the studies are listed in Table 3
(Explanation of Quality Analysis Headings)
7Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Although blinding participants and clinicians is theoretically pos-
sible it is difficult to plan a double-blind study with immunother-
apy This is due to the substantial acute and late toxicities associ-
ated with immunotherapy in one group No study was described
as double-blinded The groups at baseline were in general similar
with a description of most prognostic factors related to metastatic
melanoma (gender performance status age prior therapy liver
metastasis)
In three studies almost all methodological aspects of the trials
were described poorly (Gorbonova 2000 Kirkwood 1990 Spieth
2003)
Allocation
All the included studies were described as randomised as this
was a selection criterion However most papers did not describe
the method of randomisation The method of generation of the
randomised sequence was described and considered adequate in
only 6 out of 18 studies Eleven of 18 studies provided information
on allocation concealment all of which were considered adequate
Blinding
Blinding of outcome assessment and detection bias
We did not find information about blinding of the outcome as-
sessors in any included study
Incomplete outcome data
Handling of losses and attrition bias
In general there were few participants lost to follow up in the
studies The highest number of people lost was 24 in a total of 262
participants (Bajetta 1994) Eleven studies included an intention-
to-treat analysis
Effects of interventions
Primary outcome
Overall survival (eight studies)
This was considered as the number of participants alive at the end
of the trial Sufficient data were available from 8 of the 18 studies
There was no statistically significant difference in survival between
chemoimmunotherapy and chemotherapy with a hazard ratio
(HR) of improved survival of 089 (95 CI 072 to 111 P = 031
Analysis 11) in favour of chemoimmunotherapy In other words
overall survival was slightly lower in the chemoimmunotherapy
group but this was not statistically significant There was no het-
erogeneity across trials (I2 = 0) The funnel plot method using
overall survival as the outcome is presented in Figure 1 It shows
that there was no evidence of substantial publication bias but in-
terpretation of the funnel plot is likely to be unreliable since only
eight relatively large studies were found
When we evaluated the influence of the type of immunotherapy
used in the chemoimmunotherapy group (IL-2 plus IFN-alpha
or IFN-alpha only) we found no statistically significant difference
between the groups with a HR of 096 (95 CI 074 to 124 P =
076 Analysis 11) for chemoimmunotherapy with IL-2 plus IFN-
alpha and a HR of 074 (95 CI 049 to 112 P = 015 Analysis
11) for chemoimmunotherapy associated with only IFN-alpha
Secondary outcomes
One two and five-year survival rates (13 studies)
The number of participants alive at one two and five year follow-
ups were analyzed Data from 13 trials evaluating one year survival
were pooled There was no statistically significant difference in one
year survival between the groups with a risk ratio (RR) of 106
(95 CI 091 to 124 P = 048 Analysis 12) and no significant
heterogeneity across trials (I2 = 363)
Data from 11 trials evaluating 2 year survival were extracted and
pooled Again there was no statistically significant difference be-
tween the groups with a RR of 108 (95 CI 086 to 136 P =
050 Analysis 13) without heterogeneity across trials (I2 = 0)
Only two trials reported data about five year survival The meta-
analysis showed no statistically significant difference in 5 year sur-
vival between the groups with a RR of survival of 234 (95
CI 097 to 565 P = 006 Analysis 14) favouring chemoim-
munotherapy There was no heterogeneity across trials (I2 = 0)
Response rates (17 studies)
Data regarding the number of participants with partial or com-
plete responses from 17 trials were used to evaluate objective re-
sponse rates The analysis detected a statistically significant differ-
ence in favor of chemoimmunotherapy in global response rates
with a RR of 140 (95 CI 120 to 163 P lt 00001 Analysis
21) There was no heterogeneity across trials (I2 = 42) We
tried to evaluate the influence of the type of immunotherapeutic
in the group of chemoimmunotherapy (IL-2 plus IFN-alpha or
IFN-alpha only) We found similar results with a RR of global
response of 146 (95 CI 119 to 179 p = 00002 Analysis 21)
in favor of chemoimmunotherapy with IL-2 plus IFN-alpha and
a RR of 132 (95 CI 102 to 171 p = 004 Analysis 21) in favor
of chemoimmunotherapy with IFN-alpha There was no hetero-
geneity across trials (I2 = 0)
8Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Data from 15 trials were used to evaluate partial and complete
response rates We found a statistically significant difference in
favour of chemoimmunotherapy in both analyses with an HR of
131 (95 CI 107 to 159 p = 0008 Analysis 23) for partial
response rates and an HR of 158 (95 CI 106 to 236 p = 003
Analysis 23) for complete response rates
Progression-free survival (3 studies)
Only three studies had extractable data about the number of par-
ticipants with no disease progression at the end of the trial When
pooled together there was no statistically significant difference be-
tween the groups with an HR of 076 (95 CI 057 to 102 p =
007 Analysis 31) There was no heterogeneity across these trials
(I2 = 0)
Treatment related toxicity (11 studies)
Data from 11 studies were collected with the number of partici-
pants developing clinically significant hematological toxicity (de-
fined as grade 3 or 4) Eight studies had estimated points that
showed enhanced toxicities in the chemoimmunotherapy group
The meta-analysis of the studies showed extreme heterogeneity
(I2 = 941) across the trials We performed a sensitivity anal-
ysis excluding the studies with relatively low doses of chemo-
therapeutic drugs in the chemoimmunotherapy group (Danson
2003 Middleton 2000) but we found similar heterogeneity (I2 =
978)
When we analyzed data from the four studies with similar rela-
tive doses of chemotherapeutics associated with interferon-alpha
without interleukin-2 we found an increase of clinically signifi-
cant hematological toxicities in the chemoimmunotherapy group
with a RR 454 (95 CI 235 to 879 p lt 000001) There was
no heterogeneity across these trials (I2 = 0) When we analyzed
data from studies with combination of interferon-alpha plus in-
terleukin-2 in the chemoimmunotherapy group we again found
extreme heterogeneity across the trials (I2 = 979)
Despite the heterogeneity in global meta-analysis we concluded
that it was not possible to quantify the differences in hematologi-
cal toxicity in such different trials In order to explore these differ-
ences we noted that one study referred to hematological toxicity
in 100 of participants treated with chemoimmunotherapy and
in 96 of participants treated with chemotherapy (Eton 2002)
Another study referred to hematological toxicity only in 2 and
1 respectively (Bajetta 1994)
Non-hematological toxicities were described in almost all stud-
ies and were mainly described as nausea vomiting flu-like syn-
drome asthenia hypotension and fever Data from six similar
studies were extractable and were pooled in the meta-analysis re-
sulting in a statistically significant difference against the chemoim-
munotherapy group with a RR of 274 (95 CI 206 to 364 p
lt 000001 Analysis 42) There was no heterogeneity across trials
(I2 = 0) These results must be treated with caution because of
similar difficulties in pooling these data on hematological toxici-
ties with different therapeutic schemes and several trials described
non-hematological toxicities but we were not able to extract the
data
Data about treatment-related mortality were available in 11 stud-
ies We found no significant difference between the groups with a
RR of 078 (95 CI 026 to 232 p = 065 Analysis 43) There
was no heterogeneity across the trials (I2 = 0)
Quality of life (three studies)
Only three studies reported data on quality of life (Ridolfi 2002
Thomson 1993 Young 2001) all using different methods One
trial described quality of life analysis in detail in an additional pub-
lication (Chiarion-Sileni 2003 Ridolfi 2002) This study found
a significant decrease of overall quality of life in the chemoim-
munotherapy group in comparison to the chemotherapy group
(p = 003) The other two studies did not find differences in global
quality of life between the groups (Thomson 1993 Young 2001)
Thomson did not report global quality of life (Thomson 1993)
Young found no significant differences in quality of life for the
change in scores over time (z = -129 p = 020) (Young 2001)
It was not possible to pool the data as all three studies did not
provide extractable data
Sensitivity analyses on the influence of source of funding baseline
assessment and allocation concealment on the survival analysis
and response rate analyses revealed that there was no relation be-
tween these methodological aspects and the outcome There was
no statistically significant difference in survival between the groups
in all analyses and the difference in response rates in favour of
chemoimmunotherapy was found to be significant
D I S C U S S I O N
Metastatic melanoma is reputed as refractory to most systemic
treatments and little progress has been made in treatment of
metastatic melanoma These concepts are supported by results
from previous systematic reviews One review concluded that there
is no evidence derived from RCTs that systemic treatment is better
than best supportive care (Crosby 2000) Another review of 20
randomised trials (involving 3273 participants) comparing single-
agent DTIC with DTIC in combination with other drugs with or
without immunotherapy concluded that combination of drugs in-
creased response rates but not overall survival (Huncharek 2001)
This systematic review summarises the evidence regarding the
use of chemoimmunotherapy compared to chemotherapy alone
to treat people with metastatic malignant melanoma There are
some important observations regarding the characteristics of the
included studies in this systematic review The ideal combination
9Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
of drugs for an investigation is not well established Seven studies
evaluated chemoimmunotherapy with interferon-alpha plus inter-
leukin-2 and 11 evaluated chemoimmunotherapy only with in-
terferon-alpha The treatment plans with drugs and dosages used
differed between studies
Most studies did not contribute in answering relevant questions
about the impact of chemoimmunotherapy in the treatment of
metastatic melanoma The outcomes were not clearly described in
several of the studies (Atkins 2003 Del Vecchio 2003 Gorbonova
2000 Kirkwood 1990 Spieth 2003 Thomson 1993) Two of
them did not report survival rates evaluating only response rates
(Gorbonova 2000 Kirkwood 1990) All these aspects influenced
the comparability of the trials and must be considered in the data
interpretation
On the basis of a meta-analysis of data coming from eight studies
this review showed no evidence of a difference in overall survival to
support the addition of immunotherapy to chemotherapy in the
systemic treatment of metastatic melanoma (Atkins 2003 Danson
2003 Eton 2002 Falkson 1991 Johnston 1998 Ridolfi 2002
Spieth 2003 Young 2001) Evaluation of one two and five-year
survival with data from other studies again showed no survival
advantage of the drug combination treatment
We found higher clinical response rates in people treated with
chemoimmunotherapy in comparison with people treated with
chemotherapy which was not translated into survival benefit
Additionally we found higher toxicity rates in people treated
with chemoimmunotherapy Despite the importance of evaluat-
ing quality of life there was no available data to perform the meta-
analysis in this systematic review Only three studies reported data
about quality of life all with different methods One trial described
poorer quality of life in people treated with chemoimmunother-
apy related to more intense side effects (Ridolfi 2002) Two trials
however showed no difference between groups (Thomson 1993
Young 2001) It is important that quality of life is included in all
future studies
Our meta-analysis did not find differences between treatment re-
lated mortality Subgroup analysis comparing combinations with
interferon-alpha and with interferon-alpha plus interleukin-2 did
not show different results in survival or response rates
The use of chemoimmunotherapy ie a combination of chemo-
therapy with interferon-alpha or interleukin-2 or both has not
been shown to be beneficial in this review Although short term
response rates were better overall in the chemoimmunotherapy
groups survival was not improved and drug-related toxicities were
higher in the combined chemoimmunotherapy group To date no
treatment regimen has shown efficiency in prolonging survival in
people with metastatic melanoma Little has changed in the sys-
temic management of metastatic melanoma in the last few years
The standard of care remains single-agent DTIC and the role of
immunotherapy remains in doubt
The use of chemoimmunotherapy in the treatment of melanoma
is justified only in the context of clinical trials
A U T H O R S rsquo C O N C L U S I O N S
Implications for practice
We failed to find any evidence to support the view that the
use of chemoimmunotherapy prolongs survival in people with
metastatic melanoma when compared to chemotherapy alone Al-
though short-term clinical responses were higher in the chemoim-
munotherapy group this was associated with a higher rate of
serious adverse events esp haematological toxicity Our review
does not support the use of a combination of immunother-
apy and chemotherapy in chemoimmunotherapy regimens out-
side of clinical trials The standard of care for people with
advanced melanoma remains chemotherapy with single-agent
DTIC Chemoimmunotherapy must not be recommended to peo-
ple in daily practice
Implications for research
Research related to the development of more effective treatments
for people with metastatic melanoma is urgently needed
For people with an incurable disease the primary outcome needs
to be overall survival and all studies should include a quality of life
analysis
Future trials should be designed to define the best systemic treat-
ment and should use chemotherapy with (DTIC) as a standard
control group in order to permit comparisons to be made
A C K N O W L E D G E M E N T S
The authors wish to thank Raquel Gebara Lima for her kind
support in grammar and style
The editorial base would like to thank the following people who
were external referees for this review Keith Wheatley and Pat
Lawton (content experts) and Kathie Godfrey (consumer)
10Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
R E F E R E N C E S
References to studies included in this review
Atkins 2003 published data only
Atkins MB Lee S Flaherty LE Sosman JA Sondak VK
Kirkwood JM A prospective randomized phase III trial
of concurrent biochemotherapy (BCT) with cisplatin
vinblastine dacarbazine (CVD) IL-2 and interferon alpha-
2b (IFN) versus CVD alone in patients with metastatic
melanoma (E3695) An ECOG-coordinated intergroup
trial In ASCO Annual Meeting 2003 2003 p ASCO
Annual Meeting - Proceedings 2003Abstract 2847
Atzpodien 2002 published data only
Atzpodien J Neuber K Kamanabrou D Fluck M Brocker
EB Neumann C et alCombination chemotherapy with or
without sc IL-2 and IFN-alpha results of a prospectively
randomized trial of the Cooperative Advanced Malignant
Melanoma Chemoimmunotherapy Group (ACIMM)
British journal of cancer 200286(2)179ndash84
Bajetta 1994 published data only
Bajetta E Di Leo A Zampino MG Sertoli MR Comella
G Barduagni M et alMulticenter randomized trial of
dacarbazine alone or in combination with two different
doses and schedules of interferon alfa-2a in the treatment
of advanced melanoma Journal of clinical oncology official
journal of the American Society of Clinical Oncology 199412
(4)806ndash11
Danson 2003 published data only
Danson S Lorigan P Arance A Clamp A Ranson
M Hodgetts J et alRandomized phase II study of
temozolomide given every 8 hours or daily with either
interferon alfa-2b or thalidomide in metastatic malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 200321(13)2551ndash7
Del Vecchio 2003 published data only
Del Vecchio M Bajetta E Vitali M Gattinoni L Santinami
M Daponte A et alMulticenter phase III randomized trial
of cisplatin vindesine and dacarbazine (CVD) versus CVD
plus subcutaneous (sc) interleukin-2 (IL-2) and interferon-
alpha-2b (IFN) in metastatic melanoma patients (pts) In
ASCO Annual Meeting 2003 2003 p ASCO Annual
Meeting - Proceedings 2003Abstract 2849
Eton 2002 published data only
Eton O Legha SS Bedikian AY Lee JJ Buzaid AC
Hodges C et alSequential biochemotherapy versus
chemotherapy for metastatic melanoma results from a
phase III randomized trial Journal of clinical oncology
official journal of the American Society of Clinical Oncology
200220(8)2045ndash52
Falkson 1991 published data only
Falkson CI Falkson G Falkson HC Improved results with
the addition of interferon alfa-2b to dacarbazine in the
treatment of patients with metastatic malignant melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 19919(8)1403ndash8
Falkson 1998 published data only
Falkson CI Ibrahim J Kirkwood JM Coates AS Atkins
MB Blum RH Phase III trial of dacarbazine versus
dacarbazine with interferon alpha-2b versus dacarbazine
with tamoxifen versus dacarbazine with interferon alpha-
2b and tamoxifen in patients with metastatic malignant
melanoma an Eastern Cooperative Oncology Group study
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199816(5)1743ndash51
Gorbonova 2000 published data only
Gorbonova VA Egorov GN Perevodchikova NI Orel
NF Combined chemotherapy with or without interferon
alpha N1 (IFN) for advanced malignant melanoma - a
randomized pilot phase III study Gan To Kagaku Ryoho
200027 Suppl (2)310ndash4
Johnston 1998 published data only
Johnston SR Constenla DO Moore J Atkinson H ArsquoHern
RP Dadian G et alRandomized phase II trial of BCDT
[carmustine (BCNU) cisplatin dacarbazine (DTIC)
and tamoxifen] with or without interferon alpha (IFN-
alpha) and interleukin (IL-2) in patients with metastatic
melanoma British Journal of Cancer 199877(8)1280ndash6
Kirkwood 1990 published data only
Kirkwood JM Ernstoff MS Giuliano A Gams R Robinson
WA Costanzi J et alInterferon alpha-2a and dacarbazine
in melanoma Journal of the National Cancer Institute 1990
82(12)1062ndash3
Middleton 2000 published data only
Middleton MR Grob JJ Aaronson N Fierlbeck G
Tilgen W Seiter S et alRandomized phase III study of
temozolomide versus dacarbazine in the treatment of
patients with advanced metastatic malignant melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200018(1)158ndash66
Ridolfi 2002 published data only
Ridolfi R Chiarion-Sileni V Guida M Romanini A
Labianca R Freschi A et alCisplatin dacarbazine with
or without subcutaneous interleukin-2 and interferon
alpha-2b in advanced melanoma outpatients results from
an Italian multicenter phase III randomized clinical trial
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200220(6)1600ndash7
Rosenberg 1999 published data only
Rosenberg SA Yang JC Schwartzentruber DJ Hwu P
Marincola FM Topalian SL et alProspective randomized
trial of the treatment of patients with metastatic melanoma
using chemotherapy with cisplatin dacarbazine and
tamoxifen alone or in combination with interleukin-2 and
interferon alfa-2b Journal of Clinical Oncology 199917(3)
968ndash75
Spieth 2003 published data only
Spieth K Dummer R Garbe C Mauch C Schuler G
Landthaler M et alTemozolomide in combination with
11Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
interferon alfa versus temozolomide alone in patients with
advanced metastatic melanoma A randomized phase
III multicenter study of the Dermatologic Cooperative
Oncology Group (DeCOG) In ASCO Annual Meeting
2003Abstract 2887
Thomson 1993 published data only
Thomson DB Adena M McLeod GR Hersey P Gill PG
Coates AS et alInterferon-alpha 2a does not improve
response or survival when combined with dacarbazine
in metastatic malignant melanoma results of a multi-
institutional Australian randomized trial Melanoma
Research 19933(2)133ndash8
Vorobiof 1994 published data only
Vorobiof DA Bezwoda WR A randomised trial of vindesine
plus interferon-alpha 2b compared with interferon-alpha 2b
or vindesine alone in the treatment of advanced malignant
melanoma European journal of cancer (Oxford England
1990) 199430A(6)797ndash800
Young 2001 published data only
Young AM Marsden J Goodman A Burton A Dunn
JA Prospective randomized comparison of dacarbazine
(DTIC) versus DTIC plus interferon-alpha (IFN-alpha) in
metastatic melanoma Clinical oncology (Royal College of
Radiologists (Great Britain)) 200113(6)458ndash65
References to studies excluded from this review
Bajetta 2001 published data only
Bajetta E Del Vecchio M Vitali M Martinetti A Ferrari L
Queirolo P et alA feasibility study using polychemotherapy
(cisplatin + vindesine + dacarbazine) plus interferon-alpha
or monochemotherapy with dacarbazine plus interferon-
alpha in metastatic melanoma Tumori 200187(4)219ndash22
Legha 1996 published data only
Legha SS Ring S Bedikian A Plager C Eton O Buzaid
AC et alTreatment of metastatic melanoma with combined
chemotherapy containing cisplatin vinblastine and
dacarbazine (CVD) and biotherapy using interleukin-2 and
interferon-alpha Annals of oncology official journal of the
European Society for Medical Oncology ESMO 19967(8)
827ndash35
Richtig 2004 published data only
Richtig E Hofmann-Wellenhof R Pehamberger H
Forstinger C Wolff K Mischer P et alTemozolomide and
interferon alpha 2b in metastatic melanoma stage IV British
Journal of Dermatology 2004151(1)91ndash8
Sertoli 1999 published data only
Sertoli MR Queirolo P Bajetta E DelVecchio M
Comella G Barduagni L et alMulti-institutional phase
II randomized trial of integrated therapy with cisplatin
dacarbazine vindesine subcutaneous interleukin-2
interferon alpha2a and tamoxifen in metastatic melanoma
BREMIM (Biological Response Modifiers in Melanoma)
Melanoma research 19999(5)503ndash9
Sparano 1993 published data only
Sparano JA Fisher RI Sunderland M Margolin K Ernest
ML Sznol M et alRandomized phase III trial of treatment
with high-dose interleukin-2 either alone or in combination
with interferon alfa-2a in patients with advanced melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199311(10)1969ndash77
Vuoristo 2005 published data only
Vuoristo MS Hahka-Kemppinen M Parvinen LM
Pyrhonen S Seppa H Korpela M et alRandomized trial of
dacarbazine versus bleomycin vincristine lomustine and
dacarbazine (BOLD) chemotherapy combined with natural
or recombinant interferon-alpha in patients with advanced
melanoma Melanoma research 200515(4)291ndash6
Additional references
Arance 2000
Arance A Middleton M Lorigan P Thatcher N Three-
arm phase II study of temozolomide (TMZ) in metastatic
melanoma (MM) In ASCO Annual Meeting 2000
Abstract 2257
Bafaloukos 2002
Bafaloukos D Aravantinos G Fountzilas G Stathopoulos
G Gogas H Samonis G et alDocetaxel in combination
with dacarbazine in patients with advanced melanoma
Oncology 200263(4)333ndash7
Bajetta 2002
Bajetta E Del Vecchio M Bernard-Marty C Vitali
M Buzzoni R Rixe O et alMetastatic melanoma
chemotherapy Seminars in Oncology 200229(5)427ndash45
Balch 2001
Balch CM Soong SJ Gershenwald JE Thompson JF
Reintgen DS Cascinelli N et alPrognostic factors analysis
of 17600 melanoma patients validation of the American
Joint Committee on Cancer melanoma staging system
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200119(16)3622ndash34
Barth 1995
Barth A Morton DL The role of adjuvant therapy in
melanoma management Cancer 199575 Suppl (2)
726ndash34
Chiarion-Sileni 2003
Chiarion-Sileni V Del Bianco P De Salvo GL Lo Re G
Romanini A Labianca R et alQuality of life evaluation in a
randomised trial of chemotherapy versus bio-chemotherapy
in advanced melanoma patients European journal of cancer
(Oxford England 1990) 200339(11)1577ndash85
Creagan 1984
Creagan ET Ahmann DL Green SJ Long HJ Frytak S
OrsquoFallon JR et alPhase II study of low-dose recombinant
leukocyte A interferon in disseminated malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 19842(9)1002ndash5
Crosby 2000
Crosby T Fish R Coles B Mason MD Systemic treatments
for metastatic cutaneous melanoma Cochrane Database
of Systematic Reviews 2000 Issue 2 [DOI 101002
14651858CD001215]
12Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Cure 1999
Cure H Souteyrand P Ouabdesselam R Roche H
Ravaud A DrsquoIncan M et alResults of a phase II trial
with cystemustine at 90 mgm(2) as a first- or second-line
treatment in advanced malignant melanoma a trial of the
EORTC Clinical Studies Group Melanoma Research 1999
9(6)607ndash10
Danson 2002
Danson S Arance A Lorigan P Clamp A Hodgetts J
Lomax L Thatcher N Middleton MR A randomized
study of temozolomide (TMZ) alone with interferon-
alpha (TMZ-IFN) or with thalidomide (TMZ-THAL) in
metastatic malignant melanoma (MMM) ASCO Annual
Meeting - Proceedings 2002Abstract 1369
Dorval 1986
Dorval T Palangie T Jouve M Garcia-Giralt E Israel L
Falcoff E et alClinical phase II trial of recombinant DNA
interferon (interferon alpha 2b) in patients with metastatic
malignant melanoma Cancer 198658(2)215ndash8
Dutcher 1989
Dutcher JP Creekmore S Weiss GR Margolin K
Markowitz AB Roper M et alA phase II study of
interleukin-2 and lymphokine-activated killer cells in
patients with metastatic malignant melanoma Journal of
clinical oncology official journal of the American Society of
Clinical Oncology 19897(4)477ndash85
Falkson 1995
Falkson CI Experience with interferon alpha 2b combined
with dacarbazine in the treatment of metastatic malignant
melanoma Medical oncology (Northwood London England)
199512(1)35ndash40
Garbe 1990
Garbe C Krasagakis K Zouboulis CC Schroder K Kruger
S Stadler R et alAntitumor activities of interferon alpha
beta and gamma and their combinations on human
melanoma cells in vitro changes of proliferation melanin
synthesis and immunophenotype Journal of Investigative
Dermatology 199095 Suppl (6)231ndash7
Gershenwald 1999
Gershenwald JE Thompson W Mansfield PF Lee JE
Colome MI Tseng CH et alMulti-institutional melanoma
lymphatic mapping experience the prognostic value of
sentinel lymph node status in 612 stage I or II melanoma
patients Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199917(3)976ndash83
Hanninen 1991
Hanninen EL Korfer A Hadam M Schneekloth C
Dallmann I Menzel T et alBiological monitoring of
low-dose interleukin 2 in humans soluble interleukin 2
receptors cytokines and cell surface phenotypes Cancer
Research 199151(23 Pt 1)6312ndash6
Huncharek 2001
Huncharek M Caubet JF McGarry R Single-agent
DTIC versus combination chemotherapy with or without
immunotherapy in metastatic melanoma a meta-analysis
of 3273 patients from 20 randomized trials Melanoma
Research 200111(1)75ndash81
Juni 2001
Juni P Altman DG Egger M Assessing the quality of
controlled clinical trials BMJ 200132342ndash6
Kadison 2003
Kadison AS Morton DL Immunotherapy of malignant
melanoma The Surgical Clinics of North America 200383
(2)343ndash70
Keilholz 2002
Keilholz U Gore ME Biochemotherapy for advanced
melanoma Seminars in Oncology 200229(5)456ndash61
Khayat 2002
Khayat D Bernard-Marty C Meric JB Rixe O
Biochemotherapy for advanced melanoma maybe it is real
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200220(10)2411ndash4
Koh 1991
Koh HK Cutaneous melanoma New England Journal of
Medicine 1991325(3)171ndash82
La Vecchia 1999
La Vecchia C Lucchini F Negri E Levi F Recent declines
in worldwide mortality from cutaneous melanoma in youth
and middle age International Journal of Cancer 199981(1)
62ndash6
Lee 2000
Lee ML Tomsu K Von Eschen KB Duration of survival
for disseminated malignant melanoma results of a meta-
analysis Melanoma Research 200010(1)81ndash92
Legha 1998
Legha SS Ring S Eton O Bedikian A Buzaid AC Plager
C et alDevelopment of a biochemotherapy regimen
with concurrent administration of cisplatin vinblastine
dacarbazine interferon alfa and interleukin-2 for patients
with metastatic melanoma Journal of clinical oncology
official journal of the American Society of Clinical Oncology
199816(5)1752ndash9
Leong 2003
Leong SP Future perspectives on malignant melanoma
Surgical Clinics of North America 200383(2)453ndash6
Lokich 1979
Lokich JJ Garnick MB Legg M Intralesional immune
therapy methanol extraction residue of BCG or purified
protein derivative Oncology 197936(5)236ndash41
Nathan 1998
Nathan FE Mastrangelo MJ Systemic therapy in
melanoma Seminars in Surgical Oncology 199814(4)
319ndash27
Osborn 1977
Osborn DE Castro JE Immunological response in patients
receiving Corynebacterium parvum therapy Clinical
Oncology 19773(2)155ndash64
13Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Parmar 1998
Parmar MKB TV Stewart L Extracting summary statistics
to perform meta-analyses of the published literature for
survival endpoints Statistics in Medicine 1998172815ndash34
Richards 1992
Richards JM Mehta N Ramming K Skosey P Sequential
chemoimmunotherapy in the treatment of metastatic
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199210(8)1338ndash43
Rigel 1989
Rigel DS Rivers JK Kopf AW Friedman RJ Vinokur AF
Heilman ER et alDysplastic nevi Markers for increased
risk for melanoma Cancer 198963(2)386ndash9
Rosenberg 1989
Rosenberg SA Lotze MT Yang JC Aebersold PM Linehan
WM Seipp CA et alExperience with the use of high-
dose interleukin-2 in the treatment of 652 cancer patients
Annals of Surgery 1989210(4)474-84 discussion 484-5
Sertoli 1989
Sertoli MR Bernengo MG Ardizzoni A Brunetti I Falcone
A Vidili MG et alPhase II trial of recombinant alpha-2b
interferon in the treatment of metastatic skin melanoma
Oncology 198946(2)96ndash8
Smith 1993
Smith KA Lowest dose interleukin-2 immunotherapy
Blood 199381(6)1414ndash23
Stopeck 2001
Stopeck AT Jones A Hersh EM Thompson JA
Finucane DM Gutheil JC et alPhase II study of direct
intralesional gene transfer of allovectin-7 an HLA-B7
beta2-microglobulin DNA-liposome complex in patients
with metastatic melanoma Clinical Cancer Research 20017
(8)2285ndash91
Tsang 1983
Tsang KY Fudenberg HH Pan JF Gnagy MJ Bristow
CB An in vitro study on the effects of isoprinosine on
immune responses in cancer patients International Journal
of Immunopharmacology 19835(6)481ndash90
Wingo 1995
Wingo PA Tong T Bolden S Cancer statistics 1995 CA
a cancer journal for clinicians 199545(1)8ndash30
Yusuf 1985
Yusuf S Peto R Lewis J Collins R Sleight P Beta blockade
during and after myocardial infarction an overview of the
randomized trials Progress in Cardiovascular Diseases 1985
27(5)335ndash71lowast Indicates the major publication for the study
14Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Atkins 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding public
Participants PS lt= 1
Brain mets no info
Age 20 to 80 (median 50)
Number of cycles no info
Randomised 416 a 206 b 210
Evaluable 405 a 201 b 204
Interventions a (CT) cisplatin 20mgm2 D1 to 4 vinblastin 12 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1-4 vimblastin 12 mgm2 D1-4 DTIC 800 mgm2 D1
IFN-alpha 5 mIU D1-5 D8 D10 D12 IL-2 9 mIU D1-4
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
Notes Multicentric yes
Withdrawals a five b six
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
15Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Atzpodien 2002
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding both (pharmaceutic and public)
Participants PS lt= 1
Brain mets yes Age 28 to 77 (median 57)
Number of cycles no info
Randomised 124 a 60 b 64
Evaluable 124 a 60 b 64
Interventions a (CT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily
b (ICT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily IFN-alpha 5 mIUm2 D1 week4 and 5
mIUm2 D1 D3 D5 week 5 IL-2 10 mIUm2 D1 D3 D5
(each five weeks)
Outcomes 1 Response rates
2 Overall survival
3 Progression free survival
Notes Multicentric yes
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Bajetta 1994
Methods D parallel group (three groups)
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding pharmaceutic
Participants PS lt= 2
Brain mets no
16Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Bajetta 1994 (Continued)
Age 18 to 70 (median 53)
Number of cycles 8
Randomised 266 a 88 b 86 c 92
Evaluable 242 a 82 b 76 c 84
Interventions a (CT) DTIC 800 mgm2 D1
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU 3xweek
c (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU D1 to 3 6 mIU D4 to 6 9 mIU daily
(each 21 days)
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Overall survival
Notes Multicentric yes
Withdrawals a six b ten c eight
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Danson 2003
Methods D parallel group
AC independent allocation
RS permuted blocks
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets yes Age 16 to 88 (median 58)
Number of cycles six
Randomised 125 a 59 b 62
Evaluable 121 a 55 b 62
Interventions a (CT) temozolomide 200 mgm2 88 h (5 doses)
b (ICT) Temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIU 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
17Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Danson 2003 (Continued)
Notes Multicentric no
Withdrawals a 4 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Del Vecchio 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no Age 19 to 70 (median 50)
Number of cycles no info
Randomised 151 a 75 b 76
Evaluable 145 a 72 b 73
Interventions a (CT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250 mgm2 D1 to
3
b (ICT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250m gm2 D1 to
3 IFN-alpha 5 mIUm2 D1 to 5 IL-2 9 mIUday x 5 daysweek x 2 weeks with a week of
rest
(each 21 days)
Outcomes 1 Response rates
2 Time to Progression
2 Overall Survival
Notes Multicentric yes
Withdrawals a three b three
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
18Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Eton 2002
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding pharm
Participants PS lt= 3
Brain mets yes Age median 49
Number of cycles no info
Randomised 190
Evaluable 183 a 92 b 91
Interventions a (CT) cisplatin 20m gm2 D1 to 4 vimblastin 2 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1 to 4 vinblastin 15 mgm2 D1 to 4 DTIC 800 mgm2
D1 IFN-alpha 5mIUm2 D5 to 9 D17-21 IL-2 9 mIUm2 D5 to 8 D17 to 20
(each 21 days)
Outcomes 1 Response rates
2 Time to progression
3 Overall survival
Notes Multicentric no
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1991
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size no
ITT no
Placebo no
Funding both
Participants PS lt= 1
Brain mets no
Age 22 to 79
(median 57)
Number of cycles at least two
19Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1991 (Continued)
Randomised 73 Evaluable 68 a 34 b 34
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Time to treatment failure
3 Median survival
4 Toxicity
Notes Multicentric no
Withdrawals a three b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1998
Methods D 2 x 2 factorial design
AC independent allocation
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 18 to 84
Number of cycles no info
Randomised 271 Evaluable 263 a 68 b 65 c 63 d 67
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
c (CT) DTIC 200m gm2 D1 to 5 tamoxifen 20 mgdaily
d (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek tamoxifen 20 mgdaily
(each 28 days)
Outcomes 1 Response rates
2 Toxicity rates
20Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1998 (Continued)
3 Overall survival
4 Time to treatment failure
Notes Multicentric yes
Withdrawals a one b three c three d one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Gorbonova 2000
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no
Age 23 to 75
Number of cycles no info
Randomised 30 Evaluable 28 a 14 b 14
Interventions a (CT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2
b (ICT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2 IFN-alpha 3 mIU D5 7
9 11 13 15 17 19
(each 28 days)
Outcomes 1 Response rates
Notes Multicentric no
Withdrawals a two b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
21Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Johnston 1998
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age 18 to 70
(median 45)
Number of cycles no info
Randomised 65 Evaluable 65 a 30 b 35
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to 3
Tamoxifen 40 mg daily
b (ICT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to
3 Tamoxifen 40 mg daily IFN-alpha 9 mIU D1 to 3 IL-2 18 mIU D-2 IL-2 9 mIU D-
1 and 0
(each 28 days)
Outcomes 1 Response rates
2 Time to disease progression
3 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Kirkwood 1990
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding pharm
22Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Kirkwood 1990 (Continued)
Participants PS no info
Brain mets no info
Age no info
Number of cycles no info
Randomised 74 Evaluable 68 a 24 b 23 c 21
Interventions a (CT) DTIC 250 mgm2 D1 to 5 (each 21 days)
b (I) IFN-alpha 3 mIU d1 to 5 every week for 3 weeks than 3 mIUm2 3 xweek
c (ICT) DTIC 250 mgm2 D1 to 5 (each 21 days) IFN-alpha 3 mIU d1 to 5 every week
for 3 weeks than 3 mIUm2 3 xweek
Outcomes 1 Response rates
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Middleton 2000
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets no
Age 24 to 71
(median 51)
Number of cycles six
Randomised 105 Evaluable 96 a 46 b 50
Interventions a (CT) DTIC 800 mgm2 D1 cisplatin 25 mgm2 D1 to 3 BCNU 150 mgm2 D1
tamoxifen 20 mgdaily
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 9 mIU 3 xweek
(each 21 days)
Outcomes 1 Response rates
2 One year survival
3 Median survival
23Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Middleton 2000 (Continued)
4 Toxicity
4 Time spent in hospital
Notes Multicentric no
Withdrawals a seven b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Ridolfi 2002
Methods D parallel group
AC independent allocation by telephone
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 25 to 77
Number of cycles six
Randomised 178 Evaluable 176 a 89 b 87
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1
b (ICT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1 IFN-
alpha 3 mIU 3 xweek IL-2 45 mIU D3 to 5 D8 to 12
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
3 Time to progression
4 Toxicity
Notes Multicentric yes
Withdrawals a one b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
24Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Electronic searches
Electronic databases
We searched the following electronic databases
1 MEDLINE (OVID) (Appendix 1)
2 The Cochrane Skin Group Specialised Register
3 The Cochrane Central Register of Controlled Trials
4 Medline (PubMed)
5 EMBASE
6 LILACS (Latin American and Caribbean Health Science
Information Database)
Search strategies for databases 2 to 6 are located in Appendix 2
Search of databases of ongoing trials (unpublished literature)
We asked trial authors and pharmaceutical companies about un-
published and ongoing trials Databases of major research groups
and registers of trials in the following databases were also searched
with the term rsquoMELANOMArsquo
bull Current Controlled Trials Register (httpwwwcontrolled-
trialscom) on 30th January 2006
bull European Organisation for Research and Treatment of
Cancer (httpwwweortcbe) on 20th February 2006
bull National Cancer Institute America (http
wwwcancergovclinicaltrials) on 16th November 2005
bull National Cancer Institute Canada (httphttp
wwwctgqueensucapublicClinical_Trialsclinical_trialshtml)
on 30th January 2006
bull Australian Clinical Trials Registry (httpwwwactrorgau)
on 30th January 2006
bull US Food and Drug Administration (httpwwwfdagov)
on 30th January 2006
bull ClinicalTrialsgov (httpwwwclinicaltrialsgov) on 16th
November 2005
Searching other resources
References from unpublished studies
All bibliographies of selected studies were scanned for possible
references to RCTs
Conference proceedings
We handsearched the abstracts from conference proceedings of
the ASCO (American Society of Clinical Oncology) and ESMO
(European Society of Medical Oncology)
Data collection and analysis
Where there was uncertainty we tried to contact trial authors for
clarification
A consumer (LU) was involved throughout the review process to
ensure the readability of the final review Updating will be done
every two years
Selection of studies
Two authors (ADS and ECS) checked the titles and abstracts iden-
tified from the searches If it was clear that the study did not refer
to a RCT on metastatic melanoma we excluded it Two authors
(ADS and OAC) independently assessed each remaining study to
determine whether it met the pre-defined selection criteria Any
differences were resolved through discussion with the review team
Excluded studies are listed in the Table of Excluded Studies
Data extraction and management
Two authors (ADS and ECS) independently extracted the data
from the studies All data were extracted directly from the text or
calculated according to the available information
Any differences were resolved by discussion with one author
(OAC) A data extraction form was developed and piloted in order
to summarize the trials One author (ADS) checked and entered
the data Two authors (ECS and LGC) independently checked the
data entry
Assessment of risk of bias in included studies
Assessment of methodological quality
The quality assessment included an evaluation of the following
components for each included study since there is some evidence
that these are associated with biased estimates of treatment effect
(Juni 2001)
(a) the method of generation of the randomisation sequence
(b) the method of allocation concealment - it was considered rsquoad-
equatersquo if the assignment could not be foreseen
(c) who was blindednot blinded (participants clinicians outcome
assessors)
(d) how many participants were lost to follow up in each arm and
whether participants were analysed in the groups to which they
were originally randomised (intention-to-treat)
In addition the quality assessment also included
(e) the source of funding
(f ) if the participant had a biopsy proven melanoma
(g) the baseline assessment of the participants for presence of liver
and brain metastases performance status
(h) whether the aims interventions (including drug doses and
duration of treatment) and outcome measures were clearly defined
5Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(i) the use and appropriateness of statistical analyses
We recorded all the information in a table of quality criteria and
gave a description of the quality of each study based on these
characteristics
Measures of treatment effect
Where possible we performed a meta-analysis for the outcomes
in order to calculate a weighted treatment effect across trials using
a random-effects model For binary endpoints we calculated the
risk ratio (RR) with 95 confidence intervals (Yusuf 1985) We
also expressed the results as a number needed to treat (NNT)
where appropriate for a range of plausible control event rates For
overall survival a time-to-event data we calculated the Hazard
Ratio (HR) When data were not available for direct extraction
we calculated indirectly (from different parameters using indirect
calculation of the variance and the number of observed minus
expected events) according to the method described by Parmar
(Parmar 1998) In the funnel plot (Figure 1) and comparison 1
rsquoPeto OR (IPD)rsquo is a Hazard Ratio For continuous data such as
quality of life we planned to use standardised mean differences
with 95 confidence intervals would have been used
Figure 1 Funnel plot using overall survival as the outcome
Assessment of heterogeneity
Heterogeneity was assessed using I2 Where the heterogeneity was
considerable (I2 gt 50) we explored possible reasons using the
type (interleukin-2 or interferon) and dose (high or low) of im-
munotherapy used as subgroups Where we were not able to find
an explanation we have recorded this along with appropriate cau-
tion in the interpretation of these data
Data synthesis
Analysis and presentation
Once studies had been selected critically appraised and the data
extracted we entered the data in the Characteristics of included
studies table
6Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Three studies (Bajetta 1994 Kirkwood 1990 Vorobiof 1994) eval-
uated three arms of treatment with one of them evaluating che-
motherapy alone and the two others using chemoimmunotherapy
One study (Falkson 1998) had four arms two using chemotherapy
and two using chemoimmunotherapy The data from the similar
arms were grouped considered as one and then compared to the
other arm
R E S U L T S
Description of studies
Results of the search
We scanned approximately 700 citations Initially 28 studies
were identified Four studies (Arance 2000 Chiarion-Sileni 2003
Danson 2002 Falkson 1995) had data that overlapped with three
included studies (Danson 2003 Falkson 1991 Ridolfi 2002)
Ongoing studies
No ongoing studies were available to be included in the meta-
analysis
Included studies
Eighteen studies with a total of 2625 participants met our criteria
and were included in the meta-analysis (please see Characteristics
of included studies) One study differed considerably from the oth-
ers because vindesine was used as the chemotherapy control a drug
without evidence of response in metastatic melanoma (Vorobiof
1994) Another study differed considerably as lower dose treat-
ment in the chemoimmunotherapy group was used (Middleton
2000) The first study was published in 1990 and the last studies
were published in 2003
Participants
The participants were between the ages of 16 and 88 years and
had an Eastern Cooperative Oncology Group performance status
from 0 to 3 Only three studies included participants with brain
metastasis (Atzpodien 2002 Danson 2003 Eton 2002)
Interventions
Seven studies compared chemotherapy to chemoimmunotherapy
with IFN plus IL-2 (Atkins 2003 Atzpodien 2002 Del Vecchio
2003 Eton 2002 Johnston 1998 Ridolfi 2002 Rosenberg 1999)
Eleven compared chemotherapy to chemoimmunotherapy with
IFN (Bajetta 1994 Danson 2003 Falkson 1991 Falkson 1998
Gorbonova 2000 Kirkwood 1990 Middleton 2000 Spieth 2003
Thomson 1993 Vorobiof 1994 Young 2001)
The drugs used in chemotherapeutic schemes varied between the
trials Seven trials evaluated DTIC combined with other drugs in
both arms (Atkins 2003 Atzpodien 2002 Del Vecchio 2003 Eton
2002 Johnston 1998 Ridolfi 2002 Rosenberg 1999) and six
evaluated DTIC alone as the control (Bajetta 1994 Falkson 1991
Falkson 1998 Kirkwood 1990 Thomson 1993 Young 2001)
Four studies evaluated other schemes without DTIC two trials
used temozolomide (Danson 2003 Spieth 2003) one trial used
vindesine (Vorobiof 1994) and one trial used combined drugs
based on cisplatin (Gorbonova 2000)
Only one study did not use the same scheme in both the arms
using combined drugs with DTIC as the chemotherapy control
and a lower dose for the chemoimmunotherapy group with DTIC
alone (Middleton 2000)
Setting
Ten studies were carried out in Europe four in the United States
two in South Africa and one was a multicentre worldwide trial
All trials were reported in the English language
Outcomes
Response rates were the primary outcome measures in most trials
and were described in all included studies Two studies did not
evaluate survival rates (Gorbonova 2000 Kirkwood 1990) Three
studies included quality of life analyses in the outcomes (Ridolfi
2002 Thomson 1993 Young 2001) The length of the follow-up
varied widely between the trials and sometimes it was not speci-
fied We did not find a reasonable definition about what could be
considered high or low doses of immunotherapy and the influence
of the immunotherapeutic doses on the outcomes could not be
assessed
Excluded studies
Six studies were excluded (see Characteristics of excluded studies)
The reasons for exclusion were that the study had immunotherapy
on both arms (Bajetta 2001 Richtig 2004 Sertoli 1999 Sparano
1993 Vuoristo 2005) or the study was not randomised (Legha
1996)
Risk of bias in included studies
The quality assessment consisted of a basic methodological eval-
uation of each included study and is shown in Table 1 Addi-
tional quality assessment is shown in Table 2 The criteria used for
methodological quality analysis of the studies are listed in Table 3
(Explanation of Quality Analysis Headings)
7Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Although blinding participants and clinicians is theoretically pos-
sible it is difficult to plan a double-blind study with immunother-
apy This is due to the substantial acute and late toxicities associ-
ated with immunotherapy in one group No study was described
as double-blinded The groups at baseline were in general similar
with a description of most prognostic factors related to metastatic
melanoma (gender performance status age prior therapy liver
metastasis)
In three studies almost all methodological aspects of the trials
were described poorly (Gorbonova 2000 Kirkwood 1990 Spieth
2003)
Allocation
All the included studies were described as randomised as this
was a selection criterion However most papers did not describe
the method of randomisation The method of generation of the
randomised sequence was described and considered adequate in
only 6 out of 18 studies Eleven of 18 studies provided information
on allocation concealment all of which were considered adequate
Blinding
Blinding of outcome assessment and detection bias
We did not find information about blinding of the outcome as-
sessors in any included study
Incomplete outcome data
Handling of losses and attrition bias
In general there were few participants lost to follow up in the
studies The highest number of people lost was 24 in a total of 262
participants (Bajetta 1994) Eleven studies included an intention-
to-treat analysis
Effects of interventions
Primary outcome
Overall survival (eight studies)
This was considered as the number of participants alive at the end
of the trial Sufficient data were available from 8 of the 18 studies
There was no statistically significant difference in survival between
chemoimmunotherapy and chemotherapy with a hazard ratio
(HR) of improved survival of 089 (95 CI 072 to 111 P = 031
Analysis 11) in favour of chemoimmunotherapy In other words
overall survival was slightly lower in the chemoimmunotherapy
group but this was not statistically significant There was no het-
erogeneity across trials (I2 = 0) The funnel plot method using
overall survival as the outcome is presented in Figure 1 It shows
that there was no evidence of substantial publication bias but in-
terpretation of the funnel plot is likely to be unreliable since only
eight relatively large studies were found
When we evaluated the influence of the type of immunotherapy
used in the chemoimmunotherapy group (IL-2 plus IFN-alpha
or IFN-alpha only) we found no statistically significant difference
between the groups with a HR of 096 (95 CI 074 to 124 P =
076 Analysis 11) for chemoimmunotherapy with IL-2 plus IFN-
alpha and a HR of 074 (95 CI 049 to 112 P = 015 Analysis
11) for chemoimmunotherapy associated with only IFN-alpha
Secondary outcomes
One two and five-year survival rates (13 studies)
The number of participants alive at one two and five year follow-
ups were analyzed Data from 13 trials evaluating one year survival
were pooled There was no statistically significant difference in one
year survival between the groups with a risk ratio (RR) of 106
(95 CI 091 to 124 P = 048 Analysis 12) and no significant
heterogeneity across trials (I2 = 363)
Data from 11 trials evaluating 2 year survival were extracted and
pooled Again there was no statistically significant difference be-
tween the groups with a RR of 108 (95 CI 086 to 136 P =
050 Analysis 13) without heterogeneity across trials (I2 = 0)
Only two trials reported data about five year survival The meta-
analysis showed no statistically significant difference in 5 year sur-
vival between the groups with a RR of survival of 234 (95
CI 097 to 565 P = 006 Analysis 14) favouring chemoim-
munotherapy There was no heterogeneity across trials (I2 = 0)
Response rates (17 studies)
Data regarding the number of participants with partial or com-
plete responses from 17 trials were used to evaluate objective re-
sponse rates The analysis detected a statistically significant differ-
ence in favor of chemoimmunotherapy in global response rates
with a RR of 140 (95 CI 120 to 163 P lt 00001 Analysis
21) There was no heterogeneity across trials (I2 = 42) We
tried to evaluate the influence of the type of immunotherapeutic
in the group of chemoimmunotherapy (IL-2 plus IFN-alpha or
IFN-alpha only) We found similar results with a RR of global
response of 146 (95 CI 119 to 179 p = 00002 Analysis 21)
in favor of chemoimmunotherapy with IL-2 plus IFN-alpha and
a RR of 132 (95 CI 102 to 171 p = 004 Analysis 21) in favor
of chemoimmunotherapy with IFN-alpha There was no hetero-
geneity across trials (I2 = 0)
8Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Data from 15 trials were used to evaluate partial and complete
response rates We found a statistically significant difference in
favour of chemoimmunotherapy in both analyses with an HR of
131 (95 CI 107 to 159 p = 0008 Analysis 23) for partial
response rates and an HR of 158 (95 CI 106 to 236 p = 003
Analysis 23) for complete response rates
Progression-free survival (3 studies)
Only three studies had extractable data about the number of par-
ticipants with no disease progression at the end of the trial When
pooled together there was no statistically significant difference be-
tween the groups with an HR of 076 (95 CI 057 to 102 p =
007 Analysis 31) There was no heterogeneity across these trials
(I2 = 0)
Treatment related toxicity (11 studies)
Data from 11 studies were collected with the number of partici-
pants developing clinically significant hematological toxicity (de-
fined as grade 3 or 4) Eight studies had estimated points that
showed enhanced toxicities in the chemoimmunotherapy group
The meta-analysis of the studies showed extreme heterogeneity
(I2 = 941) across the trials We performed a sensitivity anal-
ysis excluding the studies with relatively low doses of chemo-
therapeutic drugs in the chemoimmunotherapy group (Danson
2003 Middleton 2000) but we found similar heterogeneity (I2 =
978)
When we analyzed data from the four studies with similar rela-
tive doses of chemotherapeutics associated with interferon-alpha
without interleukin-2 we found an increase of clinically signifi-
cant hematological toxicities in the chemoimmunotherapy group
with a RR 454 (95 CI 235 to 879 p lt 000001) There was
no heterogeneity across these trials (I2 = 0) When we analyzed
data from studies with combination of interferon-alpha plus in-
terleukin-2 in the chemoimmunotherapy group we again found
extreme heterogeneity across the trials (I2 = 979)
Despite the heterogeneity in global meta-analysis we concluded
that it was not possible to quantify the differences in hematologi-
cal toxicity in such different trials In order to explore these differ-
ences we noted that one study referred to hematological toxicity
in 100 of participants treated with chemoimmunotherapy and
in 96 of participants treated with chemotherapy (Eton 2002)
Another study referred to hematological toxicity only in 2 and
1 respectively (Bajetta 1994)
Non-hematological toxicities were described in almost all stud-
ies and were mainly described as nausea vomiting flu-like syn-
drome asthenia hypotension and fever Data from six similar
studies were extractable and were pooled in the meta-analysis re-
sulting in a statistically significant difference against the chemoim-
munotherapy group with a RR of 274 (95 CI 206 to 364 p
lt 000001 Analysis 42) There was no heterogeneity across trials
(I2 = 0) These results must be treated with caution because of
similar difficulties in pooling these data on hematological toxici-
ties with different therapeutic schemes and several trials described
non-hematological toxicities but we were not able to extract the
data
Data about treatment-related mortality were available in 11 stud-
ies We found no significant difference between the groups with a
RR of 078 (95 CI 026 to 232 p = 065 Analysis 43) There
was no heterogeneity across the trials (I2 = 0)
Quality of life (three studies)
Only three studies reported data on quality of life (Ridolfi 2002
Thomson 1993 Young 2001) all using different methods One
trial described quality of life analysis in detail in an additional pub-
lication (Chiarion-Sileni 2003 Ridolfi 2002) This study found
a significant decrease of overall quality of life in the chemoim-
munotherapy group in comparison to the chemotherapy group
(p = 003) The other two studies did not find differences in global
quality of life between the groups (Thomson 1993 Young 2001)
Thomson did not report global quality of life (Thomson 1993)
Young found no significant differences in quality of life for the
change in scores over time (z = -129 p = 020) (Young 2001)
It was not possible to pool the data as all three studies did not
provide extractable data
Sensitivity analyses on the influence of source of funding baseline
assessment and allocation concealment on the survival analysis
and response rate analyses revealed that there was no relation be-
tween these methodological aspects and the outcome There was
no statistically significant difference in survival between the groups
in all analyses and the difference in response rates in favour of
chemoimmunotherapy was found to be significant
D I S C U S S I O N
Metastatic melanoma is reputed as refractory to most systemic
treatments and little progress has been made in treatment of
metastatic melanoma These concepts are supported by results
from previous systematic reviews One review concluded that there
is no evidence derived from RCTs that systemic treatment is better
than best supportive care (Crosby 2000) Another review of 20
randomised trials (involving 3273 participants) comparing single-
agent DTIC with DTIC in combination with other drugs with or
without immunotherapy concluded that combination of drugs in-
creased response rates but not overall survival (Huncharek 2001)
This systematic review summarises the evidence regarding the
use of chemoimmunotherapy compared to chemotherapy alone
to treat people with metastatic malignant melanoma There are
some important observations regarding the characteristics of the
included studies in this systematic review The ideal combination
9Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
of drugs for an investigation is not well established Seven studies
evaluated chemoimmunotherapy with interferon-alpha plus inter-
leukin-2 and 11 evaluated chemoimmunotherapy only with in-
terferon-alpha The treatment plans with drugs and dosages used
differed between studies
Most studies did not contribute in answering relevant questions
about the impact of chemoimmunotherapy in the treatment of
metastatic melanoma The outcomes were not clearly described in
several of the studies (Atkins 2003 Del Vecchio 2003 Gorbonova
2000 Kirkwood 1990 Spieth 2003 Thomson 1993) Two of
them did not report survival rates evaluating only response rates
(Gorbonova 2000 Kirkwood 1990) All these aspects influenced
the comparability of the trials and must be considered in the data
interpretation
On the basis of a meta-analysis of data coming from eight studies
this review showed no evidence of a difference in overall survival to
support the addition of immunotherapy to chemotherapy in the
systemic treatment of metastatic melanoma (Atkins 2003 Danson
2003 Eton 2002 Falkson 1991 Johnston 1998 Ridolfi 2002
Spieth 2003 Young 2001) Evaluation of one two and five-year
survival with data from other studies again showed no survival
advantage of the drug combination treatment
We found higher clinical response rates in people treated with
chemoimmunotherapy in comparison with people treated with
chemotherapy which was not translated into survival benefit
Additionally we found higher toxicity rates in people treated
with chemoimmunotherapy Despite the importance of evaluat-
ing quality of life there was no available data to perform the meta-
analysis in this systematic review Only three studies reported data
about quality of life all with different methods One trial described
poorer quality of life in people treated with chemoimmunother-
apy related to more intense side effects (Ridolfi 2002) Two trials
however showed no difference between groups (Thomson 1993
Young 2001) It is important that quality of life is included in all
future studies
Our meta-analysis did not find differences between treatment re-
lated mortality Subgroup analysis comparing combinations with
interferon-alpha and with interferon-alpha plus interleukin-2 did
not show different results in survival or response rates
The use of chemoimmunotherapy ie a combination of chemo-
therapy with interferon-alpha or interleukin-2 or both has not
been shown to be beneficial in this review Although short term
response rates were better overall in the chemoimmunotherapy
groups survival was not improved and drug-related toxicities were
higher in the combined chemoimmunotherapy group To date no
treatment regimen has shown efficiency in prolonging survival in
people with metastatic melanoma Little has changed in the sys-
temic management of metastatic melanoma in the last few years
The standard of care remains single-agent DTIC and the role of
immunotherapy remains in doubt
The use of chemoimmunotherapy in the treatment of melanoma
is justified only in the context of clinical trials
A U T H O R S rsquo C O N C L U S I O N S
Implications for practice
We failed to find any evidence to support the view that the
use of chemoimmunotherapy prolongs survival in people with
metastatic melanoma when compared to chemotherapy alone Al-
though short-term clinical responses were higher in the chemoim-
munotherapy group this was associated with a higher rate of
serious adverse events esp haematological toxicity Our review
does not support the use of a combination of immunother-
apy and chemotherapy in chemoimmunotherapy regimens out-
side of clinical trials The standard of care for people with
advanced melanoma remains chemotherapy with single-agent
DTIC Chemoimmunotherapy must not be recommended to peo-
ple in daily practice
Implications for research
Research related to the development of more effective treatments
for people with metastatic melanoma is urgently needed
For people with an incurable disease the primary outcome needs
to be overall survival and all studies should include a quality of life
analysis
Future trials should be designed to define the best systemic treat-
ment and should use chemotherapy with (DTIC) as a standard
control group in order to permit comparisons to be made
A C K N O W L E D G E M E N T S
The authors wish to thank Raquel Gebara Lima for her kind
support in grammar and style
The editorial base would like to thank the following people who
were external referees for this review Keith Wheatley and Pat
Lawton (content experts) and Kathie Godfrey (consumer)
10Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
R E F E R E N C E S
References to studies included in this review
Atkins 2003 published data only
Atkins MB Lee S Flaherty LE Sosman JA Sondak VK
Kirkwood JM A prospective randomized phase III trial
of concurrent biochemotherapy (BCT) with cisplatin
vinblastine dacarbazine (CVD) IL-2 and interferon alpha-
2b (IFN) versus CVD alone in patients with metastatic
melanoma (E3695) An ECOG-coordinated intergroup
trial In ASCO Annual Meeting 2003 2003 p ASCO
Annual Meeting - Proceedings 2003Abstract 2847
Atzpodien 2002 published data only
Atzpodien J Neuber K Kamanabrou D Fluck M Brocker
EB Neumann C et alCombination chemotherapy with or
without sc IL-2 and IFN-alpha results of a prospectively
randomized trial of the Cooperative Advanced Malignant
Melanoma Chemoimmunotherapy Group (ACIMM)
British journal of cancer 200286(2)179ndash84
Bajetta 1994 published data only
Bajetta E Di Leo A Zampino MG Sertoli MR Comella
G Barduagni M et alMulticenter randomized trial of
dacarbazine alone or in combination with two different
doses and schedules of interferon alfa-2a in the treatment
of advanced melanoma Journal of clinical oncology official
journal of the American Society of Clinical Oncology 199412
(4)806ndash11
Danson 2003 published data only
Danson S Lorigan P Arance A Clamp A Ranson
M Hodgetts J et alRandomized phase II study of
temozolomide given every 8 hours or daily with either
interferon alfa-2b or thalidomide in metastatic malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 200321(13)2551ndash7
Del Vecchio 2003 published data only
Del Vecchio M Bajetta E Vitali M Gattinoni L Santinami
M Daponte A et alMulticenter phase III randomized trial
of cisplatin vindesine and dacarbazine (CVD) versus CVD
plus subcutaneous (sc) interleukin-2 (IL-2) and interferon-
alpha-2b (IFN) in metastatic melanoma patients (pts) In
ASCO Annual Meeting 2003 2003 p ASCO Annual
Meeting - Proceedings 2003Abstract 2849
Eton 2002 published data only
Eton O Legha SS Bedikian AY Lee JJ Buzaid AC
Hodges C et alSequential biochemotherapy versus
chemotherapy for metastatic melanoma results from a
phase III randomized trial Journal of clinical oncology
official journal of the American Society of Clinical Oncology
200220(8)2045ndash52
Falkson 1991 published data only
Falkson CI Falkson G Falkson HC Improved results with
the addition of interferon alfa-2b to dacarbazine in the
treatment of patients with metastatic malignant melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 19919(8)1403ndash8
Falkson 1998 published data only
Falkson CI Ibrahim J Kirkwood JM Coates AS Atkins
MB Blum RH Phase III trial of dacarbazine versus
dacarbazine with interferon alpha-2b versus dacarbazine
with tamoxifen versus dacarbazine with interferon alpha-
2b and tamoxifen in patients with metastatic malignant
melanoma an Eastern Cooperative Oncology Group study
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199816(5)1743ndash51
Gorbonova 2000 published data only
Gorbonova VA Egorov GN Perevodchikova NI Orel
NF Combined chemotherapy with or without interferon
alpha N1 (IFN) for advanced malignant melanoma - a
randomized pilot phase III study Gan To Kagaku Ryoho
200027 Suppl (2)310ndash4
Johnston 1998 published data only
Johnston SR Constenla DO Moore J Atkinson H ArsquoHern
RP Dadian G et alRandomized phase II trial of BCDT
[carmustine (BCNU) cisplatin dacarbazine (DTIC)
and tamoxifen] with or without interferon alpha (IFN-
alpha) and interleukin (IL-2) in patients with metastatic
melanoma British Journal of Cancer 199877(8)1280ndash6
Kirkwood 1990 published data only
Kirkwood JM Ernstoff MS Giuliano A Gams R Robinson
WA Costanzi J et alInterferon alpha-2a and dacarbazine
in melanoma Journal of the National Cancer Institute 1990
82(12)1062ndash3
Middleton 2000 published data only
Middleton MR Grob JJ Aaronson N Fierlbeck G
Tilgen W Seiter S et alRandomized phase III study of
temozolomide versus dacarbazine in the treatment of
patients with advanced metastatic malignant melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200018(1)158ndash66
Ridolfi 2002 published data only
Ridolfi R Chiarion-Sileni V Guida M Romanini A
Labianca R Freschi A et alCisplatin dacarbazine with
or without subcutaneous interleukin-2 and interferon
alpha-2b in advanced melanoma outpatients results from
an Italian multicenter phase III randomized clinical trial
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200220(6)1600ndash7
Rosenberg 1999 published data only
Rosenberg SA Yang JC Schwartzentruber DJ Hwu P
Marincola FM Topalian SL et alProspective randomized
trial of the treatment of patients with metastatic melanoma
using chemotherapy with cisplatin dacarbazine and
tamoxifen alone or in combination with interleukin-2 and
interferon alfa-2b Journal of Clinical Oncology 199917(3)
968ndash75
Spieth 2003 published data only
Spieth K Dummer R Garbe C Mauch C Schuler G
Landthaler M et alTemozolomide in combination with
11Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
interferon alfa versus temozolomide alone in patients with
advanced metastatic melanoma A randomized phase
III multicenter study of the Dermatologic Cooperative
Oncology Group (DeCOG) In ASCO Annual Meeting
2003Abstract 2887
Thomson 1993 published data only
Thomson DB Adena M McLeod GR Hersey P Gill PG
Coates AS et alInterferon-alpha 2a does not improve
response or survival when combined with dacarbazine
in metastatic malignant melanoma results of a multi-
institutional Australian randomized trial Melanoma
Research 19933(2)133ndash8
Vorobiof 1994 published data only
Vorobiof DA Bezwoda WR A randomised trial of vindesine
plus interferon-alpha 2b compared with interferon-alpha 2b
or vindesine alone in the treatment of advanced malignant
melanoma European journal of cancer (Oxford England
1990) 199430A(6)797ndash800
Young 2001 published data only
Young AM Marsden J Goodman A Burton A Dunn
JA Prospective randomized comparison of dacarbazine
(DTIC) versus DTIC plus interferon-alpha (IFN-alpha) in
metastatic melanoma Clinical oncology (Royal College of
Radiologists (Great Britain)) 200113(6)458ndash65
References to studies excluded from this review
Bajetta 2001 published data only
Bajetta E Del Vecchio M Vitali M Martinetti A Ferrari L
Queirolo P et alA feasibility study using polychemotherapy
(cisplatin + vindesine + dacarbazine) plus interferon-alpha
or monochemotherapy with dacarbazine plus interferon-
alpha in metastatic melanoma Tumori 200187(4)219ndash22
Legha 1996 published data only
Legha SS Ring S Bedikian A Plager C Eton O Buzaid
AC et alTreatment of metastatic melanoma with combined
chemotherapy containing cisplatin vinblastine and
dacarbazine (CVD) and biotherapy using interleukin-2 and
interferon-alpha Annals of oncology official journal of the
European Society for Medical Oncology ESMO 19967(8)
827ndash35
Richtig 2004 published data only
Richtig E Hofmann-Wellenhof R Pehamberger H
Forstinger C Wolff K Mischer P et alTemozolomide and
interferon alpha 2b in metastatic melanoma stage IV British
Journal of Dermatology 2004151(1)91ndash8
Sertoli 1999 published data only
Sertoli MR Queirolo P Bajetta E DelVecchio M
Comella G Barduagni L et alMulti-institutional phase
II randomized trial of integrated therapy with cisplatin
dacarbazine vindesine subcutaneous interleukin-2
interferon alpha2a and tamoxifen in metastatic melanoma
BREMIM (Biological Response Modifiers in Melanoma)
Melanoma research 19999(5)503ndash9
Sparano 1993 published data only
Sparano JA Fisher RI Sunderland M Margolin K Ernest
ML Sznol M et alRandomized phase III trial of treatment
with high-dose interleukin-2 either alone or in combination
with interferon alfa-2a in patients with advanced melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199311(10)1969ndash77
Vuoristo 2005 published data only
Vuoristo MS Hahka-Kemppinen M Parvinen LM
Pyrhonen S Seppa H Korpela M et alRandomized trial of
dacarbazine versus bleomycin vincristine lomustine and
dacarbazine (BOLD) chemotherapy combined with natural
or recombinant interferon-alpha in patients with advanced
melanoma Melanoma research 200515(4)291ndash6
Additional references
Arance 2000
Arance A Middleton M Lorigan P Thatcher N Three-
arm phase II study of temozolomide (TMZ) in metastatic
melanoma (MM) In ASCO Annual Meeting 2000
Abstract 2257
Bafaloukos 2002
Bafaloukos D Aravantinos G Fountzilas G Stathopoulos
G Gogas H Samonis G et alDocetaxel in combination
with dacarbazine in patients with advanced melanoma
Oncology 200263(4)333ndash7
Bajetta 2002
Bajetta E Del Vecchio M Bernard-Marty C Vitali
M Buzzoni R Rixe O et alMetastatic melanoma
chemotherapy Seminars in Oncology 200229(5)427ndash45
Balch 2001
Balch CM Soong SJ Gershenwald JE Thompson JF
Reintgen DS Cascinelli N et alPrognostic factors analysis
of 17600 melanoma patients validation of the American
Joint Committee on Cancer melanoma staging system
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200119(16)3622ndash34
Barth 1995
Barth A Morton DL The role of adjuvant therapy in
melanoma management Cancer 199575 Suppl (2)
726ndash34
Chiarion-Sileni 2003
Chiarion-Sileni V Del Bianco P De Salvo GL Lo Re G
Romanini A Labianca R et alQuality of life evaluation in a
randomised trial of chemotherapy versus bio-chemotherapy
in advanced melanoma patients European journal of cancer
(Oxford England 1990) 200339(11)1577ndash85
Creagan 1984
Creagan ET Ahmann DL Green SJ Long HJ Frytak S
OrsquoFallon JR et alPhase II study of low-dose recombinant
leukocyte A interferon in disseminated malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 19842(9)1002ndash5
Crosby 2000
Crosby T Fish R Coles B Mason MD Systemic treatments
for metastatic cutaneous melanoma Cochrane Database
of Systematic Reviews 2000 Issue 2 [DOI 101002
14651858CD001215]
12Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Cure 1999
Cure H Souteyrand P Ouabdesselam R Roche H
Ravaud A DrsquoIncan M et alResults of a phase II trial
with cystemustine at 90 mgm(2) as a first- or second-line
treatment in advanced malignant melanoma a trial of the
EORTC Clinical Studies Group Melanoma Research 1999
9(6)607ndash10
Danson 2002
Danson S Arance A Lorigan P Clamp A Hodgetts J
Lomax L Thatcher N Middleton MR A randomized
study of temozolomide (TMZ) alone with interferon-
alpha (TMZ-IFN) or with thalidomide (TMZ-THAL) in
metastatic malignant melanoma (MMM) ASCO Annual
Meeting - Proceedings 2002Abstract 1369
Dorval 1986
Dorval T Palangie T Jouve M Garcia-Giralt E Israel L
Falcoff E et alClinical phase II trial of recombinant DNA
interferon (interferon alpha 2b) in patients with metastatic
malignant melanoma Cancer 198658(2)215ndash8
Dutcher 1989
Dutcher JP Creekmore S Weiss GR Margolin K
Markowitz AB Roper M et alA phase II study of
interleukin-2 and lymphokine-activated killer cells in
patients with metastatic malignant melanoma Journal of
clinical oncology official journal of the American Society of
Clinical Oncology 19897(4)477ndash85
Falkson 1995
Falkson CI Experience with interferon alpha 2b combined
with dacarbazine in the treatment of metastatic malignant
melanoma Medical oncology (Northwood London England)
199512(1)35ndash40
Garbe 1990
Garbe C Krasagakis K Zouboulis CC Schroder K Kruger
S Stadler R et alAntitumor activities of interferon alpha
beta and gamma and their combinations on human
melanoma cells in vitro changes of proliferation melanin
synthesis and immunophenotype Journal of Investigative
Dermatology 199095 Suppl (6)231ndash7
Gershenwald 1999
Gershenwald JE Thompson W Mansfield PF Lee JE
Colome MI Tseng CH et alMulti-institutional melanoma
lymphatic mapping experience the prognostic value of
sentinel lymph node status in 612 stage I or II melanoma
patients Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199917(3)976ndash83
Hanninen 1991
Hanninen EL Korfer A Hadam M Schneekloth C
Dallmann I Menzel T et alBiological monitoring of
low-dose interleukin 2 in humans soluble interleukin 2
receptors cytokines and cell surface phenotypes Cancer
Research 199151(23 Pt 1)6312ndash6
Huncharek 2001
Huncharek M Caubet JF McGarry R Single-agent
DTIC versus combination chemotherapy with or without
immunotherapy in metastatic melanoma a meta-analysis
of 3273 patients from 20 randomized trials Melanoma
Research 200111(1)75ndash81
Juni 2001
Juni P Altman DG Egger M Assessing the quality of
controlled clinical trials BMJ 200132342ndash6
Kadison 2003
Kadison AS Morton DL Immunotherapy of malignant
melanoma The Surgical Clinics of North America 200383
(2)343ndash70
Keilholz 2002
Keilholz U Gore ME Biochemotherapy for advanced
melanoma Seminars in Oncology 200229(5)456ndash61
Khayat 2002
Khayat D Bernard-Marty C Meric JB Rixe O
Biochemotherapy for advanced melanoma maybe it is real
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200220(10)2411ndash4
Koh 1991
Koh HK Cutaneous melanoma New England Journal of
Medicine 1991325(3)171ndash82
La Vecchia 1999
La Vecchia C Lucchini F Negri E Levi F Recent declines
in worldwide mortality from cutaneous melanoma in youth
and middle age International Journal of Cancer 199981(1)
62ndash6
Lee 2000
Lee ML Tomsu K Von Eschen KB Duration of survival
for disseminated malignant melanoma results of a meta-
analysis Melanoma Research 200010(1)81ndash92
Legha 1998
Legha SS Ring S Eton O Bedikian A Buzaid AC Plager
C et alDevelopment of a biochemotherapy regimen
with concurrent administration of cisplatin vinblastine
dacarbazine interferon alfa and interleukin-2 for patients
with metastatic melanoma Journal of clinical oncology
official journal of the American Society of Clinical Oncology
199816(5)1752ndash9
Leong 2003
Leong SP Future perspectives on malignant melanoma
Surgical Clinics of North America 200383(2)453ndash6
Lokich 1979
Lokich JJ Garnick MB Legg M Intralesional immune
therapy methanol extraction residue of BCG or purified
protein derivative Oncology 197936(5)236ndash41
Nathan 1998
Nathan FE Mastrangelo MJ Systemic therapy in
melanoma Seminars in Surgical Oncology 199814(4)
319ndash27
Osborn 1977
Osborn DE Castro JE Immunological response in patients
receiving Corynebacterium parvum therapy Clinical
Oncology 19773(2)155ndash64
13Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Parmar 1998
Parmar MKB TV Stewart L Extracting summary statistics
to perform meta-analyses of the published literature for
survival endpoints Statistics in Medicine 1998172815ndash34
Richards 1992
Richards JM Mehta N Ramming K Skosey P Sequential
chemoimmunotherapy in the treatment of metastatic
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199210(8)1338ndash43
Rigel 1989
Rigel DS Rivers JK Kopf AW Friedman RJ Vinokur AF
Heilman ER et alDysplastic nevi Markers for increased
risk for melanoma Cancer 198963(2)386ndash9
Rosenberg 1989
Rosenberg SA Lotze MT Yang JC Aebersold PM Linehan
WM Seipp CA et alExperience with the use of high-
dose interleukin-2 in the treatment of 652 cancer patients
Annals of Surgery 1989210(4)474-84 discussion 484-5
Sertoli 1989
Sertoli MR Bernengo MG Ardizzoni A Brunetti I Falcone
A Vidili MG et alPhase II trial of recombinant alpha-2b
interferon in the treatment of metastatic skin melanoma
Oncology 198946(2)96ndash8
Smith 1993
Smith KA Lowest dose interleukin-2 immunotherapy
Blood 199381(6)1414ndash23
Stopeck 2001
Stopeck AT Jones A Hersh EM Thompson JA
Finucane DM Gutheil JC et alPhase II study of direct
intralesional gene transfer of allovectin-7 an HLA-B7
beta2-microglobulin DNA-liposome complex in patients
with metastatic melanoma Clinical Cancer Research 20017
(8)2285ndash91
Tsang 1983
Tsang KY Fudenberg HH Pan JF Gnagy MJ Bristow
CB An in vitro study on the effects of isoprinosine on
immune responses in cancer patients International Journal
of Immunopharmacology 19835(6)481ndash90
Wingo 1995
Wingo PA Tong T Bolden S Cancer statistics 1995 CA
a cancer journal for clinicians 199545(1)8ndash30
Yusuf 1985
Yusuf S Peto R Lewis J Collins R Sleight P Beta blockade
during and after myocardial infarction an overview of the
randomized trials Progress in Cardiovascular Diseases 1985
27(5)335ndash71lowast Indicates the major publication for the study
14Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Atkins 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding public
Participants PS lt= 1
Brain mets no info
Age 20 to 80 (median 50)
Number of cycles no info
Randomised 416 a 206 b 210
Evaluable 405 a 201 b 204
Interventions a (CT) cisplatin 20mgm2 D1 to 4 vinblastin 12 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1-4 vimblastin 12 mgm2 D1-4 DTIC 800 mgm2 D1
IFN-alpha 5 mIU D1-5 D8 D10 D12 IL-2 9 mIU D1-4
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
Notes Multicentric yes
Withdrawals a five b six
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
15Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Atzpodien 2002
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding both (pharmaceutic and public)
Participants PS lt= 1
Brain mets yes Age 28 to 77 (median 57)
Number of cycles no info
Randomised 124 a 60 b 64
Evaluable 124 a 60 b 64
Interventions a (CT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily
b (ICT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily IFN-alpha 5 mIUm2 D1 week4 and 5
mIUm2 D1 D3 D5 week 5 IL-2 10 mIUm2 D1 D3 D5
(each five weeks)
Outcomes 1 Response rates
2 Overall survival
3 Progression free survival
Notes Multicentric yes
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Bajetta 1994
Methods D parallel group (three groups)
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding pharmaceutic
Participants PS lt= 2
Brain mets no
16Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Bajetta 1994 (Continued)
Age 18 to 70 (median 53)
Number of cycles 8
Randomised 266 a 88 b 86 c 92
Evaluable 242 a 82 b 76 c 84
Interventions a (CT) DTIC 800 mgm2 D1
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU 3xweek
c (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU D1 to 3 6 mIU D4 to 6 9 mIU daily
(each 21 days)
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Overall survival
Notes Multicentric yes
Withdrawals a six b ten c eight
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Danson 2003
Methods D parallel group
AC independent allocation
RS permuted blocks
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets yes Age 16 to 88 (median 58)
Number of cycles six
Randomised 125 a 59 b 62
Evaluable 121 a 55 b 62
Interventions a (CT) temozolomide 200 mgm2 88 h (5 doses)
b (ICT) Temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIU 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
17Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Danson 2003 (Continued)
Notes Multicentric no
Withdrawals a 4 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Del Vecchio 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no Age 19 to 70 (median 50)
Number of cycles no info
Randomised 151 a 75 b 76
Evaluable 145 a 72 b 73
Interventions a (CT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250 mgm2 D1 to
3
b (ICT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250m gm2 D1 to
3 IFN-alpha 5 mIUm2 D1 to 5 IL-2 9 mIUday x 5 daysweek x 2 weeks with a week of
rest
(each 21 days)
Outcomes 1 Response rates
2 Time to Progression
2 Overall Survival
Notes Multicentric yes
Withdrawals a three b three
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
18Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Eton 2002
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding pharm
Participants PS lt= 3
Brain mets yes Age median 49
Number of cycles no info
Randomised 190
Evaluable 183 a 92 b 91
Interventions a (CT) cisplatin 20m gm2 D1 to 4 vimblastin 2 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1 to 4 vinblastin 15 mgm2 D1 to 4 DTIC 800 mgm2
D1 IFN-alpha 5mIUm2 D5 to 9 D17-21 IL-2 9 mIUm2 D5 to 8 D17 to 20
(each 21 days)
Outcomes 1 Response rates
2 Time to progression
3 Overall survival
Notes Multicentric no
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1991
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size no
ITT no
Placebo no
Funding both
Participants PS lt= 1
Brain mets no
Age 22 to 79
(median 57)
Number of cycles at least two
19Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1991 (Continued)
Randomised 73 Evaluable 68 a 34 b 34
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Time to treatment failure
3 Median survival
4 Toxicity
Notes Multicentric no
Withdrawals a three b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1998
Methods D 2 x 2 factorial design
AC independent allocation
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 18 to 84
Number of cycles no info
Randomised 271 Evaluable 263 a 68 b 65 c 63 d 67
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
c (CT) DTIC 200m gm2 D1 to 5 tamoxifen 20 mgdaily
d (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek tamoxifen 20 mgdaily
(each 28 days)
Outcomes 1 Response rates
2 Toxicity rates
20Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1998 (Continued)
3 Overall survival
4 Time to treatment failure
Notes Multicentric yes
Withdrawals a one b three c three d one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Gorbonova 2000
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no
Age 23 to 75
Number of cycles no info
Randomised 30 Evaluable 28 a 14 b 14
Interventions a (CT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2
b (ICT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2 IFN-alpha 3 mIU D5 7
9 11 13 15 17 19
(each 28 days)
Outcomes 1 Response rates
Notes Multicentric no
Withdrawals a two b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
21Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Johnston 1998
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age 18 to 70
(median 45)
Number of cycles no info
Randomised 65 Evaluable 65 a 30 b 35
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to 3
Tamoxifen 40 mg daily
b (ICT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to
3 Tamoxifen 40 mg daily IFN-alpha 9 mIU D1 to 3 IL-2 18 mIU D-2 IL-2 9 mIU D-
1 and 0
(each 28 days)
Outcomes 1 Response rates
2 Time to disease progression
3 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Kirkwood 1990
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding pharm
22Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Kirkwood 1990 (Continued)
Participants PS no info
Brain mets no info
Age no info
Number of cycles no info
Randomised 74 Evaluable 68 a 24 b 23 c 21
Interventions a (CT) DTIC 250 mgm2 D1 to 5 (each 21 days)
b (I) IFN-alpha 3 mIU d1 to 5 every week for 3 weeks than 3 mIUm2 3 xweek
c (ICT) DTIC 250 mgm2 D1 to 5 (each 21 days) IFN-alpha 3 mIU d1 to 5 every week
for 3 weeks than 3 mIUm2 3 xweek
Outcomes 1 Response rates
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Middleton 2000
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets no
Age 24 to 71
(median 51)
Number of cycles six
Randomised 105 Evaluable 96 a 46 b 50
Interventions a (CT) DTIC 800 mgm2 D1 cisplatin 25 mgm2 D1 to 3 BCNU 150 mgm2 D1
tamoxifen 20 mgdaily
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 9 mIU 3 xweek
(each 21 days)
Outcomes 1 Response rates
2 One year survival
3 Median survival
23Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Middleton 2000 (Continued)
4 Toxicity
4 Time spent in hospital
Notes Multicentric no
Withdrawals a seven b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Ridolfi 2002
Methods D parallel group
AC independent allocation by telephone
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 25 to 77
Number of cycles six
Randomised 178 Evaluable 176 a 89 b 87
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1
b (ICT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1 IFN-
alpha 3 mIU 3 xweek IL-2 45 mIU D3 to 5 D8 to 12
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
3 Time to progression
4 Toxicity
Notes Multicentric yes
Withdrawals a one b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
24Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(i) the use and appropriateness of statistical analyses
We recorded all the information in a table of quality criteria and
gave a description of the quality of each study based on these
characteristics
Measures of treatment effect
Where possible we performed a meta-analysis for the outcomes
in order to calculate a weighted treatment effect across trials using
a random-effects model For binary endpoints we calculated the
risk ratio (RR) with 95 confidence intervals (Yusuf 1985) We
also expressed the results as a number needed to treat (NNT)
where appropriate for a range of plausible control event rates For
overall survival a time-to-event data we calculated the Hazard
Ratio (HR) When data were not available for direct extraction
we calculated indirectly (from different parameters using indirect
calculation of the variance and the number of observed minus
expected events) according to the method described by Parmar
(Parmar 1998) In the funnel plot (Figure 1) and comparison 1
rsquoPeto OR (IPD)rsquo is a Hazard Ratio For continuous data such as
quality of life we planned to use standardised mean differences
with 95 confidence intervals would have been used
Figure 1 Funnel plot using overall survival as the outcome
Assessment of heterogeneity
Heterogeneity was assessed using I2 Where the heterogeneity was
considerable (I2 gt 50) we explored possible reasons using the
type (interleukin-2 or interferon) and dose (high or low) of im-
munotherapy used as subgroups Where we were not able to find
an explanation we have recorded this along with appropriate cau-
tion in the interpretation of these data
Data synthesis
Analysis and presentation
Once studies had been selected critically appraised and the data
extracted we entered the data in the Characteristics of included
studies table
6Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Three studies (Bajetta 1994 Kirkwood 1990 Vorobiof 1994) eval-
uated three arms of treatment with one of them evaluating che-
motherapy alone and the two others using chemoimmunotherapy
One study (Falkson 1998) had four arms two using chemotherapy
and two using chemoimmunotherapy The data from the similar
arms were grouped considered as one and then compared to the
other arm
R E S U L T S
Description of studies
Results of the search
We scanned approximately 700 citations Initially 28 studies
were identified Four studies (Arance 2000 Chiarion-Sileni 2003
Danson 2002 Falkson 1995) had data that overlapped with three
included studies (Danson 2003 Falkson 1991 Ridolfi 2002)
Ongoing studies
No ongoing studies were available to be included in the meta-
analysis
Included studies
Eighteen studies with a total of 2625 participants met our criteria
and were included in the meta-analysis (please see Characteristics
of included studies) One study differed considerably from the oth-
ers because vindesine was used as the chemotherapy control a drug
without evidence of response in metastatic melanoma (Vorobiof
1994) Another study differed considerably as lower dose treat-
ment in the chemoimmunotherapy group was used (Middleton
2000) The first study was published in 1990 and the last studies
were published in 2003
Participants
The participants were between the ages of 16 and 88 years and
had an Eastern Cooperative Oncology Group performance status
from 0 to 3 Only three studies included participants with brain
metastasis (Atzpodien 2002 Danson 2003 Eton 2002)
Interventions
Seven studies compared chemotherapy to chemoimmunotherapy
with IFN plus IL-2 (Atkins 2003 Atzpodien 2002 Del Vecchio
2003 Eton 2002 Johnston 1998 Ridolfi 2002 Rosenberg 1999)
Eleven compared chemotherapy to chemoimmunotherapy with
IFN (Bajetta 1994 Danson 2003 Falkson 1991 Falkson 1998
Gorbonova 2000 Kirkwood 1990 Middleton 2000 Spieth 2003
Thomson 1993 Vorobiof 1994 Young 2001)
The drugs used in chemotherapeutic schemes varied between the
trials Seven trials evaluated DTIC combined with other drugs in
both arms (Atkins 2003 Atzpodien 2002 Del Vecchio 2003 Eton
2002 Johnston 1998 Ridolfi 2002 Rosenberg 1999) and six
evaluated DTIC alone as the control (Bajetta 1994 Falkson 1991
Falkson 1998 Kirkwood 1990 Thomson 1993 Young 2001)
Four studies evaluated other schemes without DTIC two trials
used temozolomide (Danson 2003 Spieth 2003) one trial used
vindesine (Vorobiof 1994) and one trial used combined drugs
based on cisplatin (Gorbonova 2000)
Only one study did not use the same scheme in both the arms
using combined drugs with DTIC as the chemotherapy control
and a lower dose for the chemoimmunotherapy group with DTIC
alone (Middleton 2000)
Setting
Ten studies were carried out in Europe four in the United States
two in South Africa and one was a multicentre worldwide trial
All trials were reported in the English language
Outcomes
Response rates were the primary outcome measures in most trials
and were described in all included studies Two studies did not
evaluate survival rates (Gorbonova 2000 Kirkwood 1990) Three
studies included quality of life analyses in the outcomes (Ridolfi
2002 Thomson 1993 Young 2001) The length of the follow-up
varied widely between the trials and sometimes it was not speci-
fied We did not find a reasonable definition about what could be
considered high or low doses of immunotherapy and the influence
of the immunotherapeutic doses on the outcomes could not be
assessed
Excluded studies
Six studies were excluded (see Characteristics of excluded studies)
The reasons for exclusion were that the study had immunotherapy
on both arms (Bajetta 2001 Richtig 2004 Sertoli 1999 Sparano
1993 Vuoristo 2005) or the study was not randomised (Legha
1996)
Risk of bias in included studies
The quality assessment consisted of a basic methodological eval-
uation of each included study and is shown in Table 1 Addi-
tional quality assessment is shown in Table 2 The criteria used for
methodological quality analysis of the studies are listed in Table 3
(Explanation of Quality Analysis Headings)
7Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Although blinding participants and clinicians is theoretically pos-
sible it is difficult to plan a double-blind study with immunother-
apy This is due to the substantial acute and late toxicities associ-
ated with immunotherapy in one group No study was described
as double-blinded The groups at baseline were in general similar
with a description of most prognostic factors related to metastatic
melanoma (gender performance status age prior therapy liver
metastasis)
In three studies almost all methodological aspects of the trials
were described poorly (Gorbonova 2000 Kirkwood 1990 Spieth
2003)
Allocation
All the included studies were described as randomised as this
was a selection criterion However most papers did not describe
the method of randomisation The method of generation of the
randomised sequence was described and considered adequate in
only 6 out of 18 studies Eleven of 18 studies provided information
on allocation concealment all of which were considered adequate
Blinding
Blinding of outcome assessment and detection bias
We did not find information about blinding of the outcome as-
sessors in any included study
Incomplete outcome data
Handling of losses and attrition bias
In general there were few participants lost to follow up in the
studies The highest number of people lost was 24 in a total of 262
participants (Bajetta 1994) Eleven studies included an intention-
to-treat analysis
Effects of interventions
Primary outcome
Overall survival (eight studies)
This was considered as the number of participants alive at the end
of the trial Sufficient data were available from 8 of the 18 studies
There was no statistically significant difference in survival between
chemoimmunotherapy and chemotherapy with a hazard ratio
(HR) of improved survival of 089 (95 CI 072 to 111 P = 031
Analysis 11) in favour of chemoimmunotherapy In other words
overall survival was slightly lower in the chemoimmunotherapy
group but this was not statistically significant There was no het-
erogeneity across trials (I2 = 0) The funnel plot method using
overall survival as the outcome is presented in Figure 1 It shows
that there was no evidence of substantial publication bias but in-
terpretation of the funnel plot is likely to be unreliable since only
eight relatively large studies were found
When we evaluated the influence of the type of immunotherapy
used in the chemoimmunotherapy group (IL-2 plus IFN-alpha
or IFN-alpha only) we found no statistically significant difference
between the groups with a HR of 096 (95 CI 074 to 124 P =
076 Analysis 11) for chemoimmunotherapy with IL-2 plus IFN-
alpha and a HR of 074 (95 CI 049 to 112 P = 015 Analysis
11) for chemoimmunotherapy associated with only IFN-alpha
Secondary outcomes
One two and five-year survival rates (13 studies)
The number of participants alive at one two and five year follow-
ups were analyzed Data from 13 trials evaluating one year survival
were pooled There was no statistically significant difference in one
year survival between the groups with a risk ratio (RR) of 106
(95 CI 091 to 124 P = 048 Analysis 12) and no significant
heterogeneity across trials (I2 = 363)
Data from 11 trials evaluating 2 year survival were extracted and
pooled Again there was no statistically significant difference be-
tween the groups with a RR of 108 (95 CI 086 to 136 P =
050 Analysis 13) without heterogeneity across trials (I2 = 0)
Only two trials reported data about five year survival The meta-
analysis showed no statistically significant difference in 5 year sur-
vival between the groups with a RR of survival of 234 (95
CI 097 to 565 P = 006 Analysis 14) favouring chemoim-
munotherapy There was no heterogeneity across trials (I2 = 0)
Response rates (17 studies)
Data regarding the number of participants with partial or com-
plete responses from 17 trials were used to evaluate objective re-
sponse rates The analysis detected a statistically significant differ-
ence in favor of chemoimmunotherapy in global response rates
with a RR of 140 (95 CI 120 to 163 P lt 00001 Analysis
21) There was no heterogeneity across trials (I2 = 42) We
tried to evaluate the influence of the type of immunotherapeutic
in the group of chemoimmunotherapy (IL-2 plus IFN-alpha or
IFN-alpha only) We found similar results with a RR of global
response of 146 (95 CI 119 to 179 p = 00002 Analysis 21)
in favor of chemoimmunotherapy with IL-2 plus IFN-alpha and
a RR of 132 (95 CI 102 to 171 p = 004 Analysis 21) in favor
of chemoimmunotherapy with IFN-alpha There was no hetero-
geneity across trials (I2 = 0)
8Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Data from 15 trials were used to evaluate partial and complete
response rates We found a statistically significant difference in
favour of chemoimmunotherapy in both analyses with an HR of
131 (95 CI 107 to 159 p = 0008 Analysis 23) for partial
response rates and an HR of 158 (95 CI 106 to 236 p = 003
Analysis 23) for complete response rates
Progression-free survival (3 studies)
Only three studies had extractable data about the number of par-
ticipants with no disease progression at the end of the trial When
pooled together there was no statistically significant difference be-
tween the groups with an HR of 076 (95 CI 057 to 102 p =
007 Analysis 31) There was no heterogeneity across these trials
(I2 = 0)
Treatment related toxicity (11 studies)
Data from 11 studies were collected with the number of partici-
pants developing clinically significant hematological toxicity (de-
fined as grade 3 or 4) Eight studies had estimated points that
showed enhanced toxicities in the chemoimmunotherapy group
The meta-analysis of the studies showed extreme heterogeneity
(I2 = 941) across the trials We performed a sensitivity anal-
ysis excluding the studies with relatively low doses of chemo-
therapeutic drugs in the chemoimmunotherapy group (Danson
2003 Middleton 2000) but we found similar heterogeneity (I2 =
978)
When we analyzed data from the four studies with similar rela-
tive doses of chemotherapeutics associated with interferon-alpha
without interleukin-2 we found an increase of clinically signifi-
cant hematological toxicities in the chemoimmunotherapy group
with a RR 454 (95 CI 235 to 879 p lt 000001) There was
no heterogeneity across these trials (I2 = 0) When we analyzed
data from studies with combination of interferon-alpha plus in-
terleukin-2 in the chemoimmunotherapy group we again found
extreme heterogeneity across the trials (I2 = 979)
Despite the heterogeneity in global meta-analysis we concluded
that it was not possible to quantify the differences in hematologi-
cal toxicity in such different trials In order to explore these differ-
ences we noted that one study referred to hematological toxicity
in 100 of participants treated with chemoimmunotherapy and
in 96 of participants treated with chemotherapy (Eton 2002)
Another study referred to hematological toxicity only in 2 and
1 respectively (Bajetta 1994)
Non-hematological toxicities were described in almost all stud-
ies and were mainly described as nausea vomiting flu-like syn-
drome asthenia hypotension and fever Data from six similar
studies were extractable and were pooled in the meta-analysis re-
sulting in a statistically significant difference against the chemoim-
munotherapy group with a RR of 274 (95 CI 206 to 364 p
lt 000001 Analysis 42) There was no heterogeneity across trials
(I2 = 0) These results must be treated with caution because of
similar difficulties in pooling these data on hematological toxici-
ties with different therapeutic schemes and several trials described
non-hematological toxicities but we were not able to extract the
data
Data about treatment-related mortality were available in 11 stud-
ies We found no significant difference between the groups with a
RR of 078 (95 CI 026 to 232 p = 065 Analysis 43) There
was no heterogeneity across the trials (I2 = 0)
Quality of life (three studies)
Only three studies reported data on quality of life (Ridolfi 2002
Thomson 1993 Young 2001) all using different methods One
trial described quality of life analysis in detail in an additional pub-
lication (Chiarion-Sileni 2003 Ridolfi 2002) This study found
a significant decrease of overall quality of life in the chemoim-
munotherapy group in comparison to the chemotherapy group
(p = 003) The other two studies did not find differences in global
quality of life between the groups (Thomson 1993 Young 2001)
Thomson did not report global quality of life (Thomson 1993)
Young found no significant differences in quality of life for the
change in scores over time (z = -129 p = 020) (Young 2001)
It was not possible to pool the data as all three studies did not
provide extractable data
Sensitivity analyses on the influence of source of funding baseline
assessment and allocation concealment on the survival analysis
and response rate analyses revealed that there was no relation be-
tween these methodological aspects and the outcome There was
no statistically significant difference in survival between the groups
in all analyses and the difference in response rates in favour of
chemoimmunotherapy was found to be significant
D I S C U S S I O N
Metastatic melanoma is reputed as refractory to most systemic
treatments and little progress has been made in treatment of
metastatic melanoma These concepts are supported by results
from previous systematic reviews One review concluded that there
is no evidence derived from RCTs that systemic treatment is better
than best supportive care (Crosby 2000) Another review of 20
randomised trials (involving 3273 participants) comparing single-
agent DTIC with DTIC in combination with other drugs with or
without immunotherapy concluded that combination of drugs in-
creased response rates but not overall survival (Huncharek 2001)
This systematic review summarises the evidence regarding the
use of chemoimmunotherapy compared to chemotherapy alone
to treat people with metastatic malignant melanoma There are
some important observations regarding the characteristics of the
included studies in this systematic review The ideal combination
9Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
of drugs for an investigation is not well established Seven studies
evaluated chemoimmunotherapy with interferon-alpha plus inter-
leukin-2 and 11 evaluated chemoimmunotherapy only with in-
terferon-alpha The treatment plans with drugs and dosages used
differed between studies
Most studies did not contribute in answering relevant questions
about the impact of chemoimmunotherapy in the treatment of
metastatic melanoma The outcomes were not clearly described in
several of the studies (Atkins 2003 Del Vecchio 2003 Gorbonova
2000 Kirkwood 1990 Spieth 2003 Thomson 1993) Two of
them did not report survival rates evaluating only response rates
(Gorbonova 2000 Kirkwood 1990) All these aspects influenced
the comparability of the trials and must be considered in the data
interpretation
On the basis of a meta-analysis of data coming from eight studies
this review showed no evidence of a difference in overall survival to
support the addition of immunotherapy to chemotherapy in the
systemic treatment of metastatic melanoma (Atkins 2003 Danson
2003 Eton 2002 Falkson 1991 Johnston 1998 Ridolfi 2002
Spieth 2003 Young 2001) Evaluation of one two and five-year
survival with data from other studies again showed no survival
advantage of the drug combination treatment
We found higher clinical response rates in people treated with
chemoimmunotherapy in comparison with people treated with
chemotherapy which was not translated into survival benefit
Additionally we found higher toxicity rates in people treated
with chemoimmunotherapy Despite the importance of evaluat-
ing quality of life there was no available data to perform the meta-
analysis in this systematic review Only three studies reported data
about quality of life all with different methods One trial described
poorer quality of life in people treated with chemoimmunother-
apy related to more intense side effects (Ridolfi 2002) Two trials
however showed no difference between groups (Thomson 1993
Young 2001) It is important that quality of life is included in all
future studies
Our meta-analysis did not find differences between treatment re-
lated mortality Subgroup analysis comparing combinations with
interferon-alpha and with interferon-alpha plus interleukin-2 did
not show different results in survival or response rates
The use of chemoimmunotherapy ie a combination of chemo-
therapy with interferon-alpha or interleukin-2 or both has not
been shown to be beneficial in this review Although short term
response rates were better overall in the chemoimmunotherapy
groups survival was not improved and drug-related toxicities were
higher in the combined chemoimmunotherapy group To date no
treatment regimen has shown efficiency in prolonging survival in
people with metastatic melanoma Little has changed in the sys-
temic management of metastatic melanoma in the last few years
The standard of care remains single-agent DTIC and the role of
immunotherapy remains in doubt
The use of chemoimmunotherapy in the treatment of melanoma
is justified only in the context of clinical trials
A U T H O R S rsquo C O N C L U S I O N S
Implications for practice
We failed to find any evidence to support the view that the
use of chemoimmunotherapy prolongs survival in people with
metastatic melanoma when compared to chemotherapy alone Al-
though short-term clinical responses were higher in the chemoim-
munotherapy group this was associated with a higher rate of
serious adverse events esp haematological toxicity Our review
does not support the use of a combination of immunother-
apy and chemotherapy in chemoimmunotherapy regimens out-
side of clinical trials The standard of care for people with
advanced melanoma remains chemotherapy with single-agent
DTIC Chemoimmunotherapy must not be recommended to peo-
ple in daily practice
Implications for research
Research related to the development of more effective treatments
for people with metastatic melanoma is urgently needed
For people with an incurable disease the primary outcome needs
to be overall survival and all studies should include a quality of life
analysis
Future trials should be designed to define the best systemic treat-
ment and should use chemotherapy with (DTIC) as a standard
control group in order to permit comparisons to be made
A C K N O W L E D G E M E N T S
The authors wish to thank Raquel Gebara Lima for her kind
support in grammar and style
The editorial base would like to thank the following people who
were external referees for this review Keith Wheatley and Pat
Lawton (content experts) and Kathie Godfrey (consumer)
10Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
R E F E R E N C E S
References to studies included in this review
Atkins 2003 published data only
Atkins MB Lee S Flaherty LE Sosman JA Sondak VK
Kirkwood JM A prospective randomized phase III trial
of concurrent biochemotherapy (BCT) with cisplatin
vinblastine dacarbazine (CVD) IL-2 and interferon alpha-
2b (IFN) versus CVD alone in patients with metastatic
melanoma (E3695) An ECOG-coordinated intergroup
trial In ASCO Annual Meeting 2003 2003 p ASCO
Annual Meeting - Proceedings 2003Abstract 2847
Atzpodien 2002 published data only
Atzpodien J Neuber K Kamanabrou D Fluck M Brocker
EB Neumann C et alCombination chemotherapy with or
without sc IL-2 and IFN-alpha results of a prospectively
randomized trial of the Cooperative Advanced Malignant
Melanoma Chemoimmunotherapy Group (ACIMM)
British journal of cancer 200286(2)179ndash84
Bajetta 1994 published data only
Bajetta E Di Leo A Zampino MG Sertoli MR Comella
G Barduagni M et alMulticenter randomized trial of
dacarbazine alone or in combination with two different
doses and schedules of interferon alfa-2a in the treatment
of advanced melanoma Journal of clinical oncology official
journal of the American Society of Clinical Oncology 199412
(4)806ndash11
Danson 2003 published data only
Danson S Lorigan P Arance A Clamp A Ranson
M Hodgetts J et alRandomized phase II study of
temozolomide given every 8 hours or daily with either
interferon alfa-2b or thalidomide in metastatic malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 200321(13)2551ndash7
Del Vecchio 2003 published data only
Del Vecchio M Bajetta E Vitali M Gattinoni L Santinami
M Daponte A et alMulticenter phase III randomized trial
of cisplatin vindesine and dacarbazine (CVD) versus CVD
plus subcutaneous (sc) interleukin-2 (IL-2) and interferon-
alpha-2b (IFN) in metastatic melanoma patients (pts) In
ASCO Annual Meeting 2003 2003 p ASCO Annual
Meeting - Proceedings 2003Abstract 2849
Eton 2002 published data only
Eton O Legha SS Bedikian AY Lee JJ Buzaid AC
Hodges C et alSequential biochemotherapy versus
chemotherapy for metastatic melanoma results from a
phase III randomized trial Journal of clinical oncology
official journal of the American Society of Clinical Oncology
200220(8)2045ndash52
Falkson 1991 published data only
Falkson CI Falkson G Falkson HC Improved results with
the addition of interferon alfa-2b to dacarbazine in the
treatment of patients with metastatic malignant melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 19919(8)1403ndash8
Falkson 1998 published data only
Falkson CI Ibrahim J Kirkwood JM Coates AS Atkins
MB Blum RH Phase III trial of dacarbazine versus
dacarbazine with interferon alpha-2b versus dacarbazine
with tamoxifen versus dacarbazine with interferon alpha-
2b and tamoxifen in patients with metastatic malignant
melanoma an Eastern Cooperative Oncology Group study
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199816(5)1743ndash51
Gorbonova 2000 published data only
Gorbonova VA Egorov GN Perevodchikova NI Orel
NF Combined chemotherapy with or without interferon
alpha N1 (IFN) for advanced malignant melanoma - a
randomized pilot phase III study Gan To Kagaku Ryoho
200027 Suppl (2)310ndash4
Johnston 1998 published data only
Johnston SR Constenla DO Moore J Atkinson H ArsquoHern
RP Dadian G et alRandomized phase II trial of BCDT
[carmustine (BCNU) cisplatin dacarbazine (DTIC)
and tamoxifen] with or without interferon alpha (IFN-
alpha) and interleukin (IL-2) in patients with metastatic
melanoma British Journal of Cancer 199877(8)1280ndash6
Kirkwood 1990 published data only
Kirkwood JM Ernstoff MS Giuliano A Gams R Robinson
WA Costanzi J et alInterferon alpha-2a and dacarbazine
in melanoma Journal of the National Cancer Institute 1990
82(12)1062ndash3
Middleton 2000 published data only
Middleton MR Grob JJ Aaronson N Fierlbeck G
Tilgen W Seiter S et alRandomized phase III study of
temozolomide versus dacarbazine in the treatment of
patients with advanced metastatic malignant melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200018(1)158ndash66
Ridolfi 2002 published data only
Ridolfi R Chiarion-Sileni V Guida M Romanini A
Labianca R Freschi A et alCisplatin dacarbazine with
or without subcutaneous interleukin-2 and interferon
alpha-2b in advanced melanoma outpatients results from
an Italian multicenter phase III randomized clinical trial
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200220(6)1600ndash7
Rosenberg 1999 published data only
Rosenberg SA Yang JC Schwartzentruber DJ Hwu P
Marincola FM Topalian SL et alProspective randomized
trial of the treatment of patients with metastatic melanoma
using chemotherapy with cisplatin dacarbazine and
tamoxifen alone or in combination with interleukin-2 and
interferon alfa-2b Journal of Clinical Oncology 199917(3)
968ndash75
Spieth 2003 published data only
Spieth K Dummer R Garbe C Mauch C Schuler G
Landthaler M et alTemozolomide in combination with
11Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
interferon alfa versus temozolomide alone in patients with
advanced metastatic melanoma A randomized phase
III multicenter study of the Dermatologic Cooperative
Oncology Group (DeCOG) In ASCO Annual Meeting
2003Abstract 2887
Thomson 1993 published data only
Thomson DB Adena M McLeod GR Hersey P Gill PG
Coates AS et alInterferon-alpha 2a does not improve
response or survival when combined with dacarbazine
in metastatic malignant melanoma results of a multi-
institutional Australian randomized trial Melanoma
Research 19933(2)133ndash8
Vorobiof 1994 published data only
Vorobiof DA Bezwoda WR A randomised trial of vindesine
plus interferon-alpha 2b compared with interferon-alpha 2b
or vindesine alone in the treatment of advanced malignant
melanoma European journal of cancer (Oxford England
1990) 199430A(6)797ndash800
Young 2001 published data only
Young AM Marsden J Goodman A Burton A Dunn
JA Prospective randomized comparison of dacarbazine
(DTIC) versus DTIC plus interferon-alpha (IFN-alpha) in
metastatic melanoma Clinical oncology (Royal College of
Radiologists (Great Britain)) 200113(6)458ndash65
References to studies excluded from this review
Bajetta 2001 published data only
Bajetta E Del Vecchio M Vitali M Martinetti A Ferrari L
Queirolo P et alA feasibility study using polychemotherapy
(cisplatin + vindesine + dacarbazine) plus interferon-alpha
or monochemotherapy with dacarbazine plus interferon-
alpha in metastatic melanoma Tumori 200187(4)219ndash22
Legha 1996 published data only
Legha SS Ring S Bedikian A Plager C Eton O Buzaid
AC et alTreatment of metastatic melanoma with combined
chemotherapy containing cisplatin vinblastine and
dacarbazine (CVD) and biotherapy using interleukin-2 and
interferon-alpha Annals of oncology official journal of the
European Society for Medical Oncology ESMO 19967(8)
827ndash35
Richtig 2004 published data only
Richtig E Hofmann-Wellenhof R Pehamberger H
Forstinger C Wolff K Mischer P et alTemozolomide and
interferon alpha 2b in metastatic melanoma stage IV British
Journal of Dermatology 2004151(1)91ndash8
Sertoli 1999 published data only
Sertoli MR Queirolo P Bajetta E DelVecchio M
Comella G Barduagni L et alMulti-institutional phase
II randomized trial of integrated therapy with cisplatin
dacarbazine vindesine subcutaneous interleukin-2
interferon alpha2a and tamoxifen in metastatic melanoma
BREMIM (Biological Response Modifiers in Melanoma)
Melanoma research 19999(5)503ndash9
Sparano 1993 published data only
Sparano JA Fisher RI Sunderland M Margolin K Ernest
ML Sznol M et alRandomized phase III trial of treatment
with high-dose interleukin-2 either alone or in combination
with interferon alfa-2a in patients with advanced melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199311(10)1969ndash77
Vuoristo 2005 published data only
Vuoristo MS Hahka-Kemppinen M Parvinen LM
Pyrhonen S Seppa H Korpela M et alRandomized trial of
dacarbazine versus bleomycin vincristine lomustine and
dacarbazine (BOLD) chemotherapy combined with natural
or recombinant interferon-alpha in patients with advanced
melanoma Melanoma research 200515(4)291ndash6
Additional references
Arance 2000
Arance A Middleton M Lorigan P Thatcher N Three-
arm phase II study of temozolomide (TMZ) in metastatic
melanoma (MM) In ASCO Annual Meeting 2000
Abstract 2257
Bafaloukos 2002
Bafaloukos D Aravantinos G Fountzilas G Stathopoulos
G Gogas H Samonis G et alDocetaxel in combination
with dacarbazine in patients with advanced melanoma
Oncology 200263(4)333ndash7
Bajetta 2002
Bajetta E Del Vecchio M Bernard-Marty C Vitali
M Buzzoni R Rixe O et alMetastatic melanoma
chemotherapy Seminars in Oncology 200229(5)427ndash45
Balch 2001
Balch CM Soong SJ Gershenwald JE Thompson JF
Reintgen DS Cascinelli N et alPrognostic factors analysis
of 17600 melanoma patients validation of the American
Joint Committee on Cancer melanoma staging system
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200119(16)3622ndash34
Barth 1995
Barth A Morton DL The role of adjuvant therapy in
melanoma management Cancer 199575 Suppl (2)
726ndash34
Chiarion-Sileni 2003
Chiarion-Sileni V Del Bianco P De Salvo GL Lo Re G
Romanini A Labianca R et alQuality of life evaluation in a
randomised trial of chemotherapy versus bio-chemotherapy
in advanced melanoma patients European journal of cancer
(Oxford England 1990) 200339(11)1577ndash85
Creagan 1984
Creagan ET Ahmann DL Green SJ Long HJ Frytak S
OrsquoFallon JR et alPhase II study of low-dose recombinant
leukocyte A interferon in disseminated malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 19842(9)1002ndash5
Crosby 2000
Crosby T Fish R Coles B Mason MD Systemic treatments
for metastatic cutaneous melanoma Cochrane Database
of Systematic Reviews 2000 Issue 2 [DOI 101002
14651858CD001215]
12Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Cure 1999
Cure H Souteyrand P Ouabdesselam R Roche H
Ravaud A DrsquoIncan M et alResults of a phase II trial
with cystemustine at 90 mgm(2) as a first- or second-line
treatment in advanced malignant melanoma a trial of the
EORTC Clinical Studies Group Melanoma Research 1999
9(6)607ndash10
Danson 2002
Danson S Arance A Lorigan P Clamp A Hodgetts J
Lomax L Thatcher N Middleton MR A randomized
study of temozolomide (TMZ) alone with interferon-
alpha (TMZ-IFN) or with thalidomide (TMZ-THAL) in
metastatic malignant melanoma (MMM) ASCO Annual
Meeting - Proceedings 2002Abstract 1369
Dorval 1986
Dorval T Palangie T Jouve M Garcia-Giralt E Israel L
Falcoff E et alClinical phase II trial of recombinant DNA
interferon (interferon alpha 2b) in patients with metastatic
malignant melanoma Cancer 198658(2)215ndash8
Dutcher 1989
Dutcher JP Creekmore S Weiss GR Margolin K
Markowitz AB Roper M et alA phase II study of
interleukin-2 and lymphokine-activated killer cells in
patients with metastatic malignant melanoma Journal of
clinical oncology official journal of the American Society of
Clinical Oncology 19897(4)477ndash85
Falkson 1995
Falkson CI Experience with interferon alpha 2b combined
with dacarbazine in the treatment of metastatic malignant
melanoma Medical oncology (Northwood London England)
199512(1)35ndash40
Garbe 1990
Garbe C Krasagakis K Zouboulis CC Schroder K Kruger
S Stadler R et alAntitumor activities of interferon alpha
beta and gamma and their combinations on human
melanoma cells in vitro changes of proliferation melanin
synthesis and immunophenotype Journal of Investigative
Dermatology 199095 Suppl (6)231ndash7
Gershenwald 1999
Gershenwald JE Thompson W Mansfield PF Lee JE
Colome MI Tseng CH et alMulti-institutional melanoma
lymphatic mapping experience the prognostic value of
sentinel lymph node status in 612 stage I or II melanoma
patients Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199917(3)976ndash83
Hanninen 1991
Hanninen EL Korfer A Hadam M Schneekloth C
Dallmann I Menzel T et alBiological monitoring of
low-dose interleukin 2 in humans soluble interleukin 2
receptors cytokines and cell surface phenotypes Cancer
Research 199151(23 Pt 1)6312ndash6
Huncharek 2001
Huncharek M Caubet JF McGarry R Single-agent
DTIC versus combination chemotherapy with or without
immunotherapy in metastatic melanoma a meta-analysis
of 3273 patients from 20 randomized trials Melanoma
Research 200111(1)75ndash81
Juni 2001
Juni P Altman DG Egger M Assessing the quality of
controlled clinical trials BMJ 200132342ndash6
Kadison 2003
Kadison AS Morton DL Immunotherapy of malignant
melanoma The Surgical Clinics of North America 200383
(2)343ndash70
Keilholz 2002
Keilholz U Gore ME Biochemotherapy for advanced
melanoma Seminars in Oncology 200229(5)456ndash61
Khayat 2002
Khayat D Bernard-Marty C Meric JB Rixe O
Biochemotherapy for advanced melanoma maybe it is real
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200220(10)2411ndash4
Koh 1991
Koh HK Cutaneous melanoma New England Journal of
Medicine 1991325(3)171ndash82
La Vecchia 1999
La Vecchia C Lucchini F Negri E Levi F Recent declines
in worldwide mortality from cutaneous melanoma in youth
and middle age International Journal of Cancer 199981(1)
62ndash6
Lee 2000
Lee ML Tomsu K Von Eschen KB Duration of survival
for disseminated malignant melanoma results of a meta-
analysis Melanoma Research 200010(1)81ndash92
Legha 1998
Legha SS Ring S Eton O Bedikian A Buzaid AC Plager
C et alDevelopment of a biochemotherapy regimen
with concurrent administration of cisplatin vinblastine
dacarbazine interferon alfa and interleukin-2 for patients
with metastatic melanoma Journal of clinical oncology
official journal of the American Society of Clinical Oncology
199816(5)1752ndash9
Leong 2003
Leong SP Future perspectives on malignant melanoma
Surgical Clinics of North America 200383(2)453ndash6
Lokich 1979
Lokich JJ Garnick MB Legg M Intralesional immune
therapy methanol extraction residue of BCG or purified
protein derivative Oncology 197936(5)236ndash41
Nathan 1998
Nathan FE Mastrangelo MJ Systemic therapy in
melanoma Seminars in Surgical Oncology 199814(4)
319ndash27
Osborn 1977
Osborn DE Castro JE Immunological response in patients
receiving Corynebacterium parvum therapy Clinical
Oncology 19773(2)155ndash64
13Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Parmar 1998
Parmar MKB TV Stewart L Extracting summary statistics
to perform meta-analyses of the published literature for
survival endpoints Statistics in Medicine 1998172815ndash34
Richards 1992
Richards JM Mehta N Ramming K Skosey P Sequential
chemoimmunotherapy in the treatment of metastatic
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199210(8)1338ndash43
Rigel 1989
Rigel DS Rivers JK Kopf AW Friedman RJ Vinokur AF
Heilman ER et alDysplastic nevi Markers for increased
risk for melanoma Cancer 198963(2)386ndash9
Rosenberg 1989
Rosenberg SA Lotze MT Yang JC Aebersold PM Linehan
WM Seipp CA et alExperience with the use of high-
dose interleukin-2 in the treatment of 652 cancer patients
Annals of Surgery 1989210(4)474-84 discussion 484-5
Sertoli 1989
Sertoli MR Bernengo MG Ardizzoni A Brunetti I Falcone
A Vidili MG et alPhase II trial of recombinant alpha-2b
interferon in the treatment of metastatic skin melanoma
Oncology 198946(2)96ndash8
Smith 1993
Smith KA Lowest dose interleukin-2 immunotherapy
Blood 199381(6)1414ndash23
Stopeck 2001
Stopeck AT Jones A Hersh EM Thompson JA
Finucane DM Gutheil JC et alPhase II study of direct
intralesional gene transfer of allovectin-7 an HLA-B7
beta2-microglobulin DNA-liposome complex in patients
with metastatic melanoma Clinical Cancer Research 20017
(8)2285ndash91
Tsang 1983
Tsang KY Fudenberg HH Pan JF Gnagy MJ Bristow
CB An in vitro study on the effects of isoprinosine on
immune responses in cancer patients International Journal
of Immunopharmacology 19835(6)481ndash90
Wingo 1995
Wingo PA Tong T Bolden S Cancer statistics 1995 CA
a cancer journal for clinicians 199545(1)8ndash30
Yusuf 1985
Yusuf S Peto R Lewis J Collins R Sleight P Beta blockade
during and after myocardial infarction an overview of the
randomized trials Progress in Cardiovascular Diseases 1985
27(5)335ndash71lowast Indicates the major publication for the study
14Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Atkins 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding public
Participants PS lt= 1
Brain mets no info
Age 20 to 80 (median 50)
Number of cycles no info
Randomised 416 a 206 b 210
Evaluable 405 a 201 b 204
Interventions a (CT) cisplatin 20mgm2 D1 to 4 vinblastin 12 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1-4 vimblastin 12 mgm2 D1-4 DTIC 800 mgm2 D1
IFN-alpha 5 mIU D1-5 D8 D10 D12 IL-2 9 mIU D1-4
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
Notes Multicentric yes
Withdrawals a five b six
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
15Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Atzpodien 2002
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding both (pharmaceutic and public)
Participants PS lt= 1
Brain mets yes Age 28 to 77 (median 57)
Number of cycles no info
Randomised 124 a 60 b 64
Evaluable 124 a 60 b 64
Interventions a (CT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily
b (ICT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily IFN-alpha 5 mIUm2 D1 week4 and 5
mIUm2 D1 D3 D5 week 5 IL-2 10 mIUm2 D1 D3 D5
(each five weeks)
Outcomes 1 Response rates
2 Overall survival
3 Progression free survival
Notes Multicentric yes
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Bajetta 1994
Methods D parallel group (three groups)
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding pharmaceutic
Participants PS lt= 2
Brain mets no
16Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Bajetta 1994 (Continued)
Age 18 to 70 (median 53)
Number of cycles 8
Randomised 266 a 88 b 86 c 92
Evaluable 242 a 82 b 76 c 84
Interventions a (CT) DTIC 800 mgm2 D1
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU 3xweek
c (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU D1 to 3 6 mIU D4 to 6 9 mIU daily
(each 21 days)
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Overall survival
Notes Multicentric yes
Withdrawals a six b ten c eight
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Danson 2003
Methods D parallel group
AC independent allocation
RS permuted blocks
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets yes Age 16 to 88 (median 58)
Number of cycles six
Randomised 125 a 59 b 62
Evaluable 121 a 55 b 62
Interventions a (CT) temozolomide 200 mgm2 88 h (5 doses)
b (ICT) Temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIU 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
17Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Danson 2003 (Continued)
Notes Multicentric no
Withdrawals a 4 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Del Vecchio 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no Age 19 to 70 (median 50)
Number of cycles no info
Randomised 151 a 75 b 76
Evaluable 145 a 72 b 73
Interventions a (CT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250 mgm2 D1 to
3
b (ICT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250m gm2 D1 to
3 IFN-alpha 5 mIUm2 D1 to 5 IL-2 9 mIUday x 5 daysweek x 2 weeks with a week of
rest
(each 21 days)
Outcomes 1 Response rates
2 Time to Progression
2 Overall Survival
Notes Multicentric yes
Withdrawals a three b three
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
18Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Eton 2002
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding pharm
Participants PS lt= 3
Brain mets yes Age median 49
Number of cycles no info
Randomised 190
Evaluable 183 a 92 b 91
Interventions a (CT) cisplatin 20m gm2 D1 to 4 vimblastin 2 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1 to 4 vinblastin 15 mgm2 D1 to 4 DTIC 800 mgm2
D1 IFN-alpha 5mIUm2 D5 to 9 D17-21 IL-2 9 mIUm2 D5 to 8 D17 to 20
(each 21 days)
Outcomes 1 Response rates
2 Time to progression
3 Overall survival
Notes Multicentric no
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1991
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size no
ITT no
Placebo no
Funding both
Participants PS lt= 1
Brain mets no
Age 22 to 79
(median 57)
Number of cycles at least two
19Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1991 (Continued)
Randomised 73 Evaluable 68 a 34 b 34
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Time to treatment failure
3 Median survival
4 Toxicity
Notes Multicentric no
Withdrawals a three b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1998
Methods D 2 x 2 factorial design
AC independent allocation
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 18 to 84
Number of cycles no info
Randomised 271 Evaluable 263 a 68 b 65 c 63 d 67
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
c (CT) DTIC 200m gm2 D1 to 5 tamoxifen 20 mgdaily
d (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek tamoxifen 20 mgdaily
(each 28 days)
Outcomes 1 Response rates
2 Toxicity rates
20Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1998 (Continued)
3 Overall survival
4 Time to treatment failure
Notes Multicentric yes
Withdrawals a one b three c three d one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Gorbonova 2000
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no
Age 23 to 75
Number of cycles no info
Randomised 30 Evaluable 28 a 14 b 14
Interventions a (CT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2
b (ICT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2 IFN-alpha 3 mIU D5 7
9 11 13 15 17 19
(each 28 days)
Outcomes 1 Response rates
Notes Multicentric no
Withdrawals a two b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
21Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Johnston 1998
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age 18 to 70
(median 45)
Number of cycles no info
Randomised 65 Evaluable 65 a 30 b 35
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to 3
Tamoxifen 40 mg daily
b (ICT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to
3 Tamoxifen 40 mg daily IFN-alpha 9 mIU D1 to 3 IL-2 18 mIU D-2 IL-2 9 mIU D-
1 and 0
(each 28 days)
Outcomes 1 Response rates
2 Time to disease progression
3 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Kirkwood 1990
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding pharm
22Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Kirkwood 1990 (Continued)
Participants PS no info
Brain mets no info
Age no info
Number of cycles no info
Randomised 74 Evaluable 68 a 24 b 23 c 21
Interventions a (CT) DTIC 250 mgm2 D1 to 5 (each 21 days)
b (I) IFN-alpha 3 mIU d1 to 5 every week for 3 weeks than 3 mIUm2 3 xweek
c (ICT) DTIC 250 mgm2 D1 to 5 (each 21 days) IFN-alpha 3 mIU d1 to 5 every week
for 3 weeks than 3 mIUm2 3 xweek
Outcomes 1 Response rates
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Middleton 2000
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets no
Age 24 to 71
(median 51)
Number of cycles six
Randomised 105 Evaluable 96 a 46 b 50
Interventions a (CT) DTIC 800 mgm2 D1 cisplatin 25 mgm2 D1 to 3 BCNU 150 mgm2 D1
tamoxifen 20 mgdaily
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 9 mIU 3 xweek
(each 21 days)
Outcomes 1 Response rates
2 One year survival
3 Median survival
23Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Middleton 2000 (Continued)
4 Toxicity
4 Time spent in hospital
Notes Multicentric no
Withdrawals a seven b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Ridolfi 2002
Methods D parallel group
AC independent allocation by telephone
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 25 to 77
Number of cycles six
Randomised 178 Evaluable 176 a 89 b 87
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1
b (ICT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1 IFN-
alpha 3 mIU 3 xweek IL-2 45 mIU D3 to 5 D8 to 12
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
3 Time to progression
4 Toxicity
Notes Multicentric yes
Withdrawals a one b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
24Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Three studies (Bajetta 1994 Kirkwood 1990 Vorobiof 1994) eval-
uated three arms of treatment with one of them evaluating che-
motherapy alone and the two others using chemoimmunotherapy
One study (Falkson 1998) had four arms two using chemotherapy
and two using chemoimmunotherapy The data from the similar
arms were grouped considered as one and then compared to the
other arm
R E S U L T S
Description of studies
Results of the search
We scanned approximately 700 citations Initially 28 studies
were identified Four studies (Arance 2000 Chiarion-Sileni 2003
Danson 2002 Falkson 1995) had data that overlapped with three
included studies (Danson 2003 Falkson 1991 Ridolfi 2002)
Ongoing studies
No ongoing studies were available to be included in the meta-
analysis
Included studies
Eighteen studies with a total of 2625 participants met our criteria
and were included in the meta-analysis (please see Characteristics
of included studies) One study differed considerably from the oth-
ers because vindesine was used as the chemotherapy control a drug
without evidence of response in metastatic melanoma (Vorobiof
1994) Another study differed considerably as lower dose treat-
ment in the chemoimmunotherapy group was used (Middleton
2000) The first study was published in 1990 and the last studies
were published in 2003
Participants
The participants were between the ages of 16 and 88 years and
had an Eastern Cooperative Oncology Group performance status
from 0 to 3 Only three studies included participants with brain
metastasis (Atzpodien 2002 Danson 2003 Eton 2002)
Interventions
Seven studies compared chemotherapy to chemoimmunotherapy
with IFN plus IL-2 (Atkins 2003 Atzpodien 2002 Del Vecchio
2003 Eton 2002 Johnston 1998 Ridolfi 2002 Rosenberg 1999)
Eleven compared chemotherapy to chemoimmunotherapy with
IFN (Bajetta 1994 Danson 2003 Falkson 1991 Falkson 1998
Gorbonova 2000 Kirkwood 1990 Middleton 2000 Spieth 2003
Thomson 1993 Vorobiof 1994 Young 2001)
The drugs used in chemotherapeutic schemes varied between the
trials Seven trials evaluated DTIC combined with other drugs in
both arms (Atkins 2003 Atzpodien 2002 Del Vecchio 2003 Eton
2002 Johnston 1998 Ridolfi 2002 Rosenberg 1999) and six
evaluated DTIC alone as the control (Bajetta 1994 Falkson 1991
Falkson 1998 Kirkwood 1990 Thomson 1993 Young 2001)
Four studies evaluated other schemes without DTIC two trials
used temozolomide (Danson 2003 Spieth 2003) one trial used
vindesine (Vorobiof 1994) and one trial used combined drugs
based on cisplatin (Gorbonova 2000)
Only one study did not use the same scheme in both the arms
using combined drugs with DTIC as the chemotherapy control
and a lower dose for the chemoimmunotherapy group with DTIC
alone (Middleton 2000)
Setting
Ten studies were carried out in Europe four in the United States
two in South Africa and one was a multicentre worldwide trial
All trials were reported in the English language
Outcomes
Response rates were the primary outcome measures in most trials
and were described in all included studies Two studies did not
evaluate survival rates (Gorbonova 2000 Kirkwood 1990) Three
studies included quality of life analyses in the outcomes (Ridolfi
2002 Thomson 1993 Young 2001) The length of the follow-up
varied widely between the trials and sometimes it was not speci-
fied We did not find a reasonable definition about what could be
considered high or low doses of immunotherapy and the influence
of the immunotherapeutic doses on the outcomes could not be
assessed
Excluded studies
Six studies were excluded (see Characteristics of excluded studies)
The reasons for exclusion were that the study had immunotherapy
on both arms (Bajetta 2001 Richtig 2004 Sertoli 1999 Sparano
1993 Vuoristo 2005) or the study was not randomised (Legha
1996)
Risk of bias in included studies
The quality assessment consisted of a basic methodological eval-
uation of each included study and is shown in Table 1 Addi-
tional quality assessment is shown in Table 2 The criteria used for
methodological quality analysis of the studies are listed in Table 3
(Explanation of Quality Analysis Headings)
7Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Although blinding participants and clinicians is theoretically pos-
sible it is difficult to plan a double-blind study with immunother-
apy This is due to the substantial acute and late toxicities associ-
ated with immunotherapy in one group No study was described
as double-blinded The groups at baseline were in general similar
with a description of most prognostic factors related to metastatic
melanoma (gender performance status age prior therapy liver
metastasis)
In three studies almost all methodological aspects of the trials
were described poorly (Gorbonova 2000 Kirkwood 1990 Spieth
2003)
Allocation
All the included studies were described as randomised as this
was a selection criterion However most papers did not describe
the method of randomisation The method of generation of the
randomised sequence was described and considered adequate in
only 6 out of 18 studies Eleven of 18 studies provided information
on allocation concealment all of which were considered adequate
Blinding
Blinding of outcome assessment and detection bias
We did not find information about blinding of the outcome as-
sessors in any included study
Incomplete outcome data
Handling of losses and attrition bias
In general there were few participants lost to follow up in the
studies The highest number of people lost was 24 in a total of 262
participants (Bajetta 1994) Eleven studies included an intention-
to-treat analysis
Effects of interventions
Primary outcome
Overall survival (eight studies)
This was considered as the number of participants alive at the end
of the trial Sufficient data were available from 8 of the 18 studies
There was no statistically significant difference in survival between
chemoimmunotherapy and chemotherapy with a hazard ratio
(HR) of improved survival of 089 (95 CI 072 to 111 P = 031
Analysis 11) in favour of chemoimmunotherapy In other words
overall survival was slightly lower in the chemoimmunotherapy
group but this was not statistically significant There was no het-
erogeneity across trials (I2 = 0) The funnel plot method using
overall survival as the outcome is presented in Figure 1 It shows
that there was no evidence of substantial publication bias but in-
terpretation of the funnel plot is likely to be unreliable since only
eight relatively large studies were found
When we evaluated the influence of the type of immunotherapy
used in the chemoimmunotherapy group (IL-2 plus IFN-alpha
or IFN-alpha only) we found no statistically significant difference
between the groups with a HR of 096 (95 CI 074 to 124 P =
076 Analysis 11) for chemoimmunotherapy with IL-2 plus IFN-
alpha and a HR of 074 (95 CI 049 to 112 P = 015 Analysis
11) for chemoimmunotherapy associated with only IFN-alpha
Secondary outcomes
One two and five-year survival rates (13 studies)
The number of participants alive at one two and five year follow-
ups were analyzed Data from 13 trials evaluating one year survival
were pooled There was no statistically significant difference in one
year survival between the groups with a risk ratio (RR) of 106
(95 CI 091 to 124 P = 048 Analysis 12) and no significant
heterogeneity across trials (I2 = 363)
Data from 11 trials evaluating 2 year survival were extracted and
pooled Again there was no statistically significant difference be-
tween the groups with a RR of 108 (95 CI 086 to 136 P =
050 Analysis 13) without heterogeneity across trials (I2 = 0)
Only two trials reported data about five year survival The meta-
analysis showed no statistically significant difference in 5 year sur-
vival between the groups with a RR of survival of 234 (95
CI 097 to 565 P = 006 Analysis 14) favouring chemoim-
munotherapy There was no heterogeneity across trials (I2 = 0)
Response rates (17 studies)
Data regarding the number of participants with partial or com-
plete responses from 17 trials were used to evaluate objective re-
sponse rates The analysis detected a statistically significant differ-
ence in favor of chemoimmunotherapy in global response rates
with a RR of 140 (95 CI 120 to 163 P lt 00001 Analysis
21) There was no heterogeneity across trials (I2 = 42) We
tried to evaluate the influence of the type of immunotherapeutic
in the group of chemoimmunotherapy (IL-2 plus IFN-alpha or
IFN-alpha only) We found similar results with a RR of global
response of 146 (95 CI 119 to 179 p = 00002 Analysis 21)
in favor of chemoimmunotherapy with IL-2 plus IFN-alpha and
a RR of 132 (95 CI 102 to 171 p = 004 Analysis 21) in favor
of chemoimmunotherapy with IFN-alpha There was no hetero-
geneity across trials (I2 = 0)
8Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Data from 15 trials were used to evaluate partial and complete
response rates We found a statistically significant difference in
favour of chemoimmunotherapy in both analyses with an HR of
131 (95 CI 107 to 159 p = 0008 Analysis 23) for partial
response rates and an HR of 158 (95 CI 106 to 236 p = 003
Analysis 23) for complete response rates
Progression-free survival (3 studies)
Only three studies had extractable data about the number of par-
ticipants with no disease progression at the end of the trial When
pooled together there was no statistically significant difference be-
tween the groups with an HR of 076 (95 CI 057 to 102 p =
007 Analysis 31) There was no heterogeneity across these trials
(I2 = 0)
Treatment related toxicity (11 studies)
Data from 11 studies were collected with the number of partici-
pants developing clinically significant hematological toxicity (de-
fined as grade 3 or 4) Eight studies had estimated points that
showed enhanced toxicities in the chemoimmunotherapy group
The meta-analysis of the studies showed extreme heterogeneity
(I2 = 941) across the trials We performed a sensitivity anal-
ysis excluding the studies with relatively low doses of chemo-
therapeutic drugs in the chemoimmunotherapy group (Danson
2003 Middleton 2000) but we found similar heterogeneity (I2 =
978)
When we analyzed data from the four studies with similar rela-
tive doses of chemotherapeutics associated with interferon-alpha
without interleukin-2 we found an increase of clinically signifi-
cant hematological toxicities in the chemoimmunotherapy group
with a RR 454 (95 CI 235 to 879 p lt 000001) There was
no heterogeneity across these trials (I2 = 0) When we analyzed
data from studies with combination of interferon-alpha plus in-
terleukin-2 in the chemoimmunotherapy group we again found
extreme heterogeneity across the trials (I2 = 979)
Despite the heterogeneity in global meta-analysis we concluded
that it was not possible to quantify the differences in hematologi-
cal toxicity in such different trials In order to explore these differ-
ences we noted that one study referred to hematological toxicity
in 100 of participants treated with chemoimmunotherapy and
in 96 of participants treated with chemotherapy (Eton 2002)
Another study referred to hematological toxicity only in 2 and
1 respectively (Bajetta 1994)
Non-hematological toxicities were described in almost all stud-
ies and were mainly described as nausea vomiting flu-like syn-
drome asthenia hypotension and fever Data from six similar
studies were extractable and were pooled in the meta-analysis re-
sulting in a statistically significant difference against the chemoim-
munotherapy group with a RR of 274 (95 CI 206 to 364 p
lt 000001 Analysis 42) There was no heterogeneity across trials
(I2 = 0) These results must be treated with caution because of
similar difficulties in pooling these data on hematological toxici-
ties with different therapeutic schemes and several trials described
non-hematological toxicities but we were not able to extract the
data
Data about treatment-related mortality were available in 11 stud-
ies We found no significant difference between the groups with a
RR of 078 (95 CI 026 to 232 p = 065 Analysis 43) There
was no heterogeneity across the trials (I2 = 0)
Quality of life (three studies)
Only three studies reported data on quality of life (Ridolfi 2002
Thomson 1993 Young 2001) all using different methods One
trial described quality of life analysis in detail in an additional pub-
lication (Chiarion-Sileni 2003 Ridolfi 2002) This study found
a significant decrease of overall quality of life in the chemoim-
munotherapy group in comparison to the chemotherapy group
(p = 003) The other two studies did not find differences in global
quality of life between the groups (Thomson 1993 Young 2001)
Thomson did not report global quality of life (Thomson 1993)
Young found no significant differences in quality of life for the
change in scores over time (z = -129 p = 020) (Young 2001)
It was not possible to pool the data as all three studies did not
provide extractable data
Sensitivity analyses on the influence of source of funding baseline
assessment and allocation concealment on the survival analysis
and response rate analyses revealed that there was no relation be-
tween these methodological aspects and the outcome There was
no statistically significant difference in survival between the groups
in all analyses and the difference in response rates in favour of
chemoimmunotherapy was found to be significant
D I S C U S S I O N
Metastatic melanoma is reputed as refractory to most systemic
treatments and little progress has been made in treatment of
metastatic melanoma These concepts are supported by results
from previous systematic reviews One review concluded that there
is no evidence derived from RCTs that systemic treatment is better
than best supportive care (Crosby 2000) Another review of 20
randomised trials (involving 3273 participants) comparing single-
agent DTIC with DTIC in combination with other drugs with or
without immunotherapy concluded that combination of drugs in-
creased response rates but not overall survival (Huncharek 2001)
This systematic review summarises the evidence regarding the
use of chemoimmunotherapy compared to chemotherapy alone
to treat people with metastatic malignant melanoma There are
some important observations regarding the characteristics of the
included studies in this systematic review The ideal combination
9Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
of drugs for an investigation is not well established Seven studies
evaluated chemoimmunotherapy with interferon-alpha plus inter-
leukin-2 and 11 evaluated chemoimmunotherapy only with in-
terferon-alpha The treatment plans with drugs and dosages used
differed between studies
Most studies did not contribute in answering relevant questions
about the impact of chemoimmunotherapy in the treatment of
metastatic melanoma The outcomes were not clearly described in
several of the studies (Atkins 2003 Del Vecchio 2003 Gorbonova
2000 Kirkwood 1990 Spieth 2003 Thomson 1993) Two of
them did not report survival rates evaluating only response rates
(Gorbonova 2000 Kirkwood 1990) All these aspects influenced
the comparability of the trials and must be considered in the data
interpretation
On the basis of a meta-analysis of data coming from eight studies
this review showed no evidence of a difference in overall survival to
support the addition of immunotherapy to chemotherapy in the
systemic treatment of metastatic melanoma (Atkins 2003 Danson
2003 Eton 2002 Falkson 1991 Johnston 1998 Ridolfi 2002
Spieth 2003 Young 2001) Evaluation of one two and five-year
survival with data from other studies again showed no survival
advantage of the drug combination treatment
We found higher clinical response rates in people treated with
chemoimmunotherapy in comparison with people treated with
chemotherapy which was not translated into survival benefit
Additionally we found higher toxicity rates in people treated
with chemoimmunotherapy Despite the importance of evaluat-
ing quality of life there was no available data to perform the meta-
analysis in this systematic review Only three studies reported data
about quality of life all with different methods One trial described
poorer quality of life in people treated with chemoimmunother-
apy related to more intense side effects (Ridolfi 2002) Two trials
however showed no difference between groups (Thomson 1993
Young 2001) It is important that quality of life is included in all
future studies
Our meta-analysis did not find differences between treatment re-
lated mortality Subgroup analysis comparing combinations with
interferon-alpha and with interferon-alpha plus interleukin-2 did
not show different results in survival or response rates
The use of chemoimmunotherapy ie a combination of chemo-
therapy with interferon-alpha or interleukin-2 or both has not
been shown to be beneficial in this review Although short term
response rates were better overall in the chemoimmunotherapy
groups survival was not improved and drug-related toxicities were
higher in the combined chemoimmunotherapy group To date no
treatment regimen has shown efficiency in prolonging survival in
people with metastatic melanoma Little has changed in the sys-
temic management of metastatic melanoma in the last few years
The standard of care remains single-agent DTIC and the role of
immunotherapy remains in doubt
The use of chemoimmunotherapy in the treatment of melanoma
is justified only in the context of clinical trials
A U T H O R S rsquo C O N C L U S I O N S
Implications for practice
We failed to find any evidence to support the view that the
use of chemoimmunotherapy prolongs survival in people with
metastatic melanoma when compared to chemotherapy alone Al-
though short-term clinical responses were higher in the chemoim-
munotherapy group this was associated with a higher rate of
serious adverse events esp haematological toxicity Our review
does not support the use of a combination of immunother-
apy and chemotherapy in chemoimmunotherapy regimens out-
side of clinical trials The standard of care for people with
advanced melanoma remains chemotherapy with single-agent
DTIC Chemoimmunotherapy must not be recommended to peo-
ple in daily practice
Implications for research
Research related to the development of more effective treatments
for people with metastatic melanoma is urgently needed
For people with an incurable disease the primary outcome needs
to be overall survival and all studies should include a quality of life
analysis
Future trials should be designed to define the best systemic treat-
ment and should use chemotherapy with (DTIC) as a standard
control group in order to permit comparisons to be made
A C K N O W L E D G E M E N T S
The authors wish to thank Raquel Gebara Lima for her kind
support in grammar and style
The editorial base would like to thank the following people who
were external referees for this review Keith Wheatley and Pat
Lawton (content experts) and Kathie Godfrey (consumer)
10Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
R E F E R E N C E S
References to studies included in this review
Atkins 2003 published data only
Atkins MB Lee S Flaherty LE Sosman JA Sondak VK
Kirkwood JM A prospective randomized phase III trial
of concurrent biochemotherapy (BCT) with cisplatin
vinblastine dacarbazine (CVD) IL-2 and interferon alpha-
2b (IFN) versus CVD alone in patients with metastatic
melanoma (E3695) An ECOG-coordinated intergroup
trial In ASCO Annual Meeting 2003 2003 p ASCO
Annual Meeting - Proceedings 2003Abstract 2847
Atzpodien 2002 published data only
Atzpodien J Neuber K Kamanabrou D Fluck M Brocker
EB Neumann C et alCombination chemotherapy with or
without sc IL-2 and IFN-alpha results of a prospectively
randomized trial of the Cooperative Advanced Malignant
Melanoma Chemoimmunotherapy Group (ACIMM)
British journal of cancer 200286(2)179ndash84
Bajetta 1994 published data only
Bajetta E Di Leo A Zampino MG Sertoli MR Comella
G Barduagni M et alMulticenter randomized trial of
dacarbazine alone or in combination with two different
doses and schedules of interferon alfa-2a in the treatment
of advanced melanoma Journal of clinical oncology official
journal of the American Society of Clinical Oncology 199412
(4)806ndash11
Danson 2003 published data only
Danson S Lorigan P Arance A Clamp A Ranson
M Hodgetts J et alRandomized phase II study of
temozolomide given every 8 hours or daily with either
interferon alfa-2b or thalidomide in metastatic malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 200321(13)2551ndash7
Del Vecchio 2003 published data only
Del Vecchio M Bajetta E Vitali M Gattinoni L Santinami
M Daponte A et alMulticenter phase III randomized trial
of cisplatin vindesine and dacarbazine (CVD) versus CVD
plus subcutaneous (sc) interleukin-2 (IL-2) and interferon-
alpha-2b (IFN) in metastatic melanoma patients (pts) In
ASCO Annual Meeting 2003 2003 p ASCO Annual
Meeting - Proceedings 2003Abstract 2849
Eton 2002 published data only
Eton O Legha SS Bedikian AY Lee JJ Buzaid AC
Hodges C et alSequential biochemotherapy versus
chemotherapy for metastatic melanoma results from a
phase III randomized trial Journal of clinical oncology
official journal of the American Society of Clinical Oncology
200220(8)2045ndash52
Falkson 1991 published data only
Falkson CI Falkson G Falkson HC Improved results with
the addition of interferon alfa-2b to dacarbazine in the
treatment of patients with metastatic malignant melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 19919(8)1403ndash8
Falkson 1998 published data only
Falkson CI Ibrahim J Kirkwood JM Coates AS Atkins
MB Blum RH Phase III trial of dacarbazine versus
dacarbazine with interferon alpha-2b versus dacarbazine
with tamoxifen versus dacarbazine with interferon alpha-
2b and tamoxifen in patients with metastatic malignant
melanoma an Eastern Cooperative Oncology Group study
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199816(5)1743ndash51
Gorbonova 2000 published data only
Gorbonova VA Egorov GN Perevodchikova NI Orel
NF Combined chemotherapy with or without interferon
alpha N1 (IFN) for advanced malignant melanoma - a
randomized pilot phase III study Gan To Kagaku Ryoho
200027 Suppl (2)310ndash4
Johnston 1998 published data only
Johnston SR Constenla DO Moore J Atkinson H ArsquoHern
RP Dadian G et alRandomized phase II trial of BCDT
[carmustine (BCNU) cisplatin dacarbazine (DTIC)
and tamoxifen] with or without interferon alpha (IFN-
alpha) and interleukin (IL-2) in patients with metastatic
melanoma British Journal of Cancer 199877(8)1280ndash6
Kirkwood 1990 published data only
Kirkwood JM Ernstoff MS Giuliano A Gams R Robinson
WA Costanzi J et alInterferon alpha-2a and dacarbazine
in melanoma Journal of the National Cancer Institute 1990
82(12)1062ndash3
Middleton 2000 published data only
Middleton MR Grob JJ Aaronson N Fierlbeck G
Tilgen W Seiter S et alRandomized phase III study of
temozolomide versus dacarbazine in the treatment of
patients with advanced metastatic malignant melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200018(1)158ndash66
Ridolfi 2002 published data only
Ridolfi R Chiarion-Sileni V Guida M Romanini A
Labianca R Freschi A et alCisplatin dacarbazine with
or without subcutaneous interleukin-2 and interferon
alpha-2b in advanced melanoma outpatients results from
an Italian multicenter phase III randomized clinical trial
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200220(6)1600ndash7
Rosenberg 1999 published data only
Rosenberg SA Yang JC Schwartzentruber DJ Hwu P
Marincola FM Topalian SL et alProspective randomized
trial of the treatment of patients with metastatic melanoma
using chemotherapy with cisplatin dacarbazine and
tamoxifen alone or in combination with interleukin-2 and
interferon alfa-2b Journal of Clinical Oncology 199917(3)
968ndash75
Spieth 2003 published data only
Spieth K Dummer R Garbe C Mauch C Schuler G
Landthaler M et alTemozolomide in combination with
11Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
interferon alfa versus temozolomide alone in patients with
advanced metastatic melanoma A randomized phase
III multicenter study of the Dermatologic Cooperative
Oncology Group (DeCOG) In ASCO Annual Meeting
2003Abstract 2887
Thomson 1993 published data only
Thomson DB Adena M McLeod GR Hersey P Gill PG
Coates AS et alInterferon-alpha 2a does not improve
response or survival when combined with dacarbazine
in metastatic malignant melanoma results of a multi-
institutional Australian randomized trial Melanoma
Research 19933(2)133ndash8
Vorobiof 1994 published data only
Vorobiof DA Bezwoda WR A randomised trial of vindesine
plus interferon-alpha 2b compared with interferon-alpha 2b
or vindesine alone in the treatment of advanced malignant
melanoma European journal of cancer (Oxford England
1990) 199430A(6)797ndash800
Young 2001 published data only
Young AM Marsden J Goodman A Burton A Dunn
JA Prospective randomized comparison of dacarbazine
(DTIC) versus DTIC plus interferon-alpha (IFN-alpha) in
metastatic melanoma Clinical oncology (Royal College of
Radiologists (Great Britain)) 200113(6)458ndash65
References to studies excluded from this review
Bajetta 2001 published data only
Bajetta E Del Vecchio M Vitali M Martinetti A Ferrari L
Queirolo P et alA feasibility study using polychemotherapy
(cisplatin + vindesine + dacarbazine) plus interferon-alpha
or monochemotherapy with dacarbazine plus interferon-
alpha in metastatic melanoma Tumori 200187(4)219ndash22
Legha 1996 published data only
Legha SS Ring S Bedikian A Plager C Eton O Buzaid
AC et alTreatment of metastatic melanoma with combined
chemotherapy containing cisplatin vinblastine and
dacarbazine (CVD) and biotherapy using interleukin-2 and
interferon-alpha Annals of oncology official journal of the
European Society for Medical Oncology ESMO 19967(8)
827ndash35
Richtig 2004 published data only
Richtig E Hofmann-Wellenhof R Pehamberger H
Forstinger C Wolff K Mischer P et alTemozolomide and
interferon alpha 2b in metastatic melanoma stage IV British
Journal of Dermatology 2004151(1)91ndash8
Sertoli 1999 published data only
Sertoli MR Queirolo P Bajetta E DelVecchio M
Comella G Barduagni L et alMulti-institutional phase
II randomized trial of integrated therapy with cisplatin
dacarbazine vindesine subcutaneous interleukin-2
interferon alpha2a and tamoxifen in metastatic melanoma
BREMIM (Biological Response Modifiers in Melanoma)
Melanoma research 19999(5)503ndash9
Sparano 1993 published data only
Sparano JA Fisher RI Sunderland M Margolin K Ernest
ML Sznol M et alRandomized phase III trial of treatment
with high-dose interleukin-2 either alone or in combination
with interferon alfa-2a in patients with advanced melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199311(10)1969ndash77
Vuoristo 2005 published data only
Vuoristo MS Hahka-Kemppinen M Parvinen LM
Pyrhonen S Seppa H Korpela M et alRandomized trial of
dacarbazine versus bleomycin vincristine lomustine and
dacarbazine (BOLD) chemotherapy combined with natural
or recombinant interferon-alpha in patients with advanced
melanoma Melanoma research 200515(4)291ndash6
Additional references
Arance 2000
Arance A Middleton M Lorigan P Thatcher N Three-
arm phase II study of temozolomide (TMZ) in metastatic
melanoma (MM) In ASCO Annual Meeting 2000
Abstract 2257
Bafaloukos 2002
Bafaloukos D Aravantinos G Fountzilas G Stathopoulos
G Gogas H Samonis G et alDocetaxel in combination
with dacarbazine in patients with advanced melanoma
Oncology 200263(4)333ndash7
Bajetta 2002
Bajetta E Del Vecchio M Bernard-Marty C Vitali
M Buzzoni R Rixe O et alMetastatic melanoma
chemotherapy Seminars in Oncology 200229(5)427ndash45
Balch 2001
Balch CM Soong SJ Gershenwald JE Thompson JF
Reintgen DS Cascinelli N et alPrognostic factors analysis
of 17600 melanoma patients validation of the American
Joint Committee on Cancer melanoma staging system
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200119(16)3622ndash34
Barth 1995
Barth A Morton DL The role of adjuvant therapy in
melanoma management Cancer 199575 Suppl (2)
726ndash34
Chiarion-Sileni 2003
Chiarion-Sileni V Del Bianco P De Salvo GL Lo Re G
Romanini A Labianca R et alQuality of life evaluation in a
randomised trial of chemotherapy versus bio-chemotherapy
in advanced melanoma patients European journal of cancer
(Oxford England 1990) 200339(11)1577ndash85
Creagan 1984
Creagan ET Ahmann DL Green SJ Long HJ Frytak S
OrsquoFallon JR et alPhase II study of low-dose recombinant
leukocyte A interferon in disseminated malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 19842(9)1002ndash5
Crosby 2000
Crosby T Fish R Coles B Mason MD Systemic treatments
for metastatic cutaneous melanoma Cochrane Database
of Systematic Reviews 2000 Issue 2 [DOI 101002
14651858CD001215]
12Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Cure 1999
Cure H Souteyrand P Ouabdesselam R Roche H
Ravaud A DrsquoIncan M et alResults of a phase II trial
with cystemustine at 90 mgm(2) as a first- or second-line
treatment in advanced malignant melanoma a trial of the
EORTC Clinical Studies Group Melanoma Research 1999
9(6)607ndash10
Danson 2002
Danson S Arance A Lorigan P Clamp A Hodgetts J
Lomax L Thatcher N Middleton MR A randomized
study of temozolomide (TMZ) alone with interferon-
alpha (TMZ-IFN) or with thalidomide (TMZ-THAL) in
metastatic malignant melanoma (MMM) ASCO Annual
Meeting - Proceedings 2002Abstract 1369
Dorval 1986
Dorval T Palangie T Jouve M Garcia-Giralt E Israel L
Falcoff E et alClinical phase II trial of recombinant DNA
interferon (interferon alpha 2b) in patients with metastatic
malignant melanoma Cancer 198658(2)215ndash8
Dutcher 1989
Dutcher JP Creekmore S Weiss GR Margolin K
Markowitz AB Roper M et alA phase II study of
interleukin-2 and lymphokine-activated killer cells in
patients with metastatic malignant melanoma Journal of
clinical oncology official journal of the American Society of
Clinical Oncology 19897(4)477ndash85
Falkson 1995
Falkson CI Experience with interferon alpha 2b combined
with dacarbazine in the treatment of metastatic malignant
melanoma Medical oncology (Northwood London England)
199512(1)35ndash40
Garbe 1990
Garbe C Krasagakis K Zouboulis CC Schroder K Kruger
S Stadler R et alAntitumor activities of interferon alpha
beta and gamma and their combinations on human
melanoma cells in vitro changes of proliferation melanin
synthesis and immunophenotype Journal of Investigative
Dermatology 199095 Suppl (6)231ndash7
Gershenwald 1999
Gershenwald JE Thompson W Mansfield PF Lee JE
Colome MI Tseng CH et alMulti-institutional melanoma
lymphatic mapping experience the prognostic value of
sentinel lymph node status in 612 stage I or II melanoma
patients Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199917(3)976ndash83
Hanninen 1991
Hanninen EL Korfer A Hadam M Schneekloth C
Dallmann I Menzel T et alBiological monitoring of
low-dose interleukin 2 in humans soluble interleukin 2
receptors cytokines and cell surface phenotypes Cancer
Research 199151(23 Pt 1)6312ndash6
Huncharek 2001
Huncharek M Caubet JF McGarry R Single-agent
DTIC versus combination chemotherapy with or without
immunotherapy in metastatic melanoma a meta-analysis
of 3273 patients from 20 randomized trials Melanoma
Research 200111(1)75ndash81
Juni 2001
Juni P Altman DG Egger M Assessing the quality of
controlled clinical trials BMJ 200132342ndash6
Kadison 2003
Kadison AS Morton DL Immunotherapy of malignant
melanoma The Surgical Clinics of North America 200383
(2)343ndash70
Keilholz 2002
Keilholz U Gore ME Biochemotherapy for advanced
melanoma Seminars in Oncology 200229(5)456ndash61
Khayat 2002
Khayat D Bernard-Marty C Meric JB Rixe O
Biochemotherapy for advanced melanoma maybe it is real
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200220(10)2411ndash4
Koh 1991
Koh HK Cutaneous melanoma New England Journal of
Medicine 1991325(3)171ndash82
La Vecchia 1999
La Vecchia C Lucchini F Negri E Levi F Recent declines
in worldwide mortality from cutaneous melanoma in youth
and middle age International Journal of Cancer 199981(1)
62ndash6
Lee 2000
Lee ML Tomsu K Von Eschen KB Duration of survival
for disseminated malignant melanoma results of a meta-
analysis Melanoma Research 200010(1)81ndash92
Legha 1998
Legha SS Ring S Eton O Bedikian A Buzaid AC Plager
C et alDevelopment of a biochemotherapy regimen
with concurrent administration of cisplatin vinblastine
dacarbazine interferon alfa and interleukin-2 for patients
with metastatic melanoma Journal of clinical oncology
official journal of the American Society of Clinical Oncology
199816(5)1752ndash9
Leong 2003
Leong SP Future perspectives on malignant melanoma
Surgical Clinics of North America 200383(2)453ndash6
Lokich 1979
Lokich JJ Garnick MB Legg M Intralesional immune
therapy methanol extraction residue of BCG or purified
protein derivative Oncology 197936(5)236ndash41
Nathan 1998
Nathan FE Mastrangelo MJ Systemic therapy in
melanoma Seminars in Surgical Oncology 199814(4)
319ndash27
Osborn 1977
Osborn DE Castro JE Immunological response in patients
receiving Corynebacterium parvum therapy Clinical
Oncology 19773(2)155ndash64
13Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Parmar 1998
Parmar MKB TV Stewart L Extracting summary statistics
to perform meta-analyses of the published literature for
survival endpoints Statistics in Medicine 1998172815ndash34
Richards 1992
Richards JM Mehta N Ramming K Skosey P Sequential
chemoimmunotherapy in the treatment of metastatic
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199210(8)1338ndash43
Rigel 1989
Rigel DS Rivers JK Kopf AW Friedman RJ Vinokur AF
Heilman ER et alDysplastic nevi Markers for increased
risk for melanoma Cancer 198963(2)386ndash9
Rosenberg 1989
Rosenberg SA Lotze MT Yang JC Aebersold PM Linehan
WM Seipp CA et alExperience with the use of high-
dose interleukin-2 in the treatment of 652 cancer patients
Annals of Surgery 1989210(4)474-84 discussion 484-5
Sertoli 1989
Sertoli MR Bernengo MG Ardizzoni A Brunetti I Falcone
A Vidili MG et alPhase II trial of recombinant alpha-2b
interferon in the treatment of metastatic skin melanoma
Oncology 198946(2)96ndash8
Smith 1993
Smith KA Lowest dose interleukin-2 immunotherapy
Blood 199381(6)1414ndash23
Stopeck 2001
Stopeck AT Jones A Hersh EM Thompson JA
Finucane DM Gutheil JC et alPhase II study of direct
intralesional gene transfer of allovectin-7 an HLA-B7
beta2-microglobulin DNA-liposome complex in patients
with metastatic melanoma Clinical Cancer Research 20017
(8)2285ndash91
Tsang 1983
Tsang KY Fudenberg HH Pan JF Gnagy MJ Bristow
CB An in vitro study on the effects of isoprinosine on
immune responses in cancer patients International Journal
of Immunopharmacology 19835(6)481ndash90
Wingo 1995
Wingo PA Tong T Bolden S Cancer statistics 1995 CA
a cancer journal for clinicians 199545(1)8ndash30
Yusuf 1985
Yusuf S Peto R Lewis J Collins R Sleight P Beta blockade
during and after myocardial infarction an overview of the
randomized trials Progress in Cardiovascular Diseases 1985
27(5)335ndash71lowast Indicates the major publication for the study
14Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Atkins 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding public
Participants PS lt= 1
Brain mets no info
Age 20 to 80 (median 50)
Number of cycles no info
Randomised 416 a 206 b 210
Evaluable 405 a 201 b 204
Interventions a (CT) cisplatin 20mgm2 D1 to 4 vinblastin 12 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1-4 vimblastin 12 mgm2 D1-4 DTIC 800 mgm2 D1
IFN-alpha 5 mIU D1-5 D8 D10 D12 IL-2 9 mIU D1-4
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
Notes Multicentric yes
Withdrawals a five b six
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
15Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Atzpodien 2002
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding both (pharmaceutic and public)
Participants PS lt= 1
Brain mets yes Age 28 to 77 (median 57)
Number of cycles no info
Randomised 124 a 60 b 64
Evaluable 124 a 60 b 64
Interventions a (CT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily
b (ICT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily IFN-alpha 5 mIUm2 D1 week4 and 5
mIUm2 D1 D3 D5 week 5 IL-2 10 mIUm2 D1 D3 D5
(each five weeks)
Outcomes 1 Response rates
2 Overall survival
3 Progression free survival
Notes Multicentric yes
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Bajetta 1994
Methods D parallel group (three groups)
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding pharmaceutic
Participants PS lt= 2
Brain mets no
16Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Bajetta 1994 (Continued)
Age 18 to 70 (median 53)
Number of cycles 8
Randomised 266 a 88 b 86 c 92
Evaluable 242 a 82 b 76 c 84
Interventions a (CT) DTIC 800 mgm2 D1
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU 3xweek
c (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU D1 to 3 6 mIU D4 to 6 9 mIU daily
(each 21 days)
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Overall survival
Notes Multicentric yes
Withdrawals a six b ten c eight
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Danson 2003
Methods D parallel group
AC independent allocation
RS permuted blocks
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets yes Age 16 to 88 (median 58)
Number of cycles six
Randomised 125 a 59 b 62
Evaluable 121 a 55 b 62
Interventions a (CT) temozolomide 200 mgm2 88 h (5 doses)
b (ICT) Temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIU 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
17Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Danson 2003 (Continued)
Notes Multicentric no
Withdrawals a 4 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Del Vecchio 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no Age 19 to 70 (median 50)
Number of cycles no info
Randomised 151 a 75 b 76
Evaluable 145 a 72 b 73
Interventions a (CT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250 mgm2 D1 to
3
b (ICT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250m gm2 D1 to
3 IFN-alpha 5 mIUm2 D1 to 5 IL-2 9 mIUday x 5 daysweek x 2 weeks with a week of
rest
(each 21 days)
Outcomes 1 Response rates
2 Time to Progression
2 Overall Survival
Notes Multicentric yes
Withdrawals a three b three
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
18Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Eton 2002
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding pharm
Participants PS lt= 3
Brain mets yes Age median 49
Number of cycles no info
Randomised 190
Evaluable 183 a 92 b 91
Interventions a (CT) cisplatin 20m gm2 D1 to 4 vimblastin 2 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1 to 4 vinblastin 15 mgm2 D1 to 4 DTIC 800 mgm2
D1 IFN-alpha 5mIUm2 D5 to 9 D17-21 IL-2 9 mIUm2 D5 to 8 D17 to 20
(each 21 days)
Outcomes 1 Response rates
2 Time to progression
3 Overall survival
Notes Multicentric no
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1991
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size no
ITT no
Placebo no
Funding both
Participants PS lt= 1
Brain mets no
Age 22 to 79
(median 57)
Number of cycles at least two
19Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1991 (Continued)
Randomised 73 Evaluable 68 a 34 b 34
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Time to treatment failure
3 Median survival
4 Toxicity
Notes Multicentric no
Withdrawals a three b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1998
Methods D 2 x 2 factorial design
AC independent allocation
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 18 to 84
Number of cycles no info
Randomised 271 Evaluable 263 a 68 b 65 c 63 d 67
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
c (CT) DTIC 200m gm2 D1 to 5 tamoxifen 20 mgdaily
d (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek tamoxifen 20 mgdaily
(each 28 days)
Outcomes 1 Response rates
2 Toxicity rates
20Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1998 (Continued)
3 Overall survival
4 Time to treatment failure
Notes Multicentric yes
Withdrawals a one b three c three d one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Gorbonova 2000
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no
Age 23 to 75
Number of cycles no info
Randomised 30 Evaluable 28 a 14 b 14
Interventions a (CT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2
b (ICT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2 IFN-alpha 3 mIU D5 7
9 11 13 15 17 19
(each 28 days)
Outcomes 1 Response rates
Notes Multicentric no
Withdrawals a two b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
21Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Johnston 1998
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age 18 to 70
(median 45)
Number of cycles no info
Randomised 65 Evaluable 65 a 30 b 35
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to 3
Tamoxifen 40 mg daily
b (ICT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to
3 Tamoxifen 40 mg daily IFN-alpha 9 mIU D1 to 3 IL-2 18 mIU D-2 IL-2 9 mIU D-
1 and 0
(each 28 days)
Outcomes 1 Response rates
2 Time to disease progression
3 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Kirkwood 1990
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding pharm
22Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Kirkwood 1990 (Continued)
Participants PS no info
Brain mets no info
Age no info
Number of cycles no info
Randomised 74 Evaluable 68 a 24 b 23 c 21
Interventions a (CT) DTIC 250 mgm2 D1 to 5 (each 21 days)
b (I) IFN-alpha 3 mIU d1 to 5 every week for 3 weeks than 3 mIUm2 3 xweek
c (ICT) DTIC 250 mgm2 D1 to 5 (each 21 days) IFN-alpha 3 mIU d1 to 5 every week
for 3 weeks than 3 mIUm2 3 xweek
Outcomes 1 Response rates
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Middleton 2000
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets no
Age 24 to 71
(median 51)
Number of cycles six
Randomised 105 Evaluable 96 a 46 b 50
Interventions a (CT) DTIC 800 mgm2 D1 cisplatin 25 mgm2 D1 to 3 BCNU 150 mgm2 D1
tamoxifen 20 mgdaily
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 9 mIU 3 xweek
(each 21 days)
Outcomes 1 Response rates
2 One year survival
3 Median survival
23Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Middleton 2000 (Continued)
4 Toxicity
4 Time spent in hospital
Notes Multicentric no
Withdrawals a seven b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Ridolfi 2002
Methods D parallel group
AC independent allocation by telephone
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 25 to 77
Number of cycles six
Randomised 178 Evaluable 176 a 89 b 87
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1
b (ICT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1 IFN-
alpha 3 mIU 3 xweek IL-2 45 mIU D3 to 5 D8 to 12
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
3 Time to progression
4 Toxicity
Notes Multicentric yes
Withdrawals a one b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
24Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Although blinding participants and clinicians is theoretically pos-
sible it is difficult to plan a double-blind study with immunother-
apy This is due to the substantial acute and late toxicities associ-
ated with immunotherapy in one group No study was described
as double-blinded The groups at baseline were in general similar
with a description of most prognostic factors related to metastatic
melanoma (gender performance status age prior therapy liver
metastasis)
In three studies almost all methodological aspects of the trials
were described poorly (Gorbonova 2000 Kirkwood 1990 Spieth
2003)
Allocation
All the included studies were described as randomised as this
was a selection criterion However most papers did not describe
the method of randomisation The method of generation of the
randomised sequence was described and considered adequate in
only 6 out of 18 studies Eleven of 18 studies provided information
on allocation concealment all of which were considered adequate
Blinding
Blinding of outcome assessment and detection bias
We did not find information about blinding of the outcome as-
sessors in any included study
Incomplete outcome data
Handling of losses and attrition bias
In general there were few participants lost to follow up in the
studies The highest number of people lost was 24 in a total of 262
participants (Bajetta 1994) Eleven studies included an intention-
to-treat analysis
Effects of interventions
Primary outcome
Overall survival (eight studies)
This was considered as the number of participants alive at the end
of the trial Sufficient data were available from 8 of the 18 studies
There was no statistically significant difference in survival between
chemoimmunotherapy and chemotherapy with a hazard ratio
(HR) of improved survival of 089 (95 CI 072 to 111 P = 031
Analysis 11) in favour of chemoimmunotherapy In other words
overall survival was slightly lower in the chemoimmunotherapy
group but this was not statistically significant There was no het-
erogeneity across trials (I2 = 0) The funnel plot method using
overall survival as the outcome is presented in Figure 1 It shows
that there was no evidence of substantial publication bias but in-
terpretation of the funnel plot is likely to be unreliable since only
eight relatively large studies were found
When we evaluated the influence of the type of immunotherapy
used in the chemoimmunotherapy group (IL-2 plus IFN-alpha
or IFN-alpha only) we found no statistically significant difference
between the groups with a HR of 096 (95 CI 074 to 124 P =
076 Analysis 11) for chemoimmunotherapy with IL-2 plus IFN-
alpha and a HR of 074 (95 CI 049 to 112 P = 015 Analysis
11) for chemoimmunotherapy associated with only IFN-alpha
Secondary outcomes
One two and five-year survival rates (13 studies)
The number of participants alive at one two and five year follow-
ups were analyzed Data from 13 trials evaluating one year survival
were pooled There was no statistically significant difference in one
year survival between the groups with a risk ratio (RR) of 106
(95 CI 091 to 124 P = 048 Analysis 12) and no significant
heterogeneity across trials (I2 = 363)
Data from 11 trials evaluating 2 year survival were extracted and
pooled Again there was no statistically significant difference be-
tween the groups with a RR of 108 (95 CI 086 to 136 P =
050 Analysis 13) without heterogeneity across trials (I2 = 0)
Only two trials reported data about five year survival The meta-
analysis showed no statistically significant difference in 5 year sur-
vival between the groups with a RR of survival of 234 (95
CI 097 to 565 P = 006 Analysis 14) favouring chemoim-
munotherapy There was no heterogeneity across trials (I2 = 0)
Response rates (17 studies)
Data regarding the number of participants with partial or com-
plete responses from 17 trials were used to evaluate objective re-
sponse rates The analysis detected a statistically significant differ-
ence in favor of chemoimmunotherapy in global response rates
with a RR of 140 (95 CI 120 to 163 P lt 00001 Analysis
21) There was no heterogeneity across trials (I2 = 42) We
tried to evaluate the influence of the type of immunotherapeutic
in the group of chemoimmunotherapy (IL-2 plus IFN-alpha or
IFN-alpha only) We found similar results with a RR of global
response of 146 (95 CI 119 to 179 p = 00002 Analysis 21)
in favor of chemoimmunotherapy with IL-2 plus IFN-alpha and
a RR of 132 (95 CI 102 to 171 p = 004 Analysis 21) in favor
of chemoimmunotherapy with IFN-alpha There was no hetero-
geneity across trials (I2 = 0)
8Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Data from 15 trials were used to evaluate partial and complete
response rates We found a statistically significant difference in
favour of chemoimmunotherapy in both analyses with an HR of
131 (95 CI 107 to 159 p = 0008 Analysis 23) for partial
response rates and an HR of 158 (95 CI 106 to 236 p = 003
Analysis 23) for complete response rates
Progression-free survival (3 studies)
Only three studies had extractable data about the number of par-
ticipants with no disease progression at the end of the trial When
pooled together there was no statistically significant difference be-
tween the groups with an HR of 076 (95 CI 057 to 102 p =
007 Analysis 31) There was no heterogeneity across these trials
(I2 = 0)
Treatment related toxicity (11 studies)
Data from 11 studies were collected with the number of partici-
pants developing clinically significant hematological toxicity (de-
fined as grade 3 or 4) Eight studies had estimated points that
showed enhanced toxicities in the chemoimmunotherapy group
The meta-analysis of the studies showed extreme heterogeneity
(I2 = 941) across the trials We performed a sensitivity anal-
ysis excluding the studies with relatively low doses of chemo-
therapeutic drugs in the chemoimmunotherapy group (Danson
2003 Middleton 2000) but we found similar heterogeneity (I2 =
978)
When we analyzed data from the four studies with similar rela-
tive doses of chemotherapeutics associated with interferon-alpha
without interleukin-2 we found an increase of clinically signifi-
cant hematological toxicities in the chemoimmunotherapy group
with a RR 454 (95 CI 235 to 879 p lt 000001) There was
no heterogeneity across these trials (I2 = 0) When we analyzed
data from studies with combination of interferon-alpha plus in-
terleukin-2 in the chemoimmunotherapy group we again found
extreme heterogeneity across the trials (I2 = 979)
Despite the heterogeneity in global meta-analysis we concluded
that it was not possible to quantify the differences in hematologi-
cal toxicity in such different trials In order to explore these differ-
ences we noted that one study referred to hematological toxicity
in 100 of participants treated with chemoimmunotherapy and
in 96 of participants treated with chemotherapy (Eton 2002)
Another study referred to hematological toxicity only in 2 and
1 respectively (Bajetta 1994)
Non-hematological toxicities were described in almost all stud-
ies and were mainly described as nausea vomiting flu-like syn-
drome asthenia hypotension and fever Data from six similar
studies were extractable and were pooled in the meta-analysis re-
sulting in a statistically significant difference against the chemoim-
munotherapy group with a RR of 274 (95 CI 206 to 364 p
lt 000001 Analysis 42) There was no heterogeneity across trials
(I2 = 0) These results must be treated with caution because of
similar difficulties in pooling these data on hematological toxici-
ties with different therapeutic schemes and several trials described
non-hematological toxicities but we were not able to extract the
data
Data about treatment-related mortality were available in 11 stud-
ies We found no significant difference between the groups with a
RR of 078 (95 CI 026 to 232 p = 065 Analysis 43) There
was no heterogeneity across the trials (I2 = 0)
Quality of life (three studies)
Only three studies reported data on quality of life (Ridolfi 2002
Thomson 1993 Young 2001) all using different methods One
trial described quality of life analysis in detail in an additional pub-
lication (Chiarion-Sileni 2003 Ridolfi 2002) This study found
a significant decrease of overall quality of life in the chemoim-
munotherapy group in comparison to the chemotherapy group
(p = 003) The other two studies did not find differences in global
quality of life between the groups (Thomson 1993 Young 2001)
Thomson did not report global quality of life (Thomson 1993)
Young found no significant differences in quality of life for the
change in scores over time (z = -129 p = 020) (Young 2001)
It was not possible to pool the data as all three studies did not
provide extractable data
Sensitivity analyses on the influence of source of funding baseline
assessment and allocation concealment on the survival analysis
and response rate analyses revealed that there was no relation be-
tween these methodological aspects and the outcome There was
no statistically significant difference in survival between the groups
in all analyses and the difference in response rates in favour of
chemoimmunotherapy was found to be significant
D I S C U S S I O N
Metastatic melanoma is reputed as refractory to most systemic
treatments and little progress has been made in treatment of
metastatic melanoma These concepts are supported by results
from previous systematic reviews One review concluded that there
is no evidence derived from RCTs that systemic treatment is better
than best supportive care (Crosby 2000) Another review of 20
randomised trials (involving 3273 participants) comparing single-
agent DTIC with DTIC in combination with other drugs with or
without immunotherapy concluded that combination of drugs in-
creased response rates but not overall survival (Huncharek 2001)
This systematic review summarises the evidence regarding the
use of chemoimmunotherapy compared to chemotherapy alone
to treat people with metastatic malignant melanoma There are
some important observations regarding the characteristics of the
included studies in this systematic review The ideal combination
9Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
of drugs for an investigation is not well established Seven studies
evaluated chemoimmunotherapy with interferon-alpha plus inter-
leukin-2 and 11 evaluated chemoimmunotherapy only with in-
terferon-alpha The treatment plans with drugs and dosages used
differed between studies
Most studies did not contribute in answering relevant questions
about the impact of chemoimmunotherapy in the treatment of
metastatic melanoma The outcomes were not clearly described in
several of the studies (Atkins 2003 Del Vecchio 2003 Gorbonova
2000 Kirkwood 1990 Spieth 2003 Thomson 1993) Two of
them did not report survival rates evaluating only response rates
(Gorbonova 2000 Kirkwood 1990) All these aspects influenced
the comparability of the trials and must be considered in the data
interpretation
On the basis of a meta-analysis of data coming from eight studies
this review showed no evidence of a difference in overall survival to
support the addition of immunotherapy to chemotherapy in the
systemic treatment of metastatic melanoma (Atkins 2003 Danson
2003 Eton 2002 Falkson 1991 Johnston 1998 Ridolfi 2002
Spieth 2003 Young 2001) Evaluation of one two and five-year
survival with data from other studies again showed no survival
advantage of the drug combination treatment
We found higher clinical response rates in people treated with
chemoimmunotherapy in comparison with people treated with
chemotherapy which was not translated into survival benefit
Additionally we found higher toxicity rates in people treated
with chemoimmunotherapy Despite the importance of evaluat-
ing quality of life there was no available data to perform the meta-
analysis in this systematic review Only three studies reported data
about quality of life all with different methods One trial described
poorer quality of life in people treated with chemoimmunother-
apy related to more intense side effects (Ridolfi 2002) Two trials
however showed no difference between groups (Thomson 1993
Young 2001) It is important that quality of life is included in all
future studies
Our meta-analysis did not find differences between treatment re-
lated mortality Subgroup analysis comparing combinations with
interferon-alpha and with interferon-alpha plus interleukin-2 did
not show different results in survival or response rates
The use of chemoimmunotherapy ie a combination of chemo-
therapy with interferon-alpha or interleukin-2 or both has not
been shown to be beneficial in this review Although short term
response rates were better overall in the chemoimmunotherapy
groups survival was not improved and drug-related toxicities were
higher in the combined chemoimmunotherapy group To date no
treatment regimen has shown efficiency in prolonging survival in
people with metastatic melanoma Little has changed in the sys-
temic management of metastatic melanoma in the last few years
The standard of care remains single-agent DTIC and the role of
immunotherapy remains in doubt
The use of chemoimmunotherapy in the treatment of melanoma
is justified only in the context of clinical trials
A U T H O R S rsquo C O N C L U S I O N S
Implications for practice
We failed to find any evidence to support the view that the
use of chemoimmunotherapy prolongs survival in people with
metastatic melanoma when compared to chemotherapy alone Al-
though short-term clinical responses were higher in the chemoim-
munotherapy group this was associated with a higher rate of
serious adverse events esp haematological toxicity Our review
does not support the use of a combination of immunother-
apy and chemotherapy in chemoimmunotherapy regimens out-
side of clinical trials The standard of care for people with
advanced melanoma remains chemotherapy with single-agent
DTIC Chemoimmunotherapy must not be recommended to peo-
ple in daily practice
Implications for research
Research related to the development of more effective treatments
for people with metastatic melanoma is urgently needed
For people with an incurable disease the primary outcome needs
to be overall survival and all studies should include a quality of life
analysis
Future trials should be designed to define the best systemic treat-
ment and should use chemotherapy with (DTIC) as a standard
control group in order to permit comparisons to be made
A C K N O W L E D G E M E N T S
The authors wish to thank Raquel Gebara Lima for her kind
support in grammar and style
The editorial base would like to thank the following people who
were external referees for this review Keith Wheatley and Pat
Lawton (content experts) and Kathie Godfrey (consumer)
10Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
R E F E R E N C E S
References to studies included in this review
Atkins 2003 published data only
Atkins MB Lee S Flaherty LE Sosman JA Sondak VK
Kirkwood JM A prospective randomized phase III trial
of concurrent biochemotherapy (BCT) with cisplatin
vinblastine dacarbazine (CVD) IL-2 and interferon alpha-
2b (IFN) versus CVD alone in patients with metastatic
melanoma (E3695) An ECOG-coordinated intergroup
trial In ASCO Annual Meeting 2003 2003 p ASCO
Annual Meeting - Proceedings 2003Abstract 2847
Atzpodien 2002 published data only
Atzpodien J Neuber K Kamanabrou D Fluck M Brocker
EB Neumann C et alCombination chemotherapy with or
without sc IL-2 and IFN-alpha results of a prospectively
randomized trial of the Cooperative Advanced Malignant
Melanoma Chemoimmunotherapy Group (ACIMM)
British journal of cancer 200286(2)179ndash84
Bajetta 1994 published data only
Bajetta E Di Leo A Zampino MG Sertoli MR Comella
G Barduagni M et alMulticenter randomized trial of
dacarbazine alone or in combination with two different
doses and schedules of interferon alfa-2a in the treatment
of advanced melanoma Journal of clinical oncology official
journal of the American Society of Clinical Oncology 199412
(4)806ndash11
Danson 2003 published data only
Danson S Lorigan P Arance A Clamp A Ranson
M Hodgetts J et alRandomized phase II study of
temozolomide given every 8 hours or daily with either
interferon alfa-2b or thalidomide in metastatic malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 200321(13)2551ndash7
Del Vecchio 2003 published data only
Del Vecchio M Bajetta E Vitali M Gattinoni L Santinami
M Daponte A et alMulticenter phase III randomized trial
of cisplatin vindesine and dacarbazine (CVD) versus CVD
plus subcutaneous (sc) interleukin-2 (IL-2) and interferon-
alpha-2b (IFN) in metastatic melanoma patients (pts) In
ASCO Annual Meeting 2003 2003 p ASCO Annual
Meeting - Proceedings 2003Abstract 2849
Eton 2002 published data only
Eton O Legha SS Bedikian AY Lee JJ Buzaid AC
Hodges C et alSequential biochemotherapy versus
chemotherapy for metastatic melanoma results from a
phase III randomized trial Journal of clinical oncology
official journal of the American Society of Clinical Oncology
200220(8)2045ndash52
Falkson 1991 published data only
Falkson CI Falkson G Falkson HC Improved results with
the addition of interferon alfa-2b to dacarbazine in the
treatment of patients with metastatic malignant melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 19919(8)1403ndash8
Falkson 1998 published data only
Falkson CI Ibrahim J Kirkwood JM Coates AS Atkins
MB Blum RH Phase III trial of dacarbazine versus
dacarbazine with interferon alpha-2b versus dacarbazine
with tamoxifen versus dacarbazine with interferon alpha-
2b and tamoxifen in patients with metastatic malignant
melanoma an Eastern Cooperative Oncology Group study
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199816(5)1743ndash51
Gorbonova 2000 published data only
Gorbonova VA Egorov GN Perevodchikova NI Orel
NF Combined chemotherapy with or without interferon
alpha N1 (IFN) for advanced malignant melanoma - a
randomized pilot phase III study Gan To Kagaku Ryoho
200027 Suppl (2)310ndash4
Johnston 1998 published data only
Johnston SR Constenla DO Moore J Atkinson H ArsquoHern
RP Dadian G et alRandomized phase II trial of BCDT
[carmustine (BCNU) cisplatin dacarbazine (DTIC)
and tamoxifen] with or without interferon alpha (IFN-
alpha) and interleukin (IL-2) in patients with metastatic
melanoma British Journal of Cancer 199877(8)1280ndash6
Kirkwood 1990 published data only
Kirkwood JM Ernstoff MS Giuliano A Gams R Robinson
WA Costanzi J et alInterferon alpha-2a and dacarbazine
in melanoma Journal of the National Cancer Institute 1990
82(12)1062ndash3
Middleton 2000 published data only
Middleton MR Grob JJ Aaronson N Fierlbeck G
Tilgen W Seiter S et alRandomized phase III study of
temozolomide versus dacarbazine in the treatment of
patients with advanced metastatic malignant melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200018(1)158ndash66
Ridolfi 2002 published data only
Ridolfi R Chiarion-Sileni V Guida M Romanini A
Labianca R Freschi A et alCisplatin dacarbazine with
or without subcutaneous interleukin-2 and interferon
alpha-2b in advanced melanoma outpatients results from
an Italian multicenter phase III randomized clinical trial
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200220(6)1600ndash7
Rosenberg 1999 published data only
Rosenberg SA Yang JC Schwartzentruber DJ Hwu P
Marincola FM Topalian SL et alProspective randomized
trial of the treatment of patients with metastatic melanoma
using chemotherapy with cisplatin dacarbazine and
tamoxifen alone or in combination with interleukin-2 and
interferon alfa-2b Journal of Clinical Oncology 199917(3)
968ndash75
Spieth 2003 published data only
Spieth K Dummer R Garbe C Mauch C Schuler G
Landthaler M et alTemozolomide in combination with
11Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
interferon alfa versus temozolomide alone in patients with
advanced metastatic melanoma A randomized phase
III multicenter study of the Dermatologic Cooperative
Oncology Group (DeCOG) In ASCO Annual Meeting
2003Abstract 2887
Thomson 1993 published data only
Thomson DB Adena M McLeod GR Hersey P Gill PG
Coates AS et alInterferon-alpha 2a does not improve
response or survival when combined with dacarbazine
in metastatic malignant melanoma results of a multi-
institutional Australian randomized trial Melanoma
Research 19933(2)133ndash8
Vorobiof 1994 published data only
Vorobiof DA Bezwoda WR A randomised trial of vindesine
plus interferon-alpha 2b compared with interferon-alpha 2b
or vindesine alone in the treatment of advanced malignant
melanoma European journal of cancer (Oxford England
1990) 199430A(6)797ndash800
Young 2001 published data only
Young AM Marsden J Goodman A Burton A Dunn
JA Prospective randomized comparison of dacarbazine
(DTIC) versus DTIC plus interferon-alpha (IFN-alpha) in
metastatic melanoma Clinical oncology (Royal College of
Radiologists (Great Britain)) 200113(6)458ndash65
References to studies excluded from this review
Bajetta 2001 published data only
Bajetta E Del Vecchio M Vitali M Martinetti A Ferrari L
Queirolo P et alA feasibility study using polychemotherapy
(cisplatin + vindesine + dacarbazine) plus interferon-alpha
or monochemotherapy with dacarbazine plus interferon-
alpha in metastatic melanoma Tumori 200187(4)219ndash22
Legha 1996 published data only
Legha SS Ring S Bedikian A Plager C Eton O Buzaid
AC et alTreatment of metastatic melanoma with combined
chemotherapy containing cisplatin vinblastine and
dacarbazine (CVD) and biotherapy using interleukin-2 and
interferon-alpha Annals of oncology official journal of the
European Society for Medical Oncology ESMO 19967(8)
827ndash35
Richtig 2004 published data only
Richtig E Hofmann-Wellenhof R Pehamberger H
Forstinger C Wolff K Mischer P et alTemozolomide and
interferon alpha 2b in metastatic melanoma stage IV British
Journal of Dermatology 2004151(1)91ndash8
Sertoli 1999 published data only
Sertoli MR Queirolo P Bajetta E DelVecchio M
Comella G Barduagni L et alMulti-institutional phase
II randomized trial of integrated therapy with cisplatin
dacarbazine vindesine subcutaneous interleukin-2
interferon alpha2a and tamoxifen in metastatic melanoma
BREMIM (Biological Response Modifiers in Melanoma)
Melanoma research 19999(5)503ndash9
Sparano 1993 published data only
Sparano JA Fisher RI Sunderland M Margolin K Ernest
ML Sznol M et alRandomized phase III trial of treatment
with high-dose interleukin-2 either alone or in combination
with interferon alfa-2a in patients with advanced melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199311(10)1969ndash77
Vuoristo 2005 published data only
Vuoristo MS Hahka-Kemppinen M Parvinen LM
Pyrhonen S Seppa H Korpela M et alRandomized trial of
dacarbazine versus bleomycin vincristine lomustine and
dacarbazine (BOLD) chemotherapy combined with natural
or recombinant interferon-alpha in patients with advanced
melanoma Melanoma research 200515(4)291ndash6
Additional references
Arance 2000
Arance A Middleton M Lorigan P Thatcher N Three-
arm phase II study of temozolomide (TMZ) in metastatic
melanoma (MM) In ASCO Annual Meeting 2000
Abstract 2257
Bafaloukos 2002
Bafaloukos D Aravantinos G Fountzilas G Stathopoulos
G Gogas H Samonis G et alDocetaxel in combination
with dacarbazine in patients with advanced melanoma
Oncology 200263(4)333ndash7
Bajetta 2002
Bajetta E Del Vecchio M Bernard-Marty C Vitali
M Buzzoni R Rixe O et alMetastatic melanoma
chemotherapy Seminars in Oncology 200229(5)427ndash45
Balch 2001
Balch CM Soong SJ Gershenwald JE Thompson JF
Reintgen DS Cascinelli N et alPrognostic factors analysis
of 17600 melanoma patients validation of the American
Joint Committee on Cancer melanoma staging system
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200119(16)3622ndash34
Barth 1995
Barth A Morton DL The role of adjuvant therapy in
melanoma management Cancer 199575 Suppl (2)
726ndash34
Chiarion-Sileni 2003
Chiarion-Sileni V Del Bianco P De Salvo GL Lo Re G
Romanini A Labianca R et alQuality of life evaluation in a
randomised trial of chemotherapy versus bio-chemotherapy
in advanced melanoma patients European journal of cancer
(Oxford England 1990) 200339(11)1577ndash85
Creagan 1984
Creagan ET Ahmann DL Green SJ Long HJ Frytak S
OrsquoFallon JR et alPhase II study of low-dose recombinant
leukocyte A interferon in disseminated malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 19842(9)1002ndash5
Crosby 2000
Crosby T Fish R Coles B Mason MD Systemic treatments
for metastatic cutaneous melanoma Cochrane Database
of Systematic Reviews 2000 Issue 2 [DOI 101002
14651858CD001215]
12Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Cure 1999
Cure H Souteyrand P Ouabdesselam R Roche H
Ravaud A DrsquoIncan M et alResults of a phase II trial
with cystemustine at 90 mgm(2) as a first- or second-line
treatment in advanced malignant melanoma a trial of the
EORTC Clinical Studies Group Melanoma Research 1999
9(6)607ndash10
Danson 2002
Danson S Arance A Lorigan P Clamp A Hodgetts J
Lomax L Thatcher N Middleton MR A randomized
study of temozolomide (TMZ) alone with interferon-
alpha (TMZ-IFN) or with thalidomide (TMZ-THAL) in
metastatic malignant melanoma (MMM) ASCO Annual
Meeting - Proceedings 2002Abstract 1369
Dorval 1986
Dorval T Palangie T Jouve M Garcia-Giralt E Israel L
Falcoff E et alClinical phase II trial of recombinant DNA
interferon (interferon alpha 2b) in patients with metastatic
malignant melanoma Cancer 198658(2)215ndash8
Dutcher 1989
Dutcher JP Creekmore S Weiss GR Margolin K
Markowitz AB Roper M et alA phase II study of
interleukin-2 and lymphokine-activated killer cells in
patients with metastatic malignant melanoma Journal of
clinical oncology official journal of the American Society of
Clinical Oncology 19897(4)477ndash85
Falkson 1995
Falkson CI Experience with interferon alpha 2b combined
with dacarbazine in the treatment of metastatic malignant
melanoma Medical oncology (Northwood London England)
199512(1)35ndash40
Garbe 1990
Garbe C Krasagakis K Zouboulis CC Schroder K Kruger
S Stadler R et alAntitumor activities of interferon alpha
beta and gamma and their combinations on human
melanoma cells in vitro changes of proliferation melanin
synthesis and immunophenotype Journal of Investigative
Dermatology 199095 Suppl (6)231ndash7
Gershenwald 1999
Gershenwald JE Thompson W Mansfield PF Lee JE
Colome MI Tseng CH et alMulti-institutional melanoma
lymphatic mapping experience the prognostic value of
sentinel lymph node status in 612 stage I or II melanoma
patients Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199917(3)976ndash83
Hanninen 1991
Hanninen EL Korfer A Hadam M Schneekloth C
Dallmann I Menzel T et alBiological monitoring of
low-dose interleukin 2 in humans soluble interleukin 2
receptors cytokines and cell surface phenotypes Cancer
Research 199151(23 Pt 1)6312ndash6
Huncharek 2001
Huncharek M Caubet JF McGarry R Single-agent
DTIC versus combination chemotherapy with or without
immunotherapy in metastatic melanoma a meta-analysis
of 3273 patients from 20 randomized trials Melanoma
Research 200111(1)75ndash81
Juni 2001
Juni P Altman DG Egger M Assessing the quality of
controlled clinical trials BMJ 200132342ndash6
Kadison 2003
Kadison AS Morton DL Immunotherapy of malignant
melanoma The Surgical Clinics of North America 200383
(2)343ndash70
Keilholz 2002
Keilholz U Gore ME Biochemotherapy for advanced
melanoma Seminars in Oncology 200229(5)456ndash61
Khayat 2002
Khayat D Bernard-Marty C Meric JB Rixe O
Biochemotherapy for advanced melanoma maybe it is real
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200220(10)2411ndash4
Koh 1991
Koh HK Cutaneous melanoma New England Journal of
Medicine 1991325(3)171ndash82
La Vecchia 1999
La Vecchia C Lucchini F Negri E Levi F Recent declines
in worldwide mortality from cutaneous melanoma in youth
and middle age International Journal of Cancer 199981(1)
62ndash6
Lee 2000
Lee ML Tomsu K Von Eschen KB Duration of survival
for disseminated malignant melanoma results of a meta-
analysis Melanoma Research 200010(1)81ndash92
Legha 1998
Legha SS Ring S Eton O Bedikian A Buzaid AC Plager
C et alDevelopment of a biochemotherapy regimen
with concurrent administration of cisplatin vinblastine
dacarbazine interferon alfa and interleukin-2 for patients
with metastatic melanoma Journal of clinical oncology
official journal of the American Society of Clinical Oncology
199816(5)1752ndash9
Leong 2003
Leong SP Future perspectives on malignant melanoma
Surgical Clinics of North America 200383(2)453ndash6
Lokich 1979
Lokich JJ Garnick MB Legg M Intralesional immune
therapy methanol extraction residue of BCG or purified
protein derivative Oncology 197936(5)236ndash41
Nathan 1998
Nathan FE Mastrangelo MJ Systemic therapy in
melanoma Seminars in Surgical Oncology 199814(4)
319ndash27
Osborn 1977
Osborn DE Castro JE Immunological response in patients
receiving Corynebacterium parvum therapy Clinical
Oncology 19773(2)155ndash64
13Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Parmar 1998
Parmar MKB TV Stewart L Extracting summary statistics
to perform meta-analyses of the published literature for
survival endpoints Statistics in Medicine 1998172815ndash34
Richards 1992
Richards JM Mehta N Ramming K Skosey P Sequential
chemoimmunotherapy in the treatment of metastatic
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199210(8)1338ndash43
Rigel 1989
Rigel DS Rivers JK Kopf AW Friedman RJ Vinokur AF
Heilman ER et alDysplastic nevi Markers for increased
risk for melanoma Cancer 198963(2)386ndash9
Rosenberg 1989
Rosenberg SA Lotze MT Yang JC Aebersold PM Linehan
WM Seipp CA et alExperience with the use of high-
dose interleukin-2 in the treatment of 652 cancer patients
Annals of Surgery 1989210(4)474-84 discussion 484-5
Sertoli 1989
Sertoli MR Bernengo MG Ardizzoni A Brunetti I Falcone
A Vidili MG et alPhase II trial of recombinant alpha-2b
interferon in the treatment of metastatic skin melanoma
Oncology 198946(2)96ndash8
Smith 1993
Smith KA Lowest dose interleukin-2 immunotherapy
Blood 199381(6)1414ndash23
Stopeck 2001
Stopeck AT Jones A Hersh EM Thompson JA
Finucane DM Gutheil JC et alPhase II study of direct
intralesional gene transfer of allovectin-7 an HLA-B7
beta2-microglobulin DNA-liposome complex in patients
with metastatic melanoma Clinical Cancer Research 20017
(8)2285ndash91
Tsang 1983
Tsang KY Fudenberg HH Pan JF Gnagy MJ Bristow
CB An in vitro study on the effects of isoprinosine on
immune responses in cancer patients International Journal
of Immunopharmacology 19835(6)481ndash90
Wingo 1995
Wingo PA Tong T Bolden S Cancer statistics 1995 CA
a cancer journal for clinicians 199545(1)8ndash30
Yusuf 1985
Yusuf S Peto R Lewis J Collins R Sleight P Beta blockade
during and after myocardial infarction an overview of the
randomized trials Progress in Cardiovascular Diseases 1985
27(5)335ndash71lowast Indicates the major publication for the study
14Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Atkins 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding public
Participants PS lt= 1
Brain mets no info
Age 20 to 80 (median 50)
Number of cycles no info
Randomised 416 a 206 b 210
Evaluable 405 a 201 b 204
Interventions a (CT) cisplatin 20mgm2 D1 to 4 vinblastin 12 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1-4 vimblastin 12 mgm2 D1-4 DTIC 800 mgm2 D1
IFN-alpha 5 mIU D1-5 D8 D10 D12 IL-2 9 mIU D1-4
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
Notes Multicentric yes
Withdrawals a five b six
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
15Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Atzpodien 2002
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding both (pharmaceutic and public)
Participants PS lt= 1
Brain mets yes Age 28 to 77 (median 57)
Number of cycles no info
Randomised 124 a 60 b 64
Evaluable 124 a 60 b 64
Interventions a (CT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily
b (ICT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily IFN-alpha 5 mIUm2 D1 week4 and 5
mIUm2 D1 D3 D5 week 5 IL-2 10 mIUm2 D1 D3 D5
(each five weeks)
Outcomes 1 Response rates
2 Overall survival
3 Progression free survival
Notes Multicentric yes
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Bajetta 1994
Methods D parallel group (three groups)
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding pharmaceutic
Participants PS lt= 2
Brain mets no
16Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Bajetta 1994 (Continued)
Age 18 to 70 (median 53)
Number of cycles 8
Randomised 266 a 88 b 86 c 92
Evaluable 242 a 82 b 76 c 84
Interventions a (CT) DTIC 800 mgm2 D1
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU 3xweek
c (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU D1 to 3 6 mIU D4 to 6 9 mIU daily
(each 21 days)
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Overall survival
Notes Multicentric yes
Withdrawals a six b ten c eight
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Danson 2003
Methods D parallel group
AC independent allocation
RS permuted blocks
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets yes Age 16 to 88 (median 58)
Number of cycles six
Randomised 125 a 59 b 62
Evaluable 121 a 55 b 62
Interventions a (CT) temozolomide 200 mgm2 88 h (5 doses)
b (ICT) Temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIU 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
17Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Danson 2003 (Continued)
Notes Multicentric no
Withdrawals a 4 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Del Vecchio 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no Age 19 to 70 (median 50)
Number of cycles no info
Randomised 151 a 75 b 76
Evaluable 145 a 72 b 73
Interventions a (CT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250 mgm2 D1 to
3
b (ICT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250m gm2 D1 to
3 IFN-alpha 5 mIUm2 D1 to 5 IL-2 9 mIUday x 5 daysweek x 2 weeks with a week of
rest
(each 21 days)
Outcomes 1 Response rates
2 Time to Progression
2 Overall Survival
Notes Multicentric yes
Withdrawals a three b three
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
18Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Eton 2002
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding pharm
Participants PS lt= 3
Brain mets yes Age median 49
Number of cycles no info
Randomised 190
Evaluable 183 a 92 b 91
Interventions a (CT) cisplatin 20m gm2 D1 to 4 vimblastin 2 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1 to 4 vinblastin 15 mgm2 D1 to 4 DTIC 800 mgm2
D1 IFN-alpha 5mIUm2 D5 to 9 D17-21 IL-2 9 mIUm2 D5 to 8 D17 to 20
(each 21 days)
Outcomes 1 Response rates
2 Time to progression
3 Overall survival
Notes Multicentric no
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1991
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size no
ITT no
Placebo no
Funding both
Participants PS lt= 1
Brain mets no
Age 22 to 79
(median 57)
Number of cycles at least two
19Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1991 (Continued)
Randomised 73 Evaluable 68 a 34 b 34
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Time to treatment failure
3 Median survival
4 Toxicity
Notes Multicentric no
Withdrawals a three b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1998
Methods D 2 x 2 factorial design
AC independent allocation
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 18 to 84
Number of cycles no info
Randomised 271 Evaluable 263 a 68 b 65 c 63 d 67
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
c (CT) DTIC 200m gm2 D1 to 5 tamoxifen 20 mgdaily
d (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek tamoxifen 20 mgdaily
(each 28 days)
Outcomes 1 Response rates
2 Toxicity rates
20Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1998 (Continued)
3 Overall survival
4 Time to treatment failure
Notes Multicentric yes
Withdrawals a one b three c three d one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Gorbonova 2000
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no
Age 23 to 75
Number of cycles no info
Randomised 30 Evaluable 28 a 14 b 14
Interventions a (CT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2
b (ICT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2 IFN-alpha 3 mIU D5 7
9 11 13 15 17 19
(each 28 days)
Outcomes 1 Response rates
Notes Multicentric no
Withdrawals a two b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
21Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Johnston 1998
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age 18 to 70
(median 45)
Number of cycles no info
Randomised 65 Evaluable 65 a 30 b 35
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to 3
Tamoxifen 40 mg daily
b (ICT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to
3 Tamoxifen 40 mg daily IFN-alpha 9 mIU D1 to 3 IL-2 18 mIU D-2 IL-2 9 mIU D-
1 and 0
(each 28 days)
Outcomes 1 Response rates
2 Time to disease progression
3 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Kirkwood 1990
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding pharm
22Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Kirkwood 1990 (Continued)
Participants PS no info
Brain mets no info
Age no info
Number of cycles no info
Randomised 74 Evaluable 68 a 24 b 23 c 21
Interventions a (CT) DTIC 250 mgm2 D1 to 5 (each 21 days)
b (I) IFN-alpha 3 mIU d1 to 5 every week for 3 weeks than 3 mIUm2 3 xweek
c (ICT) DTIC 250 mgm2 D1 to 5 (each 21 days) IFN-alpha 3 mIU d1 to 5 every week
for 3 weeks than 3 mIUm2 3 xweek
Outcomes 1 Response rates
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Middleton 2000
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets no
Age 24 to 71
(median 51)
Number of cycles six
Randomised 105 Evaluable 96 a 46 b 50
Interventions a (CT) DTIC 800 mgm2 D1 cisplatin 25 mgm2 D1 to 3 BCNU 150 mgm2 D1
tamoxifen 20 mgdaily
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 9 mIU 3 xweek
(each 21 days)
Outcomes 1 Response rates
2 One year survival
3 Median survival
23Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Middleton 2000 (Continued)
4 Toxicity
4 Time spent in hospital
Notes Multicentric no
Withdrawals a seven b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Ridolfi 2002
Methods D parallel group
AC independent allocation by telephone
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 25 to 77
Number of cycles six
Randomised 178 Evaluable 176 a 89 b 87
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1
b (ICT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1 IFN-
alpha 3 mIU 3 xweek IL-2 45 mIU D3 to 5 D8 to 12
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
3 Time to progression
4 Toxicity
Notes Multicentric yes
Withdrawals a one b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
24Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Data from 15 trials were used to evaluate partial and complete
response rates We found a statistically significant difference in
favour of chemoimmunotherapy in both analyses with an HR of
131 (95 CI 107 to 159 p = 0008 Analysis 23) for partial
response rates and an HR of 158 (95 CI 106 to 236 p = 003
Analysis 23) for complete response rates
Progression-free survival (3 studies)
Only three studies had extractable data about the number of par-
ticipants with no disease progression at the end of the trial When
pooled together there was no statistically significant difference be-
tween the groups with an HR of 076 (95 CI 057 to 102 p =
007 Analysis 31) There was no heterogeneity across these trials
(I2 = 0)
Treatment related toxicity (11 studies)
Data from 11 studies were collected with the number of partici-
pants developing clinically significant hematological toxicity (de-
fined as grade 3 or 4) Eight studies had estimated points that
showed enhanced toxicities in the chemoimmunotherapy group
The meta-analysis of the studies showed extreme heterogeneity
(I2 = 941) across the trials We performed a sensitivity anal-
ysis excluding the studies with relatively low doses of chemo-
therapeutic drugs in the chemoimmunotherapy group (Danson
2003 Middleton 2000) but we found similar heterogeneity (I2 =
978)
When we analyzed data from the four studies with similar rela-
tive doses of chemotherapeutics associated with interferon-alpha
without interleukin-2 we found an increase of clinically signifi-
cant hematological toxicities in the chemoimmunotherapy group
with a RR 454 (95 CI 235 to 879 p lt 000001) There was
no heterogeneity across these trials (I2 = 0) When we analyzed
data from studies with combination of interferon-alpha plus in-
terleukin-2 in the chemoimmunotherapy group we again found
extreme heterogeneity across the trials (I2 = 979)
Despite the heterogeneity in global meta-analysis we concluded
that it was not possible to quantify the differences in hematologi-
cal toxicity in such different trials In order to explore these differ-
ences we noted that one study referred to hematological toxicity
in 100 of participants treated with chemoimmunotherapy and
in 96 of participants treated with chemotherapy (Eton 2002)
Another study referred to hematological toxicity only in 2 and
1 respectively (Bajetta 1994)
Non-hematological toxicities were described in almost all stud-
ies and were mainly described as nausea vomiting flu-like syn-
drome asthenia hypotension and fever Data from six similar
studies were extractable and were pooled in the meta-analysis re-
sulting in a statistically significant difference against the chemoim-
munotherapy group with a RR of 274 (95 CI 206 to 364 p
lt 000001 Analysis 42) There was no heterogeneity across trials
(I2 = 0) These results must be treated with caution because of
similar difficulties in pooling these data on hematological toxici-
ties with different therapeutic schemes and several trials described
non-hematological toxicities but we were not able to extract the
data
Data about treatment-related mortality were available in 11 stud-
ies We found no significant difference between the groups with a
RR of 078 (95 CI 026 to 232 p = 065 Analysis 43) There
was no heterogeneity across the trials (I2 = 0)
Quality of life (three studies)
Only three studies reported data on quality of life (Ridolfi 2002
Thomson 1993 Young 2001) all using different methods One
trial described quality of life analysis in detail in an additional pub-
lication (Chiarion-Sileni 2003 Ridolfi 2002) This study found
a significant decrease of overall quality of life in the chemoim-
munotherapy group in comparison to the chemotherapy group
(p = 003) The other two studies did not find differences in global
quality of life between the groups (Thomson 1993 Young 2001)
Thomson did not report global quality of life (Thomson 1993)
Young found no significant differences in quality of life for the
change in scores over time (z = -129 p = 020) (Young 2001)
It was not possible to pool the data as all three studies did not
provide extractable data
Sensitivity analyses on the influence of source of funding baseline
assessment and allocation concealment on the survival analysis
and response rate analyses revealed that there was no relation be-
tween these methodological aspects and the outcome There was
no statistically significant difference in survival between the groups
in all analyses and the difference in response rates in favour of
chemoimmunotherapy was found to be significant
D I S C U S S I O N
Metastatic melanoma is reputed as refractory to most systemic
treatments and little progress has been made in treatment of
metastatic melanoma These concepts are supported by results
from previous systematic reviews One review concluded that there
is no evidence derived from RCTs that systemic treatment is better
than best supportive care (Crosby 2000) Another review of 20
randomised trials (involving 3273 participants) comparing single-
agent DTIC with DTIC in combination with other drugs with or
without immunotherapy concluded that combination of drugs in-
creased response rates but not overall survival (Huncharek 2001)
This systematic review summarises the evidence regarding the
use of chemoimmunotherapy compared to chemotherapy alone
to treat people with metastatic malignant melanoma There are
some important observations regarding the characteristics of the
included studies in this systematic review The ideal combination
9Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
of drugs for an investigation is not well established Seven studies
evaluated chemoimmunotherapy with interferon-alpha plus inter-
leukin-2 and 11 evaluated chemoimmunotherapy only with in-
terferon-alpha The treatment plans with drugs and dosages used
differed between studies
Most studies did not contribute in answering relevant questions
about the impact of chemoimmunotherapy in the treatment of
metastatic melanoma The outcomes were not clearly described in
several of the studies (Atkins 2003 Del Vecchio 2003 Gorbonova
2000 Kirkwood 1990 Spieth 2003 Thomson 1993) Two of
them did not report survival rates evaluating only response rates
(Gorbonova 2000 Kirkwood 1990) All these aspects influenced
the comparability of the trials and must be considered in the data
interpretation
On the basis of a meta-analysis of data coming from eight studies
this review showed no evidence of a difference in overall survival to
support the addition of immunotherapy to chemotherapy in the
systemic treatment of metastatic melanoma (Atkins 2003 Danson
2003 Eton 2002 Falkson 1991 Johnston 1998 Ridolfi 2002
Spieth 2003 Young 2001) Evaluation of one two and five-year
survival with data from other studies again showed no survival
advantage of the drug combination treatment
We found higher clinical response rates in people treated with
chemoimmunotherapy in comparison with people treated with
chemotherapy which was not translated into survival benefit
Additionally we found higher toxicity rates in people treated
with chemoimmunotherapy Despite the importance of evaluat-
ing quality of life there was no available data to perform the meta-
analysis in this systematic review Only three studies reported data
about quality of life all with different methods One trial described
poorer quality of life in people treated with chemoimmunother-
apy related to more intense side effects (Ridolfi 2002) Two trials
however showed no difference between groups (Thomson 1993
Young 2001) It is important that quality of life is included in all
future studies
Our meta-analysis did not find differences between treatment re-
lated mortality Subgroup analysis comparing combinations with
interferon-alpha and with interferon-alpha plus interleukin-2 did
not show different results in survival or response rates
The use of chemoimmunotherapy ie a combination of chemo-
therapy with interferon-alpha or interleukin-2 or both has not
been shown to be beneficial in this review Although short term
response rates were better overall in the chemoimmunotherapy
groups survival was not improved and drug-related toxicities were
higher in the combined chemoimmunotherapy group To date no
treatment regimen has shown efficiency in prolonging survival in
people with metastatic melanoma Little has changed in the sys-
temic management of metastatic melanoma in the last few years
The standard of care remains single-agent DTIC and the role of
immunotherapy remains in doubt
The use of chemoimmunotherapy in the treatment of melanoma
is justified only in the context of clinical trials
A U T H O R S rsquo C O N C L U S I O N S
Implications for practice
We failed to find any evidence to support the view that the
use of chemoimmunotherapy prolongs survival in people with
metastatic melanoma when compared to chemotherapy alone Al-
though short-term clinical responses were higher in the chemoim-
munotherapy group this was associated with a higher rate of
serious adverse events esp haematological toxicity Our review
does not support the use of a combination of immunother-
apy and chemotherapy in chemoimmunotherapy regimens out-
side of clinical trials The standard of care for people with
advanced melanoma remains chemotherapy with single-agent
DTIC Chemoimmunotherapy must not be recommended to peo-
ple in daily practice
Implications for research
Research related to the development of more effective treatments
for people with metastatic melanoma is urgently needed
For people with an incurable disease the primary outcome needs
to be overall survival and all studies should include a quality of life
analysis
Future trials should be designed to define the best systemic treat-
ment and should use chemotherapy with (DTIC) as a standard
control group in order to permit comparisons to be made
A C K N O W L E D G E M E N T S
The authors wish to thank Raquel Gebara Lima for her kind
support in grammar and style
The editorial base would like to thank the following people who
were external referees for this review Keith Wheatley and Pat
Lawton (content experts) and Kathie Godfrey (consumer)
10Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
R E F E R E N C E S
References to studies included in this review
Atkins 2003 published data only
Atkins MB Lee S Flaherty LE Sosman JA Sondak VK
Kirkwood JM A prospective randomized phase III trial
of concurrent biochemotherapy (BCT) with cisplatin
vinblastine dacarbazine (CVD) IL-2 and interferon alpha-
2b (IFN) versus CVD alone in patients with metastatic
melanoma (E3695) An ECOG-coordinated intergroup
trial In ASCO Annual Meeting 2003 2003 p ASCO
Annual Meeting - Proceedings 2003Abstract 2847
Atzpodien 2002 published data only
Atzpodien J Neuber K Kamanabrou D Fluck M Brocker
EB Neumann C et alCombination chemotherapy with or
without sc IL-2 and IFN-alpha results of a prospectively
randomized trial of the Cooperative Advanced Malignant
Melanoma Chemoimmunotherapy Group (ACIMM)
British journal of cancer 200286(2)179ndash84
Bajetta 1994 published data only
Bajetta E Di Leo A Zampino MG Sertoli MR Comella
G Barduagni M et alMulticenter randomized trial of
dacarbazine alone or in combination with two different
doses and schedules of interferon alfa-2a in the treatment
of advanced melanoma Journal of clinical oncology official
journal of the American Society of Clinical Oncology 199412
(4)806ndash11
Danson 2003 published data only
Danson S Lorigan P Arance A Clamp A Ranson
M Hodgetts J et alRandomized phase II study of
temozolomide given every 8 hours or daily with either
interferon alfa-2b or thalidomide in metastatic malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 200321(13)2551ndash7
Del Vecchio 2003 published data only
Del Vecchio M Bajetta E Vitali M Gattinoni L Santinami
M Daponte A et alMulticenter phase III randomized trial
of cisplatin vindesine and dacarbazine (CVD) versus CVD
plus subcutaneous (sc) interleukin-2 (IL-2) and interferon-
alpha-2b (IFN) in metastatic melanoma patients (pts) In
ASCO Annual Meeting 2003 2003 p ASCO Annual
Meeting - Proceedings 2003Abstract 2849
Eton 2002 published data only
Eton O Legha SS Bedikian AY Lee JJ Buzaid AC
Hodges C et alSequential biochemotherapy versus
chemotherapy for metastatic melanoma results from a
phase III randomized trial Journal of clinical oncology
official journal of the American Society of Clinical Oncology
200220(8)2045ndash52
Falkson 1991 published data only
Falkson CI Falkson G Falkson HC Improved results with
the addition of interferon alfa-2b to dacarbazine in the
treatment of patients with metastatic malignant melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 19919(8)1403ndash8
Falkson 1998 published data only
Falkson CI Ibrahim J Kirkwood JM Coates AS Atkins
MB Blum RH Phase III trial of dacarbazine versus
dacarbazine with interferon alpha-2b versus dacarbazine
with tamoxifen versus dacarbazine with interferon alpha-
2b and tamoxifen in patients with metastatic malignant
melanoma an Eastern Cooperative Oncology Group study
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199816(5)1743ndash51
Gorbonova 2000 published data only
Gorbonova VA Egorov GN Perevodchikova NI Orel
NF Combined chemotherapy with or without interferon
alpha N1 (IFN) for advanced malignant melanoma - a
randomized pilot phase III study Gan To Kagaku Ryoho
200027 Suppl (2)310ndash4
Johnston 1998 published data only
Johnston SR Constenla DO Moore J Atkinson H ArsquoHern
RP Dadian G et alRandomized phase II trial of BCDT
[carmustine (BCNU) cisplatin dacarbazine (DTIC)
and tamoxifen] with or without interferon alpha (IFN-
alpha) and interleukin (IL-2) in patients with metastatic
melanoma British Journal of Cancer 199877(8)1280ndash6
Kirkwood 1990 published data only
Kirkwood JM Ernstoff MS Giuliano A Gams R Robinson
WA Costanzi J et alInterferon alpha-2a and dacarbazine
in melanoma Journal of the National Cancer Institute 1990
82(12)1062ndash3
Middleton 2000 published data only
Middleton MR Grob JJ Aaronson N Fierlbeck G
Tilgen W Seiter S et alRandomized phase III study of
temozolomide versus dacarbazine in the treatment of
patients with advanced metastatic malignant melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200018(1)158ndash66
Ridolfi 2002 published data only
Ridolfi R Chiarion-Sileni V Guida M Romanini A
Labianca R Freschi A et alCisplatin dacarbazine with
or without subcutaneous interleukin-2 and interferon
alpha-2b in advanced melanoma outpatients results from
an Italian multicenter phase III randomized clinical trial
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200220(6)1600ndash7
Rosenberg 1999 published data only
Rosenberg SA Yang JC Schwartzentruber DJ Hwu P
Marincola FM Topalian SL et alProspective randomized
trial of the treatment of patients with metastatic melanoma
using chemotherapy with cisplatin dacarbazine and
tamoxifen alone or in combination with interleukin-2 and
interferon alfa-2b Journal of Clinical Oncology 199917(3)
968ndash75
Spieth 2003 published data only
Spieth K Dummer R Garbe C Mauch C Schuler G
Landthaler M et alTemozolomide in combination with
11Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
interferon alfa versus temozolomide alone in patients with
advanced metastatic melanoma A randomized phase
III multicenter study of the Dermatologic Cooperative
Oncology Group (DeCOG) In ASCO Annual Meeting
2003Abstract 2887
Thomson 1993 published data only
Thomson DB Adena M McLeod GR Hersey P Gill PG
Coates AS et alInterferon-alpha 2a does not improve
response or survival when combined with dacarbazine
in metastatic malignant melanoma results of a multi-
institutional Australian randomized trial Melanoma
Research 19933(2)133ndash8
Vorobiof 1994 published data only
Vorobiof DA Bezwoda WR A randomised trial of vindesine
plus interferon-alpha 2b compared with interferon-alpha 2b
or vindesine alone in the treatment of advanced malignant
melanoma European journal of cancer (Oxford England
1990) 199430A(6)797ndash800
Young 2001 published data only
Young AM Marsden J Goodman A Burton A Dunn
JA Prospective randomized comparison of dacarbazine
(DTIC) versus DTIC plus interferon-alpha (IFN-alpha) in
metastatic melanoma Clinical oncology (Royal College of
Radiologists (Great Britain)) 200113(6)458ndash65
References to studies excluded from this review
Bajetta 2001 published data only
Bajetta E Del Vecchio M Vitali M Martinetti A Ferrari L
Queirolo P et alA feasibility study using polychemotherapy
(cisplatin + vindesine + dacarbazine) plus interferon-alpha
or monochemotherapy with dacarbazine plus interferon-
alpha in metastatic melanoma Tumori 200187(4)219ndash22
Legha 1996 published data only
Legha SS Ring S Bedikian A Plager C Eton O Buzaid
AC et alTreatment of metastatic melanoma with combined
chemotherapy containing cisplatin vinblastine and
dacarbazine (CVD) and biotherapy using interleukin-2 and
interferon-alpha Annals of oncology official journal of the
European Society for Medical Oncology ESMO 19967(8)
827ndash35
Richtig 2004 published data only
Richtig E Hofmann-Wellenhof R Pehamberger H
Forstinger C Wolff K Mischer P et alTemozolomide and
interferon alpha 2b in metastatic melanoma stage IV British
Journal of Dermatology 2004151(1)91ndash8
Sertoli 1999 published data only
Sertoli MR Queirolo P Bajetta E DelVecchio M
Comella G Barduagni L et alMulti-institutional phase
II randomized trial of integrated therapy with cisplatin
dacarbazine vindesine subcutaneous interleukin-2
interferon alpha2a and tamoxifen in metastatic melanoma
BREMIM (Biological Response Modifiers in Melanoma)
Melanoma research 19999(5)503ndash9
Sparano 1993 published data only
Sparano JA Fisher RI Sunderland M Margolin K Ernest
ML Sznol M et alRandomized phase III trial of treatment
with high-dose interleukin-2 either alone or in combination
with interferon alfa-2a in patients with advanced melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199311(10)1969ndash77
Vuoristo 2005 published data only
Vuoristo MS Hahka-Kemppinen M Parvinen LM
Pyrhonen S Seppa H Korpela M et alRandomized trial of
dacarbazine versus bleomycin vincristine lomustine and
dacarbazine (BOLD) chemotherapy combined with natural
or recombinant interferon-alpha in patients with advanced
melanoma Melanoma research 200515(4)291ndash6
Additional references
Arance 2000
Arance A Middleton M Lorigan P Thatcher N Three-
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melanoma (MM) In ASCO Annual Meeting 2000
Abstract 2257
Bafaloukos 2002
Bafaloukos D Aravantinos G Fountzilas G Stathopoulos
G Gogas H Samonis G et alDocetaxel in combination
with dacarbazine in patients with advanced melanoma
Oncology 200263(4)333ndash7
Bajetta 2002
Bajetta E Del Vecchio M Bernard-Marty C Vitali
M Buzzoni R Rixe O et alMetastatic melanoma
chemotherapy Seminars in Oncology 200229(5)427ndash45
Balch 2001
Balch CM Soong SJ Gershenwald JE Thompson JF
Reintgen DS Cascinelli N et alPrognostic factors analysis
of 17600 melanoma patients validation of the American
Joint Committee on Cancer melanoma staging system
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200119(16)3622ndash34
Barth 1995
Barth A Morton DL The role of adjuvant therapy in
melanoma management Cancer 199575 Suppl (2)
726ndash34
Chiarion-Sileni 2003
Chiarion-Sileni V Del Bianco P De Salvo GL Lo Re G
Romanini A Labianca R et alQuality of life evaluation in a
randomised trial of chemotherapy versus bio-chemotherapy
in advanced melanoma patients European journal of cancer
(Oxford England 1990) 200339(11)1577ndash85
Creagan 1984
Creagan ET Ahmann DL Green SJ Long HJ Frytak S
OrsquoFallon JR et alPhase II study of low-dose recombinant
leukocyte A interferon in disseminated malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 19842(9)1002ndash5
Crosby 2000
Crosby T Fish R Coles B Mason MD Systemic treatments
for metastatic cutaneous melanoma Cochrane Database
of Systematic Reviews 2000 Issue 2 [DOI 101002
14651858CD001215]
12Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Cure 1999
Cure H Souteyrand P Ouabdesselam R Roche H
Ravaud A DrsquoIncan M et alResults of a phase II trial
with cystemustine at 90 mgm(2) as a first- or second-line
treatment in advanced malignant melanoma a trial of the
EORTC Clinical Studies Group Melanoma Research 1999
9(6)607ndash10
Danson 2002
Danson S Arance A Lorigan P Clamp A Hodgetts J
Lomax L Thatcher N Middleton MR A randomized
study of temozolomide (TMZ) alone with interferon-
alpha (TMZ-IFN) or with thalidomide (TMZ-THAL) in
metastatic malignant melanoma (MMM) ASCO Annual
Meeting - Proceedings 2002Abstract 1369
Dorval 1986
Dorval T Palangie T Jouve M Garcia-Giralt E Israel L
Falcoff E et alClinical phase II trial of recombinant DNA
interferon (interferon alpha 2b) in patients with metastatic
malignant melanoma Cancer 198658(2)215ndash8
Dutcher 1989
Dutcher JP Creekmore S Weiss GR Margolin K
Markowitz AB Roper M et alA phase II study of
interleukin-2 and lymphokine-activated killer cells in
patients with metastatic malignant melanoma Journal of
clinical oncology official journal of the American Society of
Clinical Oncology 19897(4)477ndash85
Falkson 1995
Falkson CI Experience with interferon alpha 2b combined
with dacarbazine in the treatment of metastatic malignant
melanoma Medical oncology (Northwood London England)
199512(1)35ndash40
Garbe 1990
Garbe C Krasagakis K Zouboulis CC Schroder K Kruger
S Stadler R et alAntitumor activities of interferon alpha
beta and gamma and their combinations on human
melanoma cells in vitro changes of proliferation melanin
synthesis and immunophenotype Journal of Investigative
Dermatology 199095 Suppl (6)231ndash7
Gershenwald 1999
Gershenwald JE Thompson W Mansfield PF Lee JE
Colome MI Tseng CH et alMulti-institutional melanoma
lymphatic mapping experience the prognostic value of
sentinel lymph node status in 612 stage I or II melanoma
patients Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199917(3)976ndash83
Hanninen 1991
Hanninen EL Korfer A Hadam M Schneekloth C
Dallmann I Menzel T et alBiological monitoring of
low-dose interleukin 2 in humans soluble interleukin 2
receptors cytokines and cell surface phenotypes Cancer
Research 199151(23 Pt 1)6312ndash6
Huncharek 2001
Huncharek M Caubet JF McGarry R Single-agent
DTIC versus combination chemotherapy with or without
immunotherapy in metastatic melanoma a meta-analysis
of 3273 patients from 20 randomized trials Melanoma
Research 200111(1)75ndash81
Juni 2001
Juni P Altman DG Egger M Assessing the quality of
controlled clinical trials BMJ 200132342ndash6
Kadison 2003
Kadison AS Morton DL Immunotherapy of malignant
melanoma The Surgical Clinics of North America 200383
(2)343ndash70
Keilholz 2002
Keilholz U Gore ME Biochemotherapy for advanced
melanoma Seminars in Oncology 200229(5)456ndash61
Khayat 2002
Khayat D Bernard-Marty C Meric JB Rixe O
Biochemotherapy for advanced melanoma maybe it is real
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200220(10)2411ndash4
Koh 1991
Koh HK Cutaneous melanoma New England Journal of
Medicine 1991325(3)171ndash82
La Vecchia 1999
La Vecchia C Lucchini F Negri E Levi F Recent declines
in worldwide mortality from cutaneous melanoma in youth
and middle age International Journal of Cancer 199981(1)
62ndash6
Lee 2000
Lee ML Tomsu K Von Eschen KB Duration of survival
for disseminated malignant melanoma results of a meta-
analysis Melanoma Research 200010(1)81ndash92
Legha 1998
Legha SS Ring S Eton O Bedikian A Buzaid AC Plager
C et alDevelopment of a biochemotherapy regimen
with concurrent administration of cisplatin vinblastine
dacarbazine interferon alfa and interleukin-2 for patients
with metastatic melanoma Journal of clinical oncology
official journal of the American Society of Clinical Oncology
199816(5)1752ndash9
Leong 2003
Leong SP Future perspectives on malignant melanoma
Surgical Clinics of North America 200383(2)453ndash6
Lokich 1979
Lokich JJ Garnick MB Legg M Intralesional immune
therapy methanol extraction residue of BCG or purified
protein derivative Oncology 197936(5)236ndash41
Nathan 1998
Nathan FE Mastrangelo MJ Systemic therapy in
melanoma Seminars in Surgical Oncology 199814(4)
319ndash27
Osborn 1977
Osborn DE Castro JE Immunological response in patients
receiving Corynebacterium parvum therapy Clinical
Oncology 19773(2)155ndash64
13Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Parmar 1998
Parmar MKB TV Stewart L Extracting summary statistics
to perform meta-analyses of the published literature for
survival endpoints Statistics in Medicine 1998172815ndash34
Richards 1992
Richards JM Mehta N Ramming K Skosey P Sequential
chemoimmunotherapy in the treatment of metastatic
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199210(8)1338ndash43
Rigel 1989
Rigel DS Rivers JK Kopf AW Friedman RJ Vinokur AF
Heilman ER et alDysplastic nevi Markers for increased
risk for melanoma Cancer 198963(2)386ndash9
Rosenberg 1989
Rosenberg SA Lotze MT Yang JC Aebersold PM Linehan
WM Seipp CA et alExperience with the use of high-
dose interleukin-2 in the treatment of 652 cancer patients
Annals of Surgery 1989210(4)474-84 discussion 484-5
Sertoli 1989
Sertoli MR Bernengo MG Ardizzoni A Brunetti I Falcone
A Vidili MG et alPhase II trial of recombinant alpha-2b
interferon in the treatment of metastatic skin melanoma
Oncology 198946(2)96ndash8
Smith 1993
Smith KA Lowest dose interleukin-2 immunotherapy
Blood 199381(6)1414ndash23
Stopeck 2001
Stopeck AT Jones A Hersh EM Thompson JA
Finucane DM Gutheil JC et alPhase II study of direct
intralesional gene transfer of allovectin-7 an HLA-B7
beta2-microglobulin DNA-liposome complex in patients
with metastatic melanoma Clinical Cancer Research 20017
(8)2285ndash91
Tsang 1983
Tsang KY Fudenberg HH Pan JF Gnagy MJ Bristow
CB An in vitro study on the effects of isoprinosine on
immune responses in cancer patients International Journal
of Immunopharmacology 19835(6)481ndash90
Wingo 1995
Wingo PA Tong T Bolden S Cancer statistics 1995 CA
a cancer journal for clinicians 199545(1)8ndash30
Yusuf 1985
Yusuf S Peto R Lewis J Collins R Sleight P Beta blockade
during and after myocardial infarction an overview of the
randomized trials Progress in Cardiovascular Diseases 1985
27(5)335ndash71lowast Indicates the major publication for the study
14Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Atkins 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding public
Participants PS lt= 1
Brain mets no info
Age 20 to 80 (median 50)
Number of cycles no info
Randomised 416 a 206 b 210
Evaluable 405 a 201 b 204
Interventions a (CT) cisplatin 20mgm2 D1 to 4 vinblastin 12 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1-4 vimblastin 12 mgm2 D1-4 DTIC 800 mgm2 D1
IFN-alpha 5 mIU D1-5 D8 D10 D12 IL-2 9 mIU D1-4
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
Notes Multicentric yes
Withdrawals a five b six
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
15Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Atzpodien 2002
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding both (pharmaceutic and public)
Participants PS lt= 1
Brain mets yes Age 28 to 77 (median 57)
Number of cycles no info
Randomised 124 a 60 b 64
Evaluable 124 a 60 b 64
Interventions a (CT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily
b (ICT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily IFN-alpha 5 mIUm2 D1 week4 and 5
mIUm2 D1 D3 D5 week 5 IL-2 10 mIUm2 D1 D3 D5
(each five weeks)
Outcomes 1 Response rates
2 Overall survival
3 Progression free survival
Notes Multicentric yes
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Bajetta 1994
Methods D parallel group (three groups)
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding pharmaceutic
Participants PS lt= 2
Brain mets no
16Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Bajetta 1994 (Continued)
Age 18 to 70 (median 53)
Number of cycles 8
Randomised 266 a 88 b 86 c 92
Evaluable 242 a 82 b 76 c 84
Interventions a (CT) DTIC 800 mgm2 D1
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU 3xweek
c (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU D1 to 3 6 mIU D4 to 6 9 mIU daily
(each 21 days)
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Overall survival
Notes Multicentric yes
Withdrawals a six b ten c eight
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Danson 2003
Methods D parallel group
AC independent allocation
RS permuted blocks
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets yes Age 16 to 88 (median 58)
Number of cycles six
Randomised 125 a 59 b 62
Evaluable 121 a 55 b 62
Interventions a (CT) temozolomide 200 mgm2 88 h (5 doses)
b (ICT) Temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIU 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
17Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Danson 2003 (Continued)
Notes Multicentric no
Withdrawals a 4 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Del Vecchio 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no Age 19 to 70 (median 50)
Number of cycles no info
Randomised 151 a 75 b 76
Evaluable 145 a 72 b 73
Interventions a (CT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250 mgm2 D1 to
3
b (ICT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250m gm2 D1 to
3 IFN-alpha 5 mIUm2 D1 to 5 IL-2 9 mIUday x 5 daysweek x 2 weeks with a week of
rest
(each 21 days)
Outcomes 1 Response rates
2 Time to Progression
2 Overall Survival
Notes Multicentric yes
Withdrawals a three b three
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
18Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Eton 2002
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding pharm
Participants PS lt= 3
Brain mets yes Age median 49
Number of cycles no info
Randomised 190
Evaluable 183 a 92 b 91
Interventions a (CT) cisplatin 20m gm2 D1 to 4 vimblastin 2 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1 to 4 vinblastin 15 mgm2 D1 to 4 DTIC 800 mgm2
D1 IFN-alpha 5mIUm2 D5 to 9 D17-21 IL-2 9 mIUm2 D5 to 8 D17 to 20
(each 21 days)
Outcomes 1 Response rates
2 Time to progression
3 Overall survival
Notes Multicentric no
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1991
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size no
ITT no
Placebo no
Funding both
Participants PS lt= 1
Brain mets no
Age 22 to 79
(median 57)
Number of cycles at least two
19Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1991 (Continued)
Randomised 73 Evaluable 68 a 34 b 34
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Time to treatment failure
3 Median survival
4 Toxicity
Notes Multicentric no
Withdrawals a three b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1998
Methods D 2 x 2 factorial design
AC independent allocation
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 18 to 84
Number of cycles no info
Randomised 271 Evaluable 263 a 68 b 65 c 63 d 67
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
c (CT) DTIC 200m gm2 D1 to 5 tamoxifen 20 mgdaily
d (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek tamoxifen 20 mgdaily
(each 28 days)
Outcomes 1 Response rates
2 Toxicity rates
20Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1998 (Continued)
3 Overall survival
4 Time to treatment failure
Notes Multicentric yes
Withdrawals a one b three c three d one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Gorbonova 2000
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no
Age 23 to 75
Number of cycles no info
Randomised 30 Evaluable 28 a 14 b 14
Interventions a (CT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2
b (ICT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2 IFN-alpha 3 mIU D5 7
9 11 13 15 17 19
(each 28 days)
Outcomes 1 Response rates
Notes Multicentric no
Withdrawals a two b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
21Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Johnston 1998
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age 18 to 70
(median 45)
Number of cycles no info
Randomised 65 Evaluable 65 a 30 b 35
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to 3
Tamoxifen 40 mg daily
b (ICT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to
3 Tamoxifen 40 mg daily IFN-alpha 9 mIU D1 to 3 IL-2 18 mIU D-2 IL-2 9 mIU D-
1 and 0
(each 28 days)
Outcomes 1 Response rates
2 Time to disease progression
3 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Kirkwood 1990
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding pharm
22Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Kirkwood 1990 (Continued)
Participants PS no info
Brain mets no info
Age no info
Number of cycles no info
Randomised 74 Evaluable 68 a 24 b 23 c 21
Interventions a (CT) DTIC 250 mgm2 D1 to 5 (each 21 days)
b (I) IFN-alpha 3 mIU d1 to 5 every week for 3 weeks than 3 mIUm2 3 xweek
c (ICT) DTIC 250 mgm2 D1 to 5 (each 21 days) IFN-alpha 3 mIU d1 to 5 every week
for 3 weeks than 3 mIUm2 3 xweek
Outcomes 1 Response rates
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Middleton 2000
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets no
Age 24 to 71
(median 51)
Number of cycles six
Randomised 105 Evaluable 96 a 46 b 50
Interventions a (CT) DTIC 800 mgm2 D1 cisplatin 25 mgm2 D1 to 3 BCNU 150 mgm2 D1
tamoxifen 20 mgdaily
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 9 mIU 3 xweek
(each 21 days)
Outcomes 1 Response rates
2 One year survival
3 Median survival
23Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Middleton 2000 (Continued)
4 Toxicity
4 Time spent in hospital
Notes Multicentric no
Withdrawals a seven b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Ridolfi 2002
Methods D parallel group
AC independent allocation by telephone
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 25 to 77
Number of cycles six
Randomised 178 Evaluable 176 a 89 b 87
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1
b (ICT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1 IFN-
alpha 3 mIU 3 xweek IL-2 45 mIU D3 to 5 D8 to 12
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
3 Time to progression
4 Toxicity
Notes Multicentric yes
Withdrawals a one b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
24Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
of drugs for an investigation is not well established Seven studies
evaluated chemoimmunotherapy with interferon-alpha plus inter-
leukin-2 and 11 evaluated chemoimmunotherapy only with in-
terferon-alpha The treatment plans with drugs and dosages used
differed between studies
Most studies did not contribute in answering relevant questions
about the impact of chemoimmunotherapy in the treatment of
metastatic melanoma The outcomes were not clearly described in
several of the studies (Atkins 2003 Del Vecchio 2003 Gorbonova
2000 Kirkwood 1990 Spieth 2003 Thomson 1993) Two of
them did not report survival rates evaluating only response rates
(Gorbonova 2000 Kirkwood 1990) All these aspects influenced
the comparability of the trials and must be considered in the data
interpretation
On the basis of a meta-analysis of data coming from eight studies
this review showed no evidence of a difference in overall survival to
support the addition of immunotherapy to chemotherapy in the
systemic treatment of metastatic melanoma (Atkins 2003 Danson
2003 Eton 2002 Falkson 1991 Johnston 1998 Ridolfi 2002
Spieth 2003 Young 2001) Evaluation of one two and five-year
survival with data from other studies again showed no survival
advantage of the drug combination treatment
We found higher clinical response rates in people treated with
chemoimmunotherapy in comparison with people treated with
chemotherapy which was not translated into survival benefit
Additionally we found higher toxicity rates in people treated
with chemoimmunotherapy Despite the importance of evaluat-
ing quality of life there was no available data to perform the meta-
analysis in this systematic review Only three studies reported data
about quality of life all with different methods One trial described
poorer quality of life in people treated with chemoimmunother-
apy related to more intense side effects (Ridolfi 2002) Two trials
however showed no difference between groups (Thomson 1993
Young 2001) It is important that quality of life is included in all
future studies
Our meta-analysis did not find differences between treatment re-
lated mortality Subgroup analysis comparing combinations with
interferon-alpha and with interferon-alpha plus interleukin-2 did
not show different results in survival or response rates
The use of chemoimmunotherapy ie a combination of chemo-
therapy with interferon-alpha or interleukin-2 or both has not
been shown to be beneficial in this review Although short term
response rates were better overall in the chemoimmunotherapy
groups survival was not improved and drug-related toxicities were
higher in the combined chemoimmunotherapy group To date no
treatment regimen has shown efficiency in prolonging survival in
people with metastatic melanoma Little has changed in the sys-
temic management of metastatic melanoma in the last few years
The standard of care remains single-agent DTIC and the role of
immunotherapy remains in doubt
The use of chemoimmunotherapy in the treatment of melanoma
is justified only in the context of clinical trials
A U T H O R S rsquo C O N C L U S I O N S
Implications for practice
We failed to find any evidence to support the view that the
use of chemoimmunotherapy prolongs survival in people with
metastatic melanoma when compared to chemotherapy alone Al-
though short-term clinical responses were higher in the chemoim-
munotherapy group this was associated with a higher rate of
serious adverse events esp haematological toxicity Our review
does not support the use of a combination of immunother-
apy and chemotherapy in chemoimmunotherapy regimens out-
side of clinical trials The standard of care for people with
advanced melanoma remains chemotherapy with single-agent
DTIC Chemoimmunotherapy must not be recommended to peo-
ple in daily practice
Implications for research
Research related to the development of more effective treatments
for people with metastatic melanoma is urgently needed
For people with an incurable disease the primary outcome needs
to be overall survival and all studies should include a quality of life
analysis
Future trials should be designed to define the best systemic treat-
ment and should use chemotherapy with (DTIC) as a standard
control group in order to permit comparisons to be made
A C K N O W L E D G E M E N T S
The authors wish to thank Raquel Gebara Lima for her kind
support in grammar and style
The editorial base would like to thank the following people who
were external referees for this review Keith Wheatley and Pat
Lawton (content experts) and Kathie Godfrey (consumer)
10Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
R E F E R E N C E S
References to studies included in this review
Atkins 2003 published data only
Atkins MB Lee S Flaherty LE Sosman JA Sondak VK
Kirkwood JM A prospective randomized phase III trial
of concurrent biochemotherapy (BCT) with cisplatin
vinblastine dacarbazine (CVD) IL-2 and interferon alpha-
2b (IFN) versus CVD alone in patients with metastatic
melanoma (E3695) An ECOG-coordinated intergroup
trial In ASCO Annual Meeting 2003 2003 p ASCO
Annual Meeting - Proceedings 2003Abstract 2847
Atzpodien 2002 published data only
Atzpodien J Neuber K Kamanabrou D Fluck M Brocker
EB Neumann C et alCombination chemotherapy with or
without sc IL-2 and IFN-alpha results of a prospectively
randomized trial of the Cooperative Advanced Malignant
Melanoma Chemoimmunotherapy Group (ACIMM)
British journal of cancer 200286(2)179ndash84
Bajetta 1994 published data only
Bajetta E Di Leo A Zampino MG Sertoli MR Comella
G Barduagni M et alMulticenter randomized trial of
dacarbazine alone or in combination with two different
doses and schedules of interferon alfa-2a in the treatment
of advanced melanoma Journal of clinical oncology official
journal of the American Society of Clinical Oncology 199412
(4)806ndash11
Danson 2003 published data only
Danson S Lorigan P Arance A Clamp A Ranson
M Hodgetts J et alRandomized phase II study of
temozolomide given every 8 hours or daily with either
interferon alfa-2b or thalidomide in metastatic malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 200321(13)2551ndash7
Del Vecchio 2003 published data only
Del Vecchio M Bajetta E Vitali M Gattinoni L Santinami
M Daponte A et alMulticenter phase III randomized trial
of cisplatin vindesine and dacarbazine (CVD) versus CVD
plus subcutaneous (sc) interleukin-2 (IL-2) and interferon-
alpha-2b (IFN) in metastatic melanoma patients (pts) In
ASCO Annual Meeting 2003 2003 p ASCO Annual
Meeting - Proceedings 2003Abstract 2849
Eton 2002 published data only
Eton O Legha SS Bedikian AY Lee JJ Buzaid AC
Hodges C et alSequential biochemotherapy versus
chemotherapy for metastatic melanoma results from a
phase III randomized trial Journal of clinical oncology
official journal of the American Society of Clinical Oncology
200220(8)2045ndash52
Falkson 1991 published data only
Falkson CI Falkson G Falkson HC Improved results with
the addition of interferon alfa-2b to dacarbazine in the
treatment of patients with metastatic malignant melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 19919(8)1403ndash8
Falkson 1998 published data only
Falkson CI Ibrahim J Kirkwood JM Coates AS Atkins
MB Blum RH Phase III trial of dacarbazine versus
dacarbazine with interferon alpha-2b versus dacarbazine
with tamoxifen versus dacarbazine with interferon alpha-
2b and tamoxifen in patients with metastatic malignant
melanoma an Eastern Cooperative Oncology Group study
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199816(5)1743ndash51
Gorbonova 2000 published data only
Gorbonova VA Egorov GN Perevodchikova NI Orel
NF Combined chemotherapy with or without interferon
alpha N1 (IFN) for advanced malignant melanoma - a
randomized pilot phase III study Gan To Kagaku Ryoho
200027 Suppl (2)310ndash4
Johnston 1998 published data only
Johnston SR Constenla DO Moore J Atkinson H ArsquoHern
RP Dadian G et alRandomized phase II trial of BCDT
[carmustine (BCNU) cisplatin dacarbazine (DTIC)
and tamoxifen] with or without interferon alpha (IFN-
alpha) and interleukin (IL-2) in patients with metastatic
melanoma British Journal of Cancer 199877(8)1280ndash6
Kirkwood 1990 published data only
Kirkwood JM Ernstoff MS Giuliano A Gams R Robinson
WA Costanzi J et alInterferon alpha-2a and dacarbazine
in melanoma Journal of the National Cancer Institute 1990
82(12)1062ndash3
Middleton 2000 published data only
Middleton MR Grob JJ Aaronson N Fierlbeck G
Tilgen W Seiter S et alRandomized phase III study of
temozolomide versus dacarbazine in the treatment of
patients with advanced metastatic malignant melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200018(1)158ndash66
Ridolfi 2002 published data only
Ridolfi R Chiarion-Sileni V Guida M Romanini A
Labianca R Freschi A et alCisplatin dacarbazine with
or without subcutaneous interleukin-2 and interferon
alpha-2b in advanced melanoma outpatients results from
an Italian multicenter phase III randomized clinical trial
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200220(6)1600ndash7
Rosenberg 1999 published data only
Rosenberg SA Yang JC Schwartzentruber DJ Hwu P
Marincola FM Topalian SL et alProspective randomized
trial of the treatment of patients with metastatic melanoma
using chemotherapy with cisplatin dacarbazine and
tamoxifen alone or in combination with interleukin-2 and
interferon alfa-2b Journal of Clinical Oncology 199917(3)
968ndash75
Spieth 2003 published data only
Spieth K Dummer R Garbe C Mauch C Schuler G
Landthaler M et alTemozolomide in combination with
11Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
interferon alfa versus temozolomide alone in patients with
advanced metastatic melanoma A randomized phase
III multicenter study of the Dermatologic Cooperative
Oncology Group (DeCOG) In ASCO Annual Meeting
2003Abstract 2887
Thomson 1993 published data only
Thomson DB Adena M McLeod GR Hersey P Gill PG
Coates AS et alInterferon-alpha 2a does not improve
response or survival when combined with dacarbazine
in metastatic malignant melanoma results of a multi-
institutional Australian randomized trial Melanoma
Research 19933(2)133ndash8
Vorobiof 1994 published data only
Vorobiof DA Bezwoda WR A randomised trial of vindesine
plus interferon-alpha 2b compared with interferon-alpha 2b
or vindesine alone in the treatment of advanced malignant
melanoma European journal of cancer (Oxford England
1990) 199430A(6)797ndash800
Young 2001 published data only
Young AM Marsden J Goodman A Burton A Dunn
JA Prospective randomized comparison of dacarbazine
(DTIC) versus DTIC plus interferon-alpha (IFN-alpha) in
metastatic melanoma Clinical oncology (Royal College of
Radiologists (Great Britain)) 200113(6)458ndash65
References to studies excluded from this review
Bajetta 2001 published data only
Bajetta E Del Vecchio M Vitali M Martinetti A Ferrari L
Queirolo P et alA feasibility study using polychemotherapy
(cisplatin + vindesine + dacarbazine) plus interferon-alpha
or monochemotherapy with dacarbazine plus interferon-
alpha in metastatic melanoma Tumori 200187(4)219ndash22
Legha 1996 published data only
Legha SS Ring S Bedikian A Plager C Eton O Buzaid
AC et alTreatment of metastatic melanoma with combined
chemotherapy containing cisplatin vinblastine and
dacarbazine (CVD) and biotherapy using interleukin-2 and
interferon-alpha Annals of oncology official journal of the
European Society for Medical Oncology ESMO 19967(8)
827ndash35
Richtig 2004 published data only
Richtig E Hofmann-Wellenhof R Pehamberger H
Forstinger C Wolff K Mischer P et alTemozolomide and
interferon alpha 2b in metastatic melanoma stage IV British
Journal of Dermatology 2004151(1)91ndash8
Sertoli 1999 published data only
Sertoli MR Queirolo P Bajetta E DelVecchio M
Comella G Barduagni L et alMulti-institutional phase
II randomized trial of integrated therapy with cisplatin
dacarbazine vindesine subcutaneous interleukin-2
interferon alpha2a and tamoxifen in metastatic melanoma
BREMIM (Biological Response Modifiers in Melanoma)
Melanoma research 19999(5)503ndash9
Sparano 1993 published data only
Sparano JA Fisher RI Sunderland M Margolin K Ernest
ML Sznol M et alRandomized phase III trial of treatment
with high-dose interleukin-2 either alone or in combination
with interferon alfa-2a in patients with advanced melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199311(10)1969ndash77
Vuoristo 2005 published data only
Vuoristo MS Hahka-Kemppinen M Parvinen LM
Pyrhonen S Seppa H Korpela M et alRandomized trial of
dacarbazine versus bleomycin vincristine lomustine and
dacarbazine (BOLD) chemotherapy combined with natural
or recombinant interferon-alpha in patients with advanced
melanoma Melanoma research 200515(4)291ndash6
Additional references
Arance 2000
Arance A Middleton M Lorigan P Thatcher N Three-
arm phase II study of temozolomide (TMZ) in metastatic
melanoma (MM) In ASCO Annual Meeting 2000
Abstract 2257
Bafaloukos 2002
Bafaloukos D Aravantinos G Fountzilas G Stathopoulos
G Gogas H Samonis G et alDocetaxel in combination
with dacarbazine in patients with advanced melanoma
Oncology 200263(4)333ndash7
Bajetta 2002
Bajetta E Del Vecchio M Bernard-Marty C Vitali
M Buzzoni R Rixe O et alMetastatic melanoma
chemotherapy Seminars in Oncology 200229(5)427ndash45
Balch 2001
Balch CM Soong SJ Gershenwald JE Thompson JF
Reintgen DS Cascinelli N et alPrognostic factors analysis
of 17600 melanoma patients validation of the American
Joint Committee on Cancer melanoma staging system
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200119(16)3622ndash34
Barth 1995
Barth A Morton DL The role of adjuvant therapy in
melanoma management Cancer 199575 Suppl (2)
726ndash34
Chiarion-Sileni 2003
Chiarion-Sileni V Del Bianco P De Salvo GL Lo Re G
Romanini A Labianca R et alQuality of life evaluation in a
randomised trial of chemotherapy versus bio-chemotherapy
in advanced melanoma patients European journal of cancer
(Oxford England 1990) 200339(11)1577ndash85
Creagan 1984
Creagan ET Ahmann DL Green SJ Long HJ Frytak S
OrsquoFallon JR et alPhase II study of low-dose recombinant
leukocyte A interferon in disseminated malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 19842(9)1002ndash5
Crosby 2000
Crosby T Fish R Coles B Mason MD Systemic treatments
for metastatic cutaneous melanoma Cochrane Database
of Systematic Reviews 2000 Issue 2 [DOI 101002
14651858CD001215]
12Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Cure 1999
Cure H Souteyrand P Ouabdesselam R Roche H
Ravaud A DrsquoIncan M et alResults of a phase II trial
with cystemustine at 90 mgm(2) as a first- or second-line
treatment in advanced malignant melanoma a trial of the
EORTC Clinical Studies Group Melanoma Research 1999
9(6)607ndash10
Danson 2002
Danson S Arance A Lorigan P Clamp A Hodgetts J
Lomax L Thatcher N Middleton MR A randomized
study of temozolomide (TMZ) alone with interferon-
alpha (TMZ-IFN) or with thalidomide (TMZ-THAL) in
metastatic malignant melanoma (MMM) ASCO Annual
Meeting - Proceedings 2002Abstract 1369
Dorval 1986
Dorval T Palangie T Jouve M Garcia-Giralt E Israel L
Falcoff E et alClinical phase II trial of recombinant DNA
interferon (interferon alpha 2b) in patients with metastatic
malignant melanoma Cancer 198658(2)215ndash8
Dutcher 1989
Dutcher JP Creekmore S Weiss GR Margolin K
Markowitz AB Roper M et alA phase II study of
interleukin-2 and lymphokine-activated killer cells in
patients with metastatic malignant melanoma Journal of
clinical oncology official journal of the American Society of
Clinical Oncology 19897(4)477ndash85
Falkson 1995
Falkson CI Experience with interferon alpha 2b combined
with dacarbazine in the treatment of metastatic malignant
melanoma Medical oncology (Northwood London England)
199512(1)35ndash40
Garbe 1990
Garbe C Krasagakis K Zouboulis CC Schroder K Kruger
S Stadler R et alAntitumor activities of interferon alpha
beta and gamma and their combinations on human
melanoma cells in vitro changes of proliferation melanin
synthesis and immunophenotype Journal of Investigative
Dermatology 199095 Suppl (6)231ndash7
Gershenwald 1999
Gershenwald JE Thompson W Mansfield PF Lee JE
Colome MI Tseng CH et alMulti-institutional melanoma
lymphatic mapping experience the prognostic value of
sentinel lymph node status in 612 stage I or II melanoma
patients Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199917(3)976ndash83
Hanninen 1991
Hanninen EL Korfer A Hadam M Schneekloth C
Dallmann I Menzel T et alBiological monitoring of
low-dose interleukin 2 in humans soluble interleukin 2
receptors cytokines and cell surface phenotypes Cancer
Research 199151(23 Pt 1)6312ndash6
Huncharek 2001
Huncharek M Caubet JF McGarry R Single-agent
DTIC versus combination chemotherapy with or without
immunotherapy in metastatic melanoma a meta-analysis
of 3273 patients from 20 randomized trials Melanoma
Research 200111(1)75ndash81
Juni 2001
Juni P Altman DG Egger M Assessing the quality of
controlled clinical trials BMJ 200132342ndash6
Kadison 2003
Kadison AS Morton DL Immunotherapy of malignant
melanoma The Surgical Clinics of North America 200383
(2)343ndash70
Keilholz 2002
Keilholz U Gore ME Biochemotherapy for advanced
melanoma Seminars in Oncology 200229(5)456ndash61
Khayat 2002
Khayat D Bernard-Marty C Meric JB Rixe O
Biochemotherapy for advanced melanoma maybe it is real
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200220(10)2411ndash4
Koh 1991
Koh HK Cutaneous melanoma New England Journal of
Medicine 1991325(3)171ndash82
La Vecchia 1999
La Vecchia C Lucchini F Negri E Levi F Recent declines
in worldwide mortality from cutaneous melanoma in youth
and middle age International Journal of Cancer 199981(1)
62ndash6
Lee 2000
Lee ML Tomsu K Von Eschen KB Duration of survival
for disseminated malignant melanoma results of a meta-
analysis Melanoma Research 200010(1)81ndash92
Legha 1998
Legha SS Ring S Eton O Bedikian A Buzaid AC Plager
C et alDevelopment of a biochemotherapy regimen
with concurrent administration of cisplatin vinblastine
dacarbazine interferon alfa and interleukin-2 for patients
with metastatic melanoma Journal of clinical oncology
official journal of the American Society of Clinical Oncology
199816(5)1752ndash9
Leong 2003
Leong SP Future perspectives on malignant melanoma
Surgical Clinics of North America 200383(2)453ndash6
Lokich 1979
Lokich JJ Garnick MB Legg M Intralesional immune
therapy methanol extraction residue of BCG or purified
protein derivative Oncology 197936(5)236ndash41
Nathan 1998
Nathan FE Mastrangelo MJ Systemic therapy in
melanoma Seminars in Surgical Oncology 199814(4)
319ndash27
Osborn 1977
Osborn DE Castro JE Immunological response in patients
receiving Corynebacterium parvum therapy Clinical
Oncology 19773(2)155ndash64
13Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Parmar 1998
Parmar MKB TV Stewart L Extracting summary statistics
to perform meta-analyses of the published literature for
survival endpoints Statistics in Medicine 1998172815ndash34
Richards 1992
Richards JM Mehta N Ramming K Skosey P Sequential
chemoimmunotherapy in the treatment of metastatic
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199210(8)1338ndash43
Rigel 1989
Rigel DS Rivers JK Kopf AW Friedman RJ Vinokur AF
Heilman ER et alDysplastic nevi Markers for increased
risk for melanoma Cancer 198963(2)386ndash9
Rosenberg 1989
Rosenberg SA Lotze MT Yang JC Aebersold PM Linehan
WM Seipp CA et alExperience with the use of high-
dose interleukin-2 in the treatment of 652 cancer patients
Annals of Surgery 1989210(4)474-84 discussion 484-5
Sertoli 1989
Sertoli MR Bernengo MG Ardizzoni A Brunetti I Falcone
A Vidili MG et alPhase II trial of recombinant alpha-2b
interferon in the treatment of metastatic skin melanoma
Oncology 198946(2)96ndash8
Smith 1993
Smith KA Lowest dose interleukin-2 immunotherapy
Blood 199381(6)1414ndash23
Stopeck 2001
Stopeck AT Jones A Hersh EM Thompson JA
Finucane DM Gutheil JC et alPhase II study of direct
intralesional gene transfer of allovectin-7 an HLA-B7
beta2-microglobulin DNA-liposome complex in patients
with metastatic melanoma Clinical Cancer Research 20017
(8)2285ndash91
Tsang 1983
Tsang KY Fudenberg HH Pan JF Gnagy MJ Bristow
CB An in vitro study on the effects of isoprinosine on
immune responses in cancer patients International Journal
of Immunopharmacology 19835(6)481ndash90
Wingo 1995
Wingo PA Tong T Bolden S Cancer statistics 1995 CA
a cancer journal for clinicians 199545(1)8ndash30
Yusuf 1985
Yusuf S Peto R Lewis J Collins R Sleight P Beta blockade
during and after myocardial infarction an overview of the
randomized trials Progress in Cardiovascular Diseases 1985
27(5)335ndash71lowast Indicates the major publication for the study
14Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Atkins 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding public
Participants PS lt= 1
Brain mets no info
Age 20 to 80 (median 50)
Number of cycles no info
Randomised 416 a 206 b 210
Evaluable 405 a 201 b 204
Interventions a (CT) cisplatin 20mgm2 D1 to 4 vinblastin 12 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1-4 vimblastin 12 mgm2 D1-4 DTIC 800 mgm2 D1
IFN-alpha 5 mIU D1-5 D8 D10 D12 IL-2 9 mIU D1-4
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
Notes Multicentric yes
Withdrawals a five b six
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
15Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Atzpodien 2002
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding both (pharmaceutic and public)
Participants PS lt= 1
Brain mets yes Age 28 to 77 (median 57)
Number of cycles no info
Randomised 124 a 60 b 64
Evaluable 124 a 60 b 64
Interventions a (CT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily
b (ICT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily IFN-alpha 5 mIUm2 D1 week4 and 5
mIUm2 D1 D3 D5 week 5 IL-2 10 mIUm2 D1 D3 D5
(each five weeks)
Outcomes 1 Response rates
2 Overall survival
3 Progression free survival
Notes Multicentric yes
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Bajetta 1994
Methods D parallel group (three groups)
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding pharmaceutic
Participants PS lt= 2
Brain mets no
16Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Bajetta 1994 (Continued)
Age 18 to 70 (median 53)
Number of cycles 8
Randomised 266 a 88 b 86 c 92
Evaluable 242 a 82 b 76 c 84
Interventions a (CT) DTIC 800 mgm2 D1
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU 3xweek
c (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU D1 to 3 6 mIU D4 to 6 9 mIU daily
(each 21 days)
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Overall survival
Notes Multicentric yes
Withdrawals a six b ten c eight
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Danson 2003
Methods D parallel group
AC independent allocation
RS permuted blocks
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets yes Age 16 to 88 (median 58)
Number of cycles six
Randomised 125 a 59 b 62
Evaluable 121 a 55 b 62
Interventions a (CT) temozolomide 200 mgm2 88 h (5 doses)
b (ICT) Temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIU 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
17Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Danson 2003 (Continued)
Notes Multicentric no
Withdrawals a 4 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Del Vecchio 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no Age 19 to 70 (median 50)
Number of cycles no info
Randomised 151 a 75 b 76
Evaluable 145 a 72 b 73
Interventions a (CT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250 mgm2 D1 to
3
b (ICT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250m gm2 D1 to
3 IFN-alpha 5 mIUm2 D1 to 5 IL-2 9 mIUday x 5 daysweek x 2 weeks with a week of
rest
(each 21 days)
Outcomes 1 Response rates
2 Time to Progression
2 Overall Survival
Notes Multicentric yes
Withdrawals a three b three
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
18Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Eton 2002
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding pharm
Participants PS lt= 3
Brain mets yes Age median 49
Number of cycles no info
Randomised 190
Evaluable 183 a 92 b 91
Interventions a (CT) cisplatin 20m gm2 D1 to 4 vimblastin 2 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1 to 4 vinblastin 15 mgm2 D1 to 4 DTIC 800 mgm2
D1 IFN-alpha 5mIUm2 D5 to 9 D17-21 IL-2 9 mIUm2 D5 to 8 D17 to 20
(each 21 days)
Outcomes 1 Response rates
2 Time to progression
3 Overall survival
Notes Multicentric no
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1991
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size no
ITT no
Placebo no
Funding both
Participants PS lt= 1
Brain mets no
Age 22 to 79
(median 57)
Number of cycles at least two
19Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1991 (Continued)
Randomised 73 Evaluable 68 a 34 b 34
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Time to treatment failure
3 Median survival
4 Toxicity
Notes Multicentric no
Withdrawals a three b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1998
Methods D 2 x 2 factorial design
AC independent allocation
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 18 to 84
Number of cycles no info
Randomised 271 Evaluable 263 a 68 b 65 c 63 d 67
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
c (CT) DTIC 200m gm2 D1 to 5 tamoxifen 20 mgdaily
d (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek tamoxifen 20 mgdaily
(each 28 days)
Outcomes 1 Response rates
2 Toxicity rates
20Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1998 (Continued)
3 Overall survival
4 Time to treatment failure
Notes Multicentric yes
Withdrawals a one b three c three d one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Gorbonova 2000
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no
Age 23 to 75
Number of cycles no info
Randomised 30 Evaluable 28 a 14 b 14
Interventions a (CT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2
b (ICT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2 IFN-alpha 3 mIU D5 7
9 11 13 15 17 19
(each 28 days)
Outcomes 1 Response rates
Notes Multicentric no
Withdrawals a two b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
21Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Johnston 1998
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age 18 to 70
(median 45)
Number of cycles no info
Randomised 65 Evaluable 65 a 30 b 35
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to 3
Tamoxifen 40 mg daily
b (ICT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to
3 Tamoxifen 40 mg daily IFN-alpha 9 mIU D1 to 3 IL-2 18 mIU D-2 IL-2 9 mIU D-
1 and 0
(each 28 days)
Outcomes 1 Response rates
2 Time to disease progression
3 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Kirkwood 1990
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding pharm
22Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Kirkwood 1990 (Continued)
Participants PS no info
Brain mets no info
Age no info
Number of cycles no info
Randomised 74 Evaluable 68 a 24 b 23 c 21
Interventions a (CT) DTIC 250 mgm2 D1 to 5 (each 21 days)
b (I) IFN-alpha 3 mIU d1 to 5 every week for 3 weeks than 3 mIUm2 3 xweek
c (ICT) DTIC 250 mgm2 D1 to 5 (each 21 days) IFN-alpha 3 mIU d1 to 5 every week
for 3 weeks than 3 mIUm2 3 xweek
Outcomes 1 Response rates
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Middleton 2000
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets no
Age 24 to 71
(median 51)
Number of cycles six
Randomised 105 Evaluable 96 a 46 b 50
Interventions a (CT) DTIC 800 mgm2 D1 cisplatin 25 mgm2 D1 to 3 BCNU 150 mgm2 D1
tamoxifen 20 mgdaily
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 9 mIU 3 xweek
(each 21 days)
Outcomes 1 Response rates
2 One year survival
3 Median survival
23Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Middleton 2000 (Continued)
4 Toxicity
4 Time spent in hospital
Notes Multicentric no
Withdrawals a seven b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Ridolfi 2002
Methods D parallel group
AC independent allocation by telephone
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 25 to 77
Number of cycles six
Randomised 178 Evaluable 176 a 89 b 87
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1
b (ICT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1 IFN-
alpha 3 mIU 3 xweek IL-2 45 mIU D3 to 5 D8 to 12
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
3 Time to progression
4 Toxicity
Notes Multicentric yes
Withdrawals a one b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
24Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
R E F E R E N C E S
References to studies included in this review
Atkins 2003 published data only
Atkins MB Lee S Flaherty LE Sosman JA Sondak VK
Kirkwood JM A prospective randomized phase III trial
of concurrent biochemotherapy (BCT) with cisplatin
vinblastine dacarbazine (CVD) IL-2 and interferon alpha-
2b (IFN) versus CVD alone in patients with metastatic
melanoma (E3695) An ECOG-coordinated intergroup
trial In ASCO Annual Meeting 2003 2003 p ASCO
Annual Meeting - Proceedings 2003Abstract 2847
Atzpodien 2002 published data only
Atzpodien J Neuber K Kamanabrou D Fluck M Brocker
EB Neumann C et alCombination chemotherapy with or
without sc IL-2 and IFN-alpha results of a prospectively
randomized trial of the Cooperative Advanced Malignant
Melanoma Chemoimmunotherapy Group (ACIMM)
British journal of cancer 200286(2)179ndash84
Bajetta 1994 published data only
Bajetta E Di Leo A Zampino MG Sertoli MR Comella
G Barduagni M et alMulticenter randomized trial of
dacarbazine alone or in combination with two different
doses and schedules of interferon alfa-2a in the treatment
of advanced melanoma Journal of clinical oncology official
journal of the American Society of Clinical Oncology 199412
(4)806ndash11
Danson 2003 published data only
Danson S Lorigan P Arance A Clamp A Ranson
M Hodgetts J et alRandomized phase II study of
temozolomide given every 8 hours or daily with either
interferon alfa-2b or thalidomide in metastatic malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 200321(13)2551ndash7
Del Vecchio 2003 published data only
Del Vecchio M Bajetta E Vitali M Gattinoni L Santinami
M Daponte A et alMulticenter phase III randomized trial
of cisplatin vindesine and dacarbazine (CVD) versus CVD
plus subcutaneous (sc) interleukin-2 (IL-2) and interferon-
alpha-2b (IFN) in metastatic melanoma patients (pts) In
ASCO Annual Meeting 2003 2003 p ASCO Annual
Meeting - Proceedings 2003Abstract 2849
Eton 2002 published data only
Eton O Legha SS Bedikian AY Lee JJ Buzaid AC
Hodges C et alSequential biochemotherapy versus
chemotherapy for metastatic melanoma results from a
phase III randomized trial Journal of clinical oncology
official journal of the American Society of Clinical Oncology
200220(8)2045ndash52
Falkson 1991 published data only
Falkson CI Falkson G Falkson HC Improved results with
the addition of interferon alfa-2b to dacarbazine in the
treatment of patients with metastatic malignant melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 19919(8)1403ndash8
Falkson 1998 published data only
Falkson CI Ibrahim J Kirkwood JM Coates AS Atkins
MB Blum RH Phase III trial of dacarbazine versus
dacarbazine with interferon alpha-2b versus dacarbazine
with tamoxifen versus dacarbazine with interferon alpha-
2b and tamoxifen in patients with metastatic malignant
melanoma an Eastern Cooperative Oncology Group study
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199816(5)1743ndash51
Gorbonova 2000 published data only
Gorbonova VA Egorov GN Perevodchikova NI Orel
NF Combined chemotherapy with or without interferon
alpha N1 (IFN) for advanced malignant melanoma - a
randomized pilot phase III study Gan To Kagaku Ryoho
200027 Suppl (2)310ndash4
Johnston 1998 published data only
Johnston SR Constenla DO Moore J Atkinson H ArsquoHern
RP Dadian G et alRandomized phase II trial of BCDT
[carmustine (BCNU) cisplatin dacarbazine (DTIC)
and tamoxifen] with or without interferon alpha (IFN-
alpha) and interleukin (IL-2) in patients with metastatic
melanoma British Journal of Cancer 199877(8)1280ndash6
Kirkwood 1990 published data only
Kirkwood JM Ernstoff MS Giuliano A Gams R Robinson
WA Costanzi J et alInterferon alpha-2a and dacarbazine
in melanoma Journal of the National Cancer Institute 1990
82(12)1062ndash3
Middleton 2000 published data only
Middleton MR Grob JJ Aaronson N Fierlbeck G
Tilgen W Seiter S et alRandomized phase III study of
temozolomide versus dacarbazine in the treatment of
patients with advanced metastatic malignant melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200018(1)158ndash66
Ridolfi 2002 published data only
Ridolfi R Chiarion-Sileni V Guida M Romanini A
Labianca R Freschi A et alCisplatin dacarbazine with
or without subcutaneous interleukin-2 and interferon
alpha-2b in advanced melanoma outpatients results from
an Italian multicenter phase III randomized clinical trial
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200220(6)1600ndash7
Rosenberg 1999 published data only
Rosenberg SA Yang JC Schwartzentruber DJ Hwu P
Marincola FM Topalian SL et alProspective randomized
trial of the treatment of patients with metastatic melanoma
using chemotherapy with cisplatin dacarbazine and
tamoxifen alone or in combination with interleukin-2 and
interferon alfa-2b Journal of Clinical Oncology 199917(3)
968ndash75
Spieth 2003 published data only
Spieth K Dummer R Garbe C Mauch C Schuler G
Landthaler M et alTemozolomide in combination with
11Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
interferon alfa versus temozolomide alone in patients with
advanced metastatic melanoma A randomized phase
III multicenter study of the Dermatologic Cooperative
Oncology Group (DeCOG) In ASCO Annual Meeting
2003Abstract 2887
Thomson 1993 published data only
Thomson DB Adena M McLeod GR Hersey P Gill PG
Coates AS et alInterferon-alpha 2a does not improve
response or survival when combined with dacarbazine
in metastatic malignant melanoma results of a multi-
institutional Australian randomized trial Melanoma
Research 19933(2)133ndash8
Vorobiof 1994 published data only
Vorobiof DA Bezwoda WR A randomised trial of vindesine
plus interferon-alpha 2b compared with interferon-alpha 2b
or vindesine alone in the treatment of advanced malignant
melanoma European journal of cancer (Oxford England
1990) 199430A(6)797ndash800
Young 2001 published data only
Young AM Marsden J Goodman A Burton A Dunn
JA Prospective randomized comparison of dacarbazine
(DTIC) versus DTIC plus interferon-alpha (IFN-alpha) in
metastatic melanoma Clinical oncology (Royal College of
Radiologists (Great Britain)) 200113(6)458ndash65
References to studies excluded from this review
Bajetta 2001 published data only
Bajetta E Del Vecchio M Vitali M Martinetti A Ferrari L
Queirolo P et alA feasibility study using polychemotherapy
(cisplatin + vindesine + dacarbazine) plus interferon-alpha
or monochemotherapy with dacarbazine plus interferon-
alpha in metastatic melanoma Tumori 200187(4)219ndash22
Legha 1996 published data only
Legha SS Ring S Bedikian A Plager C Eton O Buzaid
AC et alTreatment of metastatic melanoma with combined
chemotherapy containing cisplatin vinblastine and
dacarbazine (CVD) and biotherapy using interleukin-2 and
interferon-alpha Annals of oncology official journal of the
European Society for Medical Oncology ESMO 19967(8)
827ndash35
Richtig 2004 published data only
Richtig E Hofmann-Wellenhof R Pehamberger H
Forstinger C Wolff K Mischer P et alTemozolomide and
interferon alpha 2b in metastatic melanoma stage IV British
Journal of Dermatology 2004151(1)91ndash8
Sertoli 1999 published data only
Sertoli MR Queirolo P Bajetta E DelVecchio M
Comella G Barduagni L et alMulti-institutional phase
II randomized trial of integrated therapy with cisplatin
dacarbazine vindesine subcutaneous interleukin-2
interferon alpha2a and tamoxifen in metastatic melanoma
BREMIM (Biological Response Modifiers in Melanoma)
Melanoma research 19999(5)503ndash9
Sparano 1993 published data only
Sparano JA Fisher RI Sunderland M Margolin K Ernest
ML Sznol M et alRandomized phase III trial of treatment
with high-dose interleukin-2 either alone or in combination
with interferon alfa-2a in patients with advanced melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199311(10)1969ndash77
Vuoristo 2005 published data only
Vuoristo MS Hahka-Kemppinen M Parvinen LM
Pyrhonen S Seppa H Korpela M et alRandomized trial of
dacarbazine versus bleomycin vincristine lomustine and
dacarbazine (BOLD) chemotherapy combined with natural
or recombinant interferon-alpha in patients with advanced
melanoma Melanoma research 200515(4)291ndash6
Additional references
Arance 2000
Arance A Middleton M Lorigan P Thatcher N Three-
arm phase II study of temozolomide (TMZ) in metastatic
melanoma (MM) In ASCO Annual Meeting 2000
Abstract 2257
Bafaloukos 2002
Bafaloukos D Aravantinos G Fountzilas G Stathopoulos
G Gogas H Samonis G et alDocetaxel in combination
with dacarbazine in patients with advanced melanoma
Oncology 200263(4)333ndash7
Bajetta 2002
Bajetta E Del Vecchio M Bernard-Marty C Vitali
M Buzzoni R Rixe O et alMetastatic melanoma
chemotherapy Seminars in Oncology 200229(5)427ndash45
Balch 2001
Balch CM Soong SJ Gershenwald JE Thompson JF
Reintgen DS Cascinelli N et alPrognostic factors analysis
of 17600 melanoma patients validation of the American
Joint Committee on Cancer melanoma staging system
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200119(16)3622ndash34
Barth 1995
Barth A Morton DL The role of adjuvant therapy in
melanoma management Cancer 199575 Suppl (2)
726ndash34
Chiarion-Sileni 2003
Chiarion-Sileni V Del Bianco P De Salvo GL Lo Re G
Romanini A Labianca R et alQuality of life evaluation in a
randomised trial of chemotherapy versus bio-chemotherapy
in advanced melanoma patients European journal of cancer
(Oxford England 1990) 200339(11)1577ndash85
Creagan 1984
Creagan ET Ahmann DL Green SJ Long HJ Frytak S
OrsquoFallon JR et alPhase II study of low-dose recombinant
leukocyte A interferon in disseminated malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 19842(9)1002ndash5
Crosby 2000
Crosby T Fish R Coles B Mason MD Systemic treatments
for metastatic cutaneous melanoma Cochrane Database
of Systematic Reviews 2000 Issue 2 [DOI 101002
14651858CD001215]
12Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Cure 1999
Cure H Souteyrand P Ouabdesselam R Roche H
Ravaud A DrsquoIncan M et alResults of a phase II trial
with cystemustine at 90 mgm(2) as a first- or second-line
treatment in advanced malignant melanoma a trial of the
EORTC Clinical Studies Group Melanoma Research 1999
9(6)607ndash10
Danson 2002
Danson S Arance A Lorigan P Clamp A Hodgetts J
Lomax L Thatcher N Middleton MR A randomized
study of temozolomide (TMZ) alone with interferon-
alpha (TMZ-IFN) or with thalidomide (TMZ-THAL) in
metastatic malignant melanoma (MMM) ASCO Annual
Meeting - Proceedings 2002Abstract 1369
Dorval 1986
Dorval T Palangie T Jouve M Garcia-Giralt E Israel L
Falcoff E et alClinical phase II trial of recombinant DNA
interferon (interferon alpha 2b) in patients with metastatic
malignant melanoma Cancer 198658(2)215ndash8
Dutcher 1989
Dutcher JP Creekmore S Weiss GR Margolin K
Markowitz AB Roper M et alA phase II study of
interleukin-2 and lymphokine-activated killer cells in
patients with metastatic malignant melanoma Journal of
clinical oncology official journal of the American Society of
Clinical Oncology 19897(4)477ndash85
Falkson 1995
Falkson CI Experience with interferon alpha 2b combined
with dacarbazine in the treatment of metastatic malignant
melanoma Medical oncology (Northwood London England)
199512(1)35ndash40
Garbe 1990
Garbe C Krasagakis K Zouboulis CC Schroder K Kruger
S Stadler R et alAntitumor activities of interferon alpha
beta and gamma and their combinations on human
melanoma cells in vitro changes of proliferation melanin
synthesis and immunophenotype Journal of Investigative
Dermatology 199095 Suppl (6)231ndash7
Gershenwald 1999
Gershenwald JE Thompson W Mansfield PF Lee JE
Colome MI Tseng CH et alMulti-institutional melanoma
lymphatic mapping experience the prognostic value of
sentinel lymph node status in 612 stage I or II melanoma
patients Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199917(3)976ndash83
Hanninen 1991
Hanninen EL Korfer A Hadam M Schneekloth C
Dallmann I Menzel T et alBiological monitoring of
low-dose interleukin 2 in humans soluble interleukin 2
receptors cytokines and cell surface phenotypes Cancer
Research 199151(23 Pt 1)6312ndash6
Huncharek 2001
Huncharek M Caubet JF McGarry R Single-agent
DTIC versus combination chemotherapy with or without
immunotherapy in metastatic melanoma a meta-analysis
of 3273 patients from 20 randomized trials Melanoma
Research 200111(1)75ndash81
Juni 2001
Juni P Altman DG Egger M Assessing the quality of
controlled clinical trials BMJ 200132342ndash6
Kadison 2003
Kadison AS Morton DL Immunotherapy of malignant
melanoma The Surgical Clinics of North America 200383
(2)343ndash70
Keilholz 2002
Keilholz U Gore ME Biochemotherapy for advanced
melanoma Seminars in Oncology 200229(5)456ndash61
Khayat 2002
Khayat D Bernard-Marty C Meric JB Rixe O
Biochemotherapy for advanced melanoma maybe it is real
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200220(10)2411ndash4
Koh 1991
Koh HK Cutaneous melanoma New England Journal of
Medicine 1991325(3)171ndash82
La Vecchia 1999
La Vecchia C Lucchini F Negri E Levi F Recent declines
in worldwide mortality from cutaneous melanoma in youth
and middle age International Journal of Cancer 199981(1)
62ndash6
Lee 2000
Lee ML Tomsu K Von Eschen KB Duration of survival
for disseminated malignant melanoma results of a meta-
analysis Melanoma Research 200010(1)81ndash92
Legha 1998
Legha SS Ring S Eton O Bedikian A Buzaid AC Plager
C et alDevelopment of a biochemotherapy regimen
with concurrent administration of cisplatin vinblastine
dacarbazine interferon alfa and interleukin-2 for patients
with metastatic melanoma Journal of clinical oncology
official journal of the American Society of Clinical Oncology
199816(5)1752ndash9
Leong 2003
Leong SP Future perspectives on malignant melanoma
Surgical Clinics of North America 200383(2)453ndash6
Lokich 1979
Lokich JJ Garnick MB Legg M Intralesional immune
therapy methanol extraction residue of BCG or purified
protein derivative Oncology 197936(5)236ndash41
Nathan 1998
Nathan FE Mastrangelo MJ Systemic therapy in
melanoma Seminars in Surgical Oncology 199814(4)
319ndash27
Osborn 1977
Osborn DE Castro JE Immunological response in patients
receiving Corynebacterium parvum therapy Clinical
Oncology 19773(2)155ndash64
13Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Parmar 1998
Parmar MKB TV Stewart L Extracting summary statistics
to perform meta-analyses of the published literature for
survival endpoints Statistics in Medicine 1998172815ndash34
Richards 1992
Richards JM Mehta N Ramming K Skosey P Sequential
chemoimmunotherapy in the treatment of metastatic
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199210(8)1338ndash43
Rigel 1989
Rigel DS Rivers JK Kopf AW Friedman RJ Vinokur AF
Heilman ER et alDysplastic nevi Markers for increased
risk for melanoma Cancer 198963(2)386ndash9
Rosenberg 1989
Rosenberg SA Lotze MT Yang JC Aebersold PM Linehan
WM Seipp CA et alExperience with the use of high-
dose interleukin-2 in the treatment of 652 cancer patients
Annals of Surgery 1989210(4)474-84 discussion 484-5
Sertoli 1989
Sertoli MR Bernengo MG Ardizzoni A Brunetti I Falcone
A Vidili MG et alPhase II trial of recombinant alpha-2b
interferon in the treatment of metastatic skin melanoma
Oncology 198946(2)96ndash8
Smith 1993
Smith KA Lowest dose interleukin-2 immunotherapy
Blood 199381(6)1414ndash23
Stopeck 2001
Stopeck AT Jones A Hersh EM Thompson JA
Finucane DM Gutheil JC et alPhase II study of direct
intralesional gene transfer of allovectin-7 an HLA-B7
beta2-microglobulin DNA-liposome complex in patients
with metastatic melanoma Clinical Cancer Research 20017
(8)2285ndash91
Tsang 1983
Tsang KY Fudenberg HH Pan JF Gnagy MJ Bristow
CB An in vitro study on the effects of isoprinosine on
immune responses in cancer patients International Journal
of Immunopharmacology 19835(6)481ndash90
Wingo 1995
Wingo PA Tong T Bolden S Cancer statistics 1995 CA
a cancer journal for clinicians 199545(1)8ndash30
Yusuf 1985
Yusuf S Peto R Lewis J Collins R Sleight P Beta blockade
during and after myocardial infarction an overview of the
randomized trials Progress in Cardiovascular Diseases 1985
27(5)335ndash71lowast Indicates the major publication for the study
14Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Atkins 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding public
Participants PS lt= 1
Brain mets no info
Age 20 to 80 (median 50)
Number of cycles no info
Randomised 416 a 206 b 210
Evaluable 405 a 201 b 204
Interventions a (CT) cisplatin 20mgm2 D1 to 4 vinblastin 12 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1-4 vimblastin 12 mgm2 D1-4 DTIC 800 mgm2 D1
IFN-alpha 5 mIU D1-5 D8 D10 D12 IL-2 9 mIU D1-4
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
Notes Multicentric yes
Withdrawals a five b six
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
15Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Atzpodien 2002
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding both (pharmaceutic and public)
Participants PS lt= 1
Brain mets yes Age 28 to 77 (median 57)
Number of cycles no info
Randomised 124 a 60 b 64
Evaluable 124 a 60 b 64
Interventions a (CT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily
b (ICT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily IFN-alpha 5 mIUm2 D1 week4 and 5
mIUm2 D1 D3 D5 week 5 IL-2 10 mIUm2 D1 D3 D5
(each five weeks)
Outcomes 1 Response rates
2 Overall survival
3 Progression free survival
Notes Multicentric yes
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Bajetta 1994
Methods D parallel group (three groups)
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding pharmaceutic
Participants PS lt= 2
Brain mets no
16Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Bajetta 1994 (Continued)
Age 18 to 70 (median 53)
Number of cycles 8
Randomised 266 a 88 b 86 c 92
Evaluable 242 a 82 b 76 c 84
Interventions a (CT) DTIC 800 mgm2 D1
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU 3xweek
c (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU D1 to 3 6 mIU D4 to 6 9 mIU daily
(each 21 days)
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Overall survival
Notes Multicentric yes
Withdrawals a six b ten c eight
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Danson 2003
Methods D parallel group
AC independent allocation
RS permuted blocks
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets yes Age 16 to 88 (median 58)
Number of cycles six
Randomised 125 a 59 b 62
Evaluable 121 a 55 b 62
Interventions a (CT) temozolomide 200 mgm2 88 h (5 doses)
b (ICT) Temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIU 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
17Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Danson 2003 (Continued)
Notes Multicentric no
Withdrawals a 4 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Del Vecchio 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no Age 19 to 70 (median 50)
Number of cycles no info
Randomised 151 a 75 b 76
Evaluable 145 a 72 b 73
Interventions a (CT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250 mgm2 D1 to
3
b (ICT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250m gm2 D1 to
3 IFN-alpha 5 mIUm2 D1 to 5 IL-2 9 mIUday x 5 daysweek x 2 weeks with a week of
rest
(each 21 days)
Outcomes 1 Response rates
2 Time to Progression
2 Overall Survival
Notes Multicentric yes
Withdrawals a three b three
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
18Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Eton 2002
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding pharm
Participants PS lt= 3
Brain mets yes Age median 49
Number of cycles no info
Randomised 190
Evaluable 183 a 92 b 91
Interventions a (CT) cisplatin 20m gm2 D1 to 4 vimblastin 2 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1 to 4 vinblastin 15 mgm2 D1 to 4 DTIC 800 mgm2
D1 IFN-alpha 5mIUm2 D5 to 9 D17-21 IL-2 9 mIUm2 D5 to 8 D17 to 20
(each 21 days)
Outcomes 1 Response rates
2 Time to progression
3 Overall survival
Notes Multicentric no
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1991
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size no
ITT no
Placebo no
Funding both
Participants PS lt= 1
Brain mets no
Age 22 to 79
(median 57)
Number of cycles at least two
19Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1991 (Continued)
Randomised 73 Evaluable 68 a 34 b 34
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Time to treatment failure
3 Median survival
4 Toxicity
Notes Multicentric no
Withdrawals a three b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1998
Methods D 2 x 2 factorial design
AC independent allocation
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 18 to 84
Number of cycles no info
Randomised 271 Evaluable 263 a 68 b 65 c 63 d 67
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
c (CT) DTIC 200m gm2 D1 to 5 tamoxifen 20 mgdaily
d (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek tamoxifen 20 mgdaily
(each 28 days)
Outcomes 1 Response rates
2 Toxicity rates
20Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1998 (Continued)
3 Overall survival
4 Time to treatment failure
Notes Multicentric yes
Withdrawals a one b three c three d one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Gorbonova 2000
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no
Age 23 to 75
Number of cycles no info
Randomised 30 Evaluable 28 a 14 b 14
Interventions a (CT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2
b (ICT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2 IFN-alpha 3 mIU D5 7
9 11 13 15 17 19
(each 28 days)
Outcomes 1 Response rates
Notes Multicentric no
Withdrawals a two b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
21Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Johnston 1998
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age 18 to 70
(median 45)
Number of cycles no info
Randomised 65 Evaluable 65 a 30 b 35
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to 3
Tamoxifen 40 mg daily
b (ICT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to
3 Tamoxifen 40 mg daily IFN-alpha 9 mIU D1 to 3 IL-2 18 mIU D-2 IL-2 9 mIU D-
1 and 0
(each 28 days)
Outcomes 1 Response rates
2 Time to disease progression
3 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Kirkwood 1990
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding pharm
22Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Kirkwood 1990 (Continued)
Participants PS no info
Brain mets no info
Age no info
Number of cycles no info
Randomised 74 Evaluable 68 a 24 b 23 c 21
Interventions a (CT) DTIC 250 mgm2 D1 to 5 (each 21 days)
b (I) IFN-alpha 3 mIU d1 to 5 every week for 3 weeks than 3 mIUm2 3 xweek
c (ICT) DTIC 250 mgm2 D1 to 5 (each 21 days) IFN-alpha 3 mIU d1 to 5 every week
for 3 weeks than 3 mIUm2 3 xweek
Outcomes 1 Response rates
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Middleton 2000
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets no
Age 24 to 71
(median 51)
Number of cycles six
Randomised 105 Evaluable 96 a 46 b 50
Interventions a (CT) DTIC 800 mgm2 D1 cisplatin 25 mgm2 D1 to 3 BCNU 150 mgm2 D1
tamoxifen 20 mgdaily
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 9 mIU 3 xweek
(each 21 days)
Outcomes 1 Response rates
2 One year survival
3 Median survival
23Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Middleton 2000 (Continued)
4 Toxicity
4 Time spent in hospital
Notes Multicentric no
Withdrawals a seven b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Ridolfi 2002
Methods D parallel group
AC independent allocation by telephone
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 25 to 77
Number of cycles six
Randomised 178 Evaluable 176 a 89 b 87
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1
b (ICT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1 IFN-
alpha 3 mIU 3 xweek IL-2 45 mIU D3 to 5 D8 to 12
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
3 Time to progression
4 Toxicity
Notes Multicentric yes
Withdrawals a one b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
24Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
interferon alfa versus temozolomide alone in patients with
advanced metastatic melanoma A randomized phase
III multicenter study of the Dermatologic Cooperative
Oncology Group (DeCOG) In ASCO Annual Meeting
2003Abstract 2887
Thomson 1993 published data only
Thomson DB Adena M McLeod GR Hersey P Gill PG
Coates AS et alInterferon-alpha 2a does not improve
response or survival when combined with dacarbazine
in metastatic malignant melanoma results of a multi-
institutional Australian randomized trial Melanoma
Research 19933(2)133ndash8
Vorobiof 1994 published data only
Vorobiof DA Bezwoda WR A randomised trial of vindesine
plus interferon-alpha 2b compared with interferon-alpha 2b
or vindesine alone in the treatment of advanced malignant
melanoma European journal of cancer (Oxford England
1990) 199430A(6)797ndash800
Young 2001 published data only
Young AM Marsden J Goodman A Burton A Dunn
JA Prospective randomized comparison of dacarbazine
(DTIC) versus DTIC plus interferon-alpha (IFN-alpha) in
metastatic melanoma Clinical oncology (Royal College of
Radiologists (Great Britain)) 200113(6)458ndash65
References to studies excluded from this review
Bajetta 2001 published data only
Bajetta E Del Vecchio M Vitali M Martinetti A Ferrari L
Queirolo P et alA feasibility study using polychemotherapy
(cisplatin + vindesine + dacarbazine) plus interferon-alpha
or monochemotherapy with dacarbazine plus interferon-
alpha in metastatic melanoma Tumori 200187(4)219ndash22
Legha 1996 published data only
Legha SS Ring S Bedikian A Plager C Eton O Buzaid
AC et alTreatment of metastatic melanoma with combined
chemotherapy containing cisplatin vinblastine and
dacarbazine (CVD) and biotherapy using interleukin-2 and
interferon-alpha Annals of oncology official journal of the
European Society for Medical Oncology ESMO 19967(8)
827ndash35
Richtig 2004 published data only
Richtig E Hofmann-Wellenhof R Pehamberger H
Forstinger C Wolff K Mischer P et alTemozolomide and
interferon alpha 2b in metastatic melanoma stage IV British
Journal of Dermatology 2004151(1)91ndash8
Sertoli 1999 published data only
Sertoli MR Queirolo P Bajetta E DelVecchio M
Comella G Barduagni L et alMulti-institutional phase
II randomized trial of integrated therapy with cisplatin
dacarbazine vindesine subcutaneous interleukin-2
interferon alpha2a and tamoxifen in metastatic melanoma
BREMIM (Biological Response Modifiers in Melanoma)
Melanoma research 19999(5)503ndash9
Sparano 1993 published data only
Sparano JA Fisher RI Sunderland M Margolin K Ernest
ML Sznol M et alRandomized phase III trial of treatment
with high-dose interleukin-2 either alone or in combination
with interferon alfa-2a in patients with advanced melanoma
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 199311(10)1969ndash77
Vuoristo 2005 published data only
Vuoristo MS Hahka-Kemppinen M Parvinen LM
Pyrhonen S Seppa H Korpela M et alRandomized trial of
dacarbazine versus bleomycin vincristine lomustine and
dacarbazine (BOLD) chemotherapy combined with natural
or recombinant interferon-alpha in patients with advanced
melanoma Melanoma research 200515(4)291ndash6
Additional references
Arance 2000
Arance A Middleton M Lorigan P Thatcher N Three-
arm phase II study of temozolomide (TMZ) in metastatic
melanoma (MM) In ASCO Annual Meeting 2000
Abstract 2257
Bafaloukos 2002
Bafaloukos D Aravantinos G Fountzilas G Stathopoulos
G Gogas H Samonis G et alDocetaxel in combination
with dacarbazine in patients with advanced melanoma
Oncology 200263(4)333ndash7
Bajetta 2002
Bajetta E Del Vecchio M Bernard-Marty C Vitali
M Buzzoni R Rixe O et alMetastatic melanoma
chemotherapy Seminars in Oncology 200229(5)427ndash45
Balch 2001
Balch CM Soong SJ Gershenwald JE Thompson JF
Reintgen DS Cascinelli N et alPrognostic factors analysis
of 17600 melanoma patients validation of the American
Joint Committee on Cancer melanoma staging system
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200119(16)3622ndash34
Barth 1995
Barth A Morton DL The role of adjuvant therapy in
melanoma management Cancer 199575 Suppl (2)
726ndash34
Chiarion-Sileni 2003
Chiarion-Sileni V Del Bianco P De Salvo GL Lo Re G
Romanini A Labianca R et alQuality of life evaluation in a
randomised trial of chemotherapy versus bio-chemotherapy
in advanced melanoma patients European journal of cancer
(Oxford England 1990) 200339(11)1577ndash85
Creagan 1984
Creagan ET Ahmann DL Green SJ Long HJ Frytak S
OrsquoFallon JR et alPhase II study of low-dose recombinant
leukocyte A interferon in disseminated malignant
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 19842(9)1002ndash5
Crosby 2000
Crosby T Fish R Coles B Mason MD Systemic treatments
for metastatic cutaneous melanoma Cochrane Database
of Systematic Reviews 2000 Issue 2 [DOI 101002
14651858CD001215]
12Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Cure 1999
Cure H Souteyrand P Ouabdesselam R Roche H
Ravaud A DrsquoIncan M et alResults of a phase II trial
with cystemustine at 90 mgm(2) as a first- or second-line
treatment in advanced malignant melanoma a trial of the
EORTC Clinical Studies Group Melanoma Research 1999
9(6)607ndash10
Danson 2002
Danson S Arance A Lorigan P Clamp A Hodgetts J
Lomax L Thatcher N Middleton MR A randomized
study of temozolomide (TMZ) alone with interferon-
alpha (TMZ-IFN) or with thalidomide (TMZ-THAL) in
metastatic malignant melanoma (MMM) ASCO Annual
Meeting - Proceedings 2002Abstract 1369
Dorval 1986
Dorval T Palangie T Jouve M Garcia-Giralt E Israel L
Falcoff E et alClinical phase II trial of recombinant DNA
interferon (interferon alpha 2b) in patients with metastatic
malignant melanoma Cancer 198658(2)215ndash8
Dutcher 1989
Dutcher JP Creekmore S Weiss GR Margolin K
Markowitz AB Roper M et alA phase II study of
interleukin-2 and lymphokine-activated killer cells in
patients with metastatic malignant melanoma Journal of
clinical oncology official journal of the American Society of
Clinical Oncology 19897(4)477ndash85
Falkson 1995
Falkson CI Experience with interferon alpha 2b combined
with dacarbazine in the treatment of metastatic malignant
melanoma Medical oncology (Northwood London England)
199512(1)35ndash40
Garbe 1990
Garbe C Krasagakis K Zouboulis CC Schroder K Kruger
S Stadler R et alAntitumor activities of interferon alpha
beta and gamma and their combinations on human
melanoma cells in vitro changes of proliferation melanin
synthesis and immunophenotype Journal of Investigative
Dermatology 199095 Suppl (6)231ndash7
Gershenwald 1999
Gershenwald JE Thompson W Mansfield PF Lee JE
Colome MI Tseng CH et alMulti-institutional melanoma
lymphatic mapping experience the prognostic value of
sentinel lymph node status in 612 stage I or II melanoma
patients Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199917(3)976ndash83
Hanninen 1991
Hanninen EL Korfer A Hadam M Schneekloth C
Dallmann I Menzel T et alBiological monitoring of
low-dose interleukin 2 in humans soluble interleukin 2
receptors cytokines and cell surface phenotypes Cancer
Research 199151(23 Pt 1)6312ndash6
Huncharek 2001
Huncharek M Caubet JF McGarry R Single-agent
DTIC versus combination chemotherapy with or without
immunotherapy in metastatic melanoma a meta-analysis
of 3273 patients from 20 randomized trials Melanoma
Research 200111(1)75ndash81
Juni 2001
Juni P Altman DG Egger M Assessing the quality of
controlled clinical trials BMJ 200132342ndash6
Kadison 2003
Kadison AS Morton DL Immunotherapy of malignant
melanoma The Surgical Clinics of North America 200383
(2)343ndash70
Keilholz 2002
Keilholz U Gore ME Biochemotherapy for advanced
melanoma Seminars in Oncology 200229(5)456ndash61
Khayat 2002
Khayat D Bernard-Marty C Meric JB Rixe O
Biochemotherapy for advanced melanoma maybe it is real
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200220(10)2411ndash4
Koh 1991
Koh HK Cutaneous melanoma New England Journal of
Medicine 1991325(3)171ndash82
La Vecchia 1999
La Vecchia C Lucchini F Negri E Levi F Recent declines
in worldwide mortality from cutaneous melanoma in youth
and middle age International Journal of Cancer 199981(1)
62ndash6
Lee 2000
Lee ML Tomsu K Von Eschen KB Duration of survival
for disseminated malignant melanoma results of a meta-
analysis Melanoma Research 200010(1)81ndash92
Legha 1998
Legha SS Ring S Eton O Bedikian A Buzaid AC Plager
C et alDevelopment of a biochemotherapy regimen
with concurrent administration of cisplatin vinblastine
dacarbazine interferon alfa and interleukin-2 for patients
with metastatic melanoma Journal of clinical oncology
official journal of the American Society of Clinical Oncology
199816(5)1752ndash9
Leong 2003
Leong SP Future perspectives on malignant melanoma
Surgical Clinics of North America 200383(2)453ndash6
Lokich 1979
Lokich JJ Garnick MB Legg M Intralesional immune
therapy methanol extraction residue of BCG or purified
protein derivative Oncology 197936(5)236ndash41
Nathan 1998
Nathan FE Mastrangelo MJ Systemic therapy in
melanoma Seminars in Surgical Oncology 199814(4)
319ndash27
Osborn 1977
Osborn DE Castro JE Immunological response in patients
receiving Corynebacterium parvum therapy Clinical
Oncology 19773(2)155ndash64
13Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Parmar 1998
Parmar MKB TV Stewart L Extracting summary statistics
to perform meta-analyses of the published literature for
survival endpoints Statistics in Medicine 1998172815ndash34
Richards 1992
Richards JM Mehta N Ramming K Skosey P Sequential
chemoimmunotherapy in the treatment of metastatic
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199210(8)1338ndash43
Rigel 1989
Rigel DS Rivers JK Kopf AW Friedman RJ Vinokur AF
Heilman ER et alDysplastic nevi Markers for increased
risk for melanoma Cancer 198963(2)386ndash9
Rosenberg 1989
Rosenberg SA Lotze MT Yang JC Aebersold PM Linehan
WM Seipp CA et alExperience with the use of high-
dose interleukin-2 in the treatment of 652 cancer patients
Annals of Surgery 1989210(4)474-84 discussion 484-5
Sertoli 1989
Sertoli MR Bernengo MG Ardizzoni A Brunetti I Falcone
A Vidili MG et alPhase II trial of recombinant alpha-2b
interferon in the treatment of metastatic skin melanoma
Oncology 198946(2)96ndash8
Smith 1993
Smith KA Lowest dose interleukin-2 immunotherapy
Blood 199381(6)1414ndash23
Stopeck 2001
Stopeck AT Jones A Hersh EM Thompson JA
Finucane DM Gutheil JC et alPhase II study of direct
intralesional gene transfer of allovectin-7 an HLA-B7
beta2-microglobulin DNA-liposome complex in patients
with metastatic melanoma Clinical Cancer Research 20017
(8)2285ndash91
Tsang 1983
Tsang KY Fudenberg HH Pan JF Gnagy MJ Bristow
CB An in vitro study on the effects of isoprinosine on
immune responses in cancer patients International Journal
of Immunopharmacology 19835(6)481ndash90
Wingo 1995
Wingo PA Tong T Bolden S Cancer statistics 1995 CA
a cancer journal for clinicians 199545(1)8ndash30
Yusuf 1985
Yusuf S Peto R Lewis J Collins R Sleight P Beta blockade
during and after myocardial infarction an overview of the
randomized trials Progress in Cardiovascular Diseases 1985
27(5)335ndash71lowast Indicates the major publication for the study
14Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Atkins 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding public
Participants PS lt= 1
Brain mets no info
Age 20 to 80 (median 50)
Number of cycles no info
Randomised 416 a 206 b 210
Evaluable 405 a 201 b 204
Interventions a (CT) cisplatin 20mgm2 D1 to 4 vinblastin 12 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1-4 vimblastin 12 mgm2 D1-4 DTIC 800 mgm2 D1
IFN-alpha 5 mIU D1-5 D8 D10 D12 IL-2 9 mIU D1-4
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
Notes Multicentric yes
Withdrawals a five b six
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
15Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Atzpodien 2002
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding both (pharmaceutic and public)
Participants PS lt= 1
Brain mets yes Age 28 to 77 (median 57)
Number of cycles no info
Randomised 124 a 60 b 64
Evaluable 124 a 60 b 64
Interventions a (CT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily
b (ICT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily IFN-alpha 5 mIUm2 D1 week4 and 5
mIUm2 D1 D3 D5 week 5 IL-2 10 mIUm2 D1 D3 D5
(each five weeks)
Outcomes 1 Response rates
2 Overall survival
3 Progression free survival
Notes Multicentric yes
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Bajetta 1994
Methods D parallel group (three groups)
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding pharmaceutic
Participants PS lt= 2
Brain mets no
16Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Bajetta 1994 (Continued)
Age 18 to 70 (median 53)
Number of cycles 8
Randomised 266 a 88 b 86 c 92
Evaluable 242 a 82 b 76 c 84
Interventions a (CT) DTIC 800 mgm2 D1
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU 3xweek
c (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU D1 to 3 6 mIU D4 to 6 9 mIU daily
(each 21 days)
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Overall survival
Notes Multicentric yes
Withdrawals a six b ten c eight
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Danson 2003
Methods D parallel group
AC independent allocation
RS permuted blocks
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets yes Age 16 to 88 (median 58)
Number of cycles six
Randomised 125 a 59 b 62
Evaluable 121 a 55 b 62
Interventions a (CT) temozolomide 200 mgm2 88 h (5 doses)
b (ICT) Temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIU 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
17Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Danson 2003 (Continued)
Notes Multicentric no
Withdrawals a 4 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Del Vecchio 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no Age 19 to 70 (median 50)
Number of cycles no info
Randomised 151 a 75 b 76
Evaluable 145 a 72 b 73
Interventions a (CT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250 mgm2 D1 to
3
b (ICT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250m gm2 D1 to
3 IFN-alpha 5 mIUm2 D1 to 5 IL-2 9 mIUday x 5 daysweek x 2 weeks with a week of
rest
(each 21 days)
Outcomes 1 Response rates
2 Time to Progression
2 Overall Survival
Notes Multicentric yes
Withdrawals a three b three
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
18Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Eton 2002
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding pharm
Participants PS lt= 3
Brain mets yes Age median 49
Number of cycles no info
Randomised 190
Evaluable 183 a 92 b 91
Interventions a (CT) cisplatin 20m gm2 D1 to 4 vimblastin 2 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1 to 4 vinblastin 15 mgm2 D1 to 4 DTIC 800 mgm2
D1 IFN-alpha 5mIUm2 D5 to 9 D17-21 IL-2 9 mIUm2 D5 to 8 D17 to 20
(each 21 days)
Outcomes 1 Response rates
2 Time to progression
3 Overall survival
Notes Multicentric no
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1991
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size no
ITT no
Placebo no
Funding both
Participants PS lt= 1
Brain mets no
Age 22 to 79
(median 57)
Number of cycles at least two
19Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1991 (Continued)
Randomised 73 Evaluable 68 a 34 b 34
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Time to treatment failure
3 Median survival
4 Toxicity
Notes Multicentric no
Withdrawals a three b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1998
Methods D 2 x 2 factorial design
AC independent allocation
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 18 to 84
Number of cycles no info
Randomised 271 Evaluable 263 a 68 b 65 c 63 d 67
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
c (CT) DTIC 200m gm2 D1 to 5 tamoxifen 20 mgdaily
d (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek tamoxifen 20 mgdaily
(each 28 days)
Outcomes 1 Response rates
2 Toxicity rates
20Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1998 (Continued)
3 Overall survival
4 Time to treatment failure
Notes Multicentric yes
Withdrawals a one b three c three d one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Gorbonova 2000
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no
Age 23 to 75
Number of cycles no info
Randomised 30 Evaluable 28 a 14 b 14
Interventions a (CT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2
b (ICT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2 IFN-alpha 3 mIU D5 7
9 11 13 15 17 19
(each 28 days)
Outcomes 1 Response rates
Notes Multicentric no
Withdrawals a two b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
21Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Johnston 1998
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age 18 to 70
(median 45)
Number of cycles no info
Randomised 65 Evaluable 65 a 30 b 35
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to 3
Tamoxifen 40 mg daily
b (ICT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to
3 Tamoxifen 40 mg daily IFN-alpha 9 mIU D1 to 3 IL-2 18 mIU D-2 IL-2 9 mIU D-
1 and 0
(each 28 days)
Outcomes 1 Response rates
2 Time to disease progression
3 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Kirkwood 1990
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding pharm
22Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Kirkwood 1990 (Continued)
Participants PS no info
Brain mets no info
Age no info
Number of cycles no info
Randomised 74 Evaluable 68 a 24 b 23 c 21
Interventions a (CT) DTIC 250 mgm2 D1 to 5 (each 21 days)
b (I) IFN-alpha 3 mIU d1 to 5 every week for 3 weeks than 3 mIUm2 3 xweek
c (ICT) DTIC 250 mgm2 D1 to 5 (each 21 days) IFN-alpha 3 mIU d1 to 5 every week
for 3 weeks than 3 mIUm2 3 xweek
Outcomes 1 Response rates
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Middleton 2000
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets no
Age 24 to 71
(median 51)
Number of cycles six
Randomised 105 Evaluable 96 a 46 b 50
Interventions a (CT) DTIC 800 mgm2 D1 cisplatin 25 mgm2 D1 to 3 BCNU 150 mgm2 D1
tamoxifen 20 mgdaily
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 9 mIU 3 xweek
(each 21 days)
Outcomes 1 Response rates
2 One year survival
3 Median survival
23Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Middleton 2000 (Continued)
4 Toxicity
4 Time spent in hospital
Notes Multicentric no
Withdrawals a seven b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Ridolfi 2002
Methods D parallel group
AC independent allocation by telephone
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 25 to 77
Number of cycles six
Randomised 178 Evaluable 176 a 89 b 87
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1
b (ICT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1 IFN-
alpha 3 mIU 3 xweek IL-2 45 mIU D3 to 5 D8 to 12
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
3 Time to progression
4 Toxicity
Notes Multicentric yes
Withdrawals a one b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
24Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Cure 1999
Cure H Souteyrand P Ouabdesselam R Roche H
Ravaud A DrsquoIncan M et alResults of a phase II trial
with cystemustine at 90 mgm(2) as a first- or second-line
treatment in advanced malignant melanoma a trial of the
EORTC Clinical Studies Group Melanoma Research 1999
9(6)607ndash10
Danson 2002
Danson S Arance A Lorigan P Clamp A Hodgetts J
Lomax L Thatcher N Middleton MR A randomized
study of temozolomide (TMZ) alone with interferon-
alpha (TMZ-IFN) or with thalidomide (TMZ-THAL) in
metastatic malignant melanoma (MMM) ASCO Annual
Meeting - Proceedings 2002Abstract 1369
Dorval 1986
Dorval T Palangie T Jouve M Garcia-Giralt E Israel L
Falcoff E et alClinical phase II trial of recombinant DNA
interferon (interferon alpha 2b) in patients with metastatic
malignant melanoma Cancer 198658(2)215ndash8
Dutcher 1989
Dutcher JP Creekmore S Weiss GR Margolin K
Markowitz AB Roper M et alA phase II study of
interleukin-2 and lymphokine-activated killer cells in
patients with metastatic malignant melanoma Journal of
clinical oncology official journal of the American Society of
Clinical Oncology 19897(4)477ndash85
Falkson 1995
Falkson CI Experience with interferon alpha 2b combined
with dacarbazine in the treatment of metastatic malignant
melanoma Medical oncology (Northwood London England)
199512(1)35ndash40
Garbe 1990
Garbe C Krasagakis K Zouboulis CC Schroder K Kruger
S Stadler R et alAntitumor activities of interferon alpha
beta and gamma and their combinations on human
melanoma cells in vitro changes of proliferation melanin
synthesis and immunophenotype Journal of Investigative
Dermatology 199095 Suppl (6)231ndash7
Gershenwald 1999
Gershenwald JE Thompson W Mansfield PF Lee JE
Colome MI Tseng CH et alMulti-institutional melanoma
lymphatic mapping experience the prognostic value of
sentinel lymph node status in 612 stage I or II melanoma
patients Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199917(3)976ndash83
Hanninen 1991
Hanninen EL Korfer A Hadam M Schneekloth C
Dallmann I Menzel T et alBiological monitoring of
low-dose interleukin 2 in humans soluble interleukin 2
receptors cytokines and cell surface phenotypes Cancer
Research 199151(23 Pt 1)6312ndash6
Huncharek 2001
Huncharek M Caubet JF McGarry R Single-agent
DTIC versus combination chemotherapy with or without
immunotherapy in metastatic melanoma a meta-analysis
of 3273 patients from 20 randomized trials Melanoma
Research 200111(1)75ndash81
Juni 2001
Juni P Altman DG Egger M Assessing the quality of
controlled clinical trials BMJ 200132342ndash6
Kadison 2003
Kadison AS Morton DL Immunotherapy of malignant
melanoma The Surgical Clinics of North America 200383
(2)343ndash70
Keilholz 2002
Keilholz U Gore ME Biochemotherapy for advanced
melanoma Seminars in Oncology 200229(5)456ndash61
Khayat 2002
Khayat D Bernard-Marty C Meric JB Rixe O
Biochemotherapy for advanced melanoma maybe it is real
Journal of clinical oncology official journal of the American
Society of Clinical Oncology 200220(10)2411ndash4
Koh 1991
Koh HK Cutaneous melanoma New England Journal of
Medicine 1991325(3)171ndash82
La Vecchia 1999
La Vecchia C Lucchini F Negri E Levi F Recent declines
in worldwide mortality from cutaneous melanoma in youth
and middle age International Journal of Cancer 199981(1)
62ndash6
Lee 2000
Lee ML Tomsu K Von Eschen KB Duration of survival
for disseminated malignant melanoma results of a meta-
analysis Melanoma Research 200010(1)81ndash92
Legha 1998
Legha SS Ring S Eton O Bedikian A Buzaid AC Plager
C et alDevelopment of a biochemotherapy regimen
with concurrent administration of cisplatin vinblastine
dacarbazine interferon alfa and interleukin-2 for patients
with metastatic melanoma Journal of clinical oncology
official journal of the American Society of Clinical Oncology
199816(5)1752ndash9
Leong 2003
Leong SP Future perspectives on malignant melanoma
Surgical Clinics of North America 200383(2)453ndash6
Lokich 1979
Lokich JJ Garnick MB Legg M Intralesional immune
therapy methanol extraction residue of BCG or purified
protein derivative Oncology 197936(5)236ndash41
Nathan 1998
Nathan FE Mastrangelo MJ Systemic therapy in
melanoma Seminars in Surgical Oncology 199814(4)
319ndash27
Osborn 1977
Osborn DE Castro JE Immunological response in patients
receiving Corynebacterium parvum therapy Clinical
Oncology 19773(2)155ndash64
13Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Parmar 1998
Parmar MKB TV Stewart L Extracting summary statistics
to perform meta-analyses of the published literature for
survival endpoints Statistics in Medicine 1998172815ndash34
Richards 1992
Richards JM Mehta N Ramming K Skosey P Sequential
chemoimmunotherapy in the treatment of metastatic
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199210(8)1338ndash43
Rigel 1989
Rigel DS Rivers JK Kopf AW Friedman RJ Vinokur AF
Heilman ER et alDysplastic nevi Markers for increased
risk for melanoma Cancer 198963(2)386ndash9
Rosenberg 1989
Rosenberg SA Lotze MT Yang JC Aebersold PM Linehan
WM Seipp CA et alExperience with the use of high-
dose interleukin-2 in the treatment of 652 cancer patients
Annals of Surgery 1989210(4)474-84 discussion 484-5
Sertoli 1989
Sertoli MR Bernengo MG Ardizzoni A Brunetti I Falcone
A Vidili MG et alPhase II trial of recombinant alpha-2b
interferon in the treatment of metastatic skin melanoma
Oncology 198946(2)96ndash8
Smith 1993
Smith KA Lowest dose interleukin-2 immunotherapy
Blood 199381(6)1414ndash23
Stopeck 2001
Stopeck AT Jones A Hersh EM Thompson JA
Finucane DM Gutheil JC et alPhase II study of direct
intralesional gene transfer of allovectin-7 an HLA-B7
beta2-microglobulin DNA-liposome complex in patients
with metastatic melanoma Clinical Cancer Research 20017
(8)2285ndash91
Tsang 1983
Tsang KY Fudenberg HH Pan JF Gnagy MJ Bristow
CB An in vitro study on the effects of isoprinosine on
immune responses in cancer patients International Journal
of Immunopharmacology 19835(6)481ndash90
Wingo 1995
Wingo PA Tong T Bolden S Cancer statistics 1995 CA
a cancer journal for clinicians 199545(1)8ndash30
Yusuf 1985
Yusuf S Peto R Lewis J Collins R Sleight P Beta blockade
during and after myocardial infarction an overview of the
randomized trials Progress in Cardiovascular Diseases 1985
27(5)335ndash71lowast Indicates the major publication for the study
14Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Atkins 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding public
Participants PS lt= 1
Brain mets no info
Age 20 to 80 (median 50)
Number of cycles no info
Randomised 416 a 206 b 210
Evaluable 405 a 201 b 204
Interventions a (CT) cisplatin 20mgm2 D1 to 4 vinblastin 12 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1-4 vimblastin 12 mgm2 D1-4 DTIC 800 mgm2 D1
IFN-alpha 5 mIU D1-5 D8 D10 D12 IL-2 9 mIU D1-4
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
Notes Multicentric yes
Withdrawals a five b six
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
15Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Atzpodien 2002
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding both (pharmaceutic and public)
Participants PS lt= 1
Brain mets yes Age 28 to 77 (median 57)
Number of cycles no info
Randomised 124 a 60 b 64
Evaluable 124 a 60 b 64
Interventions a (CT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily
b (ICT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily IFN-alpha 5 mIUm2 D1 week4 and 5
mIUm2 D1 D3 D5 week 5 IL-2 10 mIUm2 D1 D3 D5
(each five weeks)
Outcomes 1 Response rates
2 Overall survival
3 Progression free survival
Notes Multicentric yes
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Bajetta 1994
Methods D parallel group (three groups)
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding pharmaceutic
Participants PS lt= 2
Brain mets no
16Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Bajetta 1994 (Continued)
Age 18 to 70 (median 53)
Number of cycles 8
Randomised 266 a 88 b 86 c 92
Evaluable 242 a 82 b 76 c 84
Interventions a (CT) DTIC 800 mgm2 D1
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU 3xweek
c (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU D1 to 3 6 mIU D4 to 6 9 mIU daily
(each 21 days)
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Overall survival
Notes Multicentric yes
Withdrawals a six b ten c eight
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Danson 2003
Methods D parallel group
AC independent allocation
RS permuted blocks
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets yes Age 16 to 88 (median 58)
Number of cycles six
Randomised 125 a 59 b 62
Evaluable 121 a 55 b 62
Interventions a (CT) temozolomide 200 mgm2 88 h (5 doses)
b (ICT) Temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIU 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
17Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Danson 2003 (Continued)
Notes Multicentric no
Withdrawals a 4 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Del Vecchio 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no Age 19 to 70 (median 50)
Number of cycles no info
Randomised 151 a 75 b 76
Evaluable 145 a 72 b 73
Interventions a (CT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250 mgm2 D1 to
3
b (ICT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250m gm2 D1 to
3 IFN-alpha 5 mIUm2 D1 to 5 IL-2 9 mIUday x 5 daysweek x 2 weeks with a week of
rest
(each 21 days)
Outcomes 1 Response rates
2 Time to Progression
2 Overall Survival
Notes Multicentric yes
Withdrawals a three b three
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
18Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Eton 2002
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding pharm
Participants PS lt= 3
Brain mets yes Age median 49
Number of cycles no info
Randomised 190
Evaluable 183 a 92 b 91
Interventions a (CT) cisplatin 20m gm2 D1 to 4 vimblastin 2 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1 to 4 vinblastin 15 mgm2 D1 to 4 DTIC 800 mgm2
D1 IFN-alpha 5mIUm2 D5 to 9 D17-21 IL-2 9 mIUm2 D5 to 8 D17 to 20
(each 21 days)
Outcomes 1 Response rates
2 Time to progression
3 Overall survival
Notes Multicentric no
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1991
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size no
ITT no
Placebo no
Funding both
Participants PS lt= 1
Brain mets no
Age 22 to 79
(median 57)
Number of cycles at least two
19Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1991 (Continued)
Randomised 73 Evaluable 68 a 34 b 34
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Time to treatment failure
3 Median survival
4 Toxicity
Notes Multicentric no
Withdrawals a three b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1998
Methods D 2 x 2 factorial design
AC independent allocation
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 18 to 84
Number of cycles no info
Randomised 271 Evaluable 263 a 68 b 65 c 63 d 67
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
c (CT) DTIC 200m gm2 D1 to 5 tamoxifen 20 mgdaily
d (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek tamoxifen 20 mgdaily
(each 28 days)
Outcomes 1 Response rates
2 Toxicity rates
20Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1998 (Continued)
3 Overall survival
4 Time to treatment failure
Notes Multicentric yes
Withdrawals a one b three c three d one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Gorbonova 2000
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no
Age 23 to 75
Number of cycles no info
Randomised 30 Evaluable 28 a 14 b 14
Interventions a (CT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2
b (ICT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2 IFN-alpha 3 mIU D5 7
9 11 13 15 17 19
(each 28 days)
Outcomes 1 Response rates
Notes Multicentric no
Withdrawals a two b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
21Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Johnston 1998
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age 18 to 70
(median 45)
Number of cycles no info
Randomised 65 Evaluable 65 a 30 b 35
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to 3
Tamoxifen 40 mg daily
b (ICT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to
3 Tamoxifen 40 mg daily IFN-alpha 9 mIU D1 to 3 IL-2 18 mIU D-2 IL-2 9 mIU D-
1 and 0
(each 28 days)
Outcomes 1 Response rates
2 Time to disease progression
3 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Kirkwood 1990
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding pharm
22Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Kirkwood 1990 (Continued)
Participants PS no info
Brain mets no info
Age no info
Number of cycles no info
Randomised 74 Evaluable 68 a 24 b 23 c 21
Interventions a (CT) DTIC 250 mgm2 D1 to 5 (each 21 days)
b (I) IFN-alpha 3 mIU d1 to 5 every week for 3 weeks than 3 mIUm2 3 xweek
c (ICT) DTIC 250 mgm2 D1 to 5 (each 21 days) IFN-alpha 3 mIU d1 to 5 every week
for 3 weeks than 3 mIUm2 3 xweek
Outcomes 1 Response rates
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Middleton 2000
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets no
Age 24 to 71
(median 51)
Number of cycles six
Randomised 105 Evaluable 96 a 46 b 50
Interventions a (CT) DTIC 800 mgm2 D1 cisplatin 25 mgm2 D1 to 3 BCNU 150 mgm2 D1
tamoxifen 20 mgdaily
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 9 mIU 3 xweek
(each 21 days)
Outcomes 1 Response rates
2 One year survival
3 Median survival
23Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Middleton 2000 (Continued)
4 Toxicity
4 Time spent in hospital
Notes Multicentric no
Withdrawals a seven b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Ridolfi 2002
Methods D parallel group
AC independent allocation by telephone
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 25 to 77
Number of cycles six
Randomised 178 Evaluable 176 a 89 b 87
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1
b (ICT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1 IFN-
alpha 3 mIU 3 xweek IL-2 45 mIU D3 to 5 D8 to 12
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
3 Time to progression
4 Toxicity
Notes Multicentric yes
Withdrawals a one b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
24Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Parmar 1998
Parmar MKB TV Stewart L Extracting summary statistics
to perform meta-analyses of the published literature for
survival endpoints Statistics in Medicine 1998172815ndash34
Richards 1992
Richards JM Mehta N Ramming K Skosey P Sequential
chemoimmunotherapy in the treatment of metastatic
melanoma Journal of clinical oncology official journal of the
American Society of Clinical Oncology 199210(8)1338ndash43
Rigel 1989
Rigel DS Rivers JK Kopf AW Friedman RJ Vinokur AF
Heilman ER et alDysplastic nevi Markers for increased
risk for melanoma Cancer 198963(2)386ndash9
Rosenberg 1989
Rosenberg SA Lotze MT Yang JC Aebersold PM Linehan
WM Seipp CA et alExperience with the use of high-
dose interleukin-2 in the treatment of 652 cancer patients
Annals of Surgery 1989210(4)474-84 discussion 484-5
Sertoli 1989
Sertoli MR Bernengo MG Ardizzoni A Brunetti I Falcone
A Vidili MG et alPhase II trial of recombinant alpha-2b
interferon in the treatment of metastatic skin melanoma
Oncology 198946(2)96ndash8
Smith 1993
Smith KA Lowest dose interleukin-2 immunotherapy
Blood 199381(6)1414ndash23
Stopeck 2001
Stopeck AT Jones A Hersh EM Thompson JA
Finucane DM Gutheil JC et alPhase II study of direct
intralesional gene transfer of allovectin-7 an HLA-B7
beta2-microglobulin DNA-liposome complex in patients
with metastatic melanoma Clinical Cancer Research 20017
(8)2285ndash91
Tsang 1983
Tsang KY Fudenberg HH Pan JF Gnagy MJ Bristow
CB An in vitro study on the effects of isoprinosine on
immune responses in cancer patients International Journal
of Immunopharmacology 19835(6)481ndash90
Wingo 1995
Wingo PA Tong T Bolden S Cancer statistics 1995 CA
a cancer journal for clinicians 199545(1)8ndash30
Yusuf 1985
Yusuf S Peto R Lewis J Collins R Sleight P Beta blockade
during and after myocardial infarction an overview of the
randomized trials Progress in Cardiovascular Diseases 1985
27(5)335ndash71lowast Indicates the major publication for the study
14Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Atkins 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding public
Participants PS lt= 1
Brain mets no info
Age 20 to 80 (median 50)
Number of cycles no info
Randomised 416 a 206 b 210
Evaluable 405 a 201 b 204
Interventions a (CT) cisplatin 20mgm2 D1 to 4 vinblastin 12 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1-4 vimblastin 12 mgm2 D1-4 DTIC 800 mgm2 D1
IFN-alpha 5 mIU D1-5 D8 D10 D12 IL-2 9 mIU D1-4
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
Notes Multicentric yes
Withdrawals a five b six
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
15Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Atzpodien 2002
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding both (pharmaceutic and public)
Participants PS lt= 1
Brain mets yes Age 28 to 77 (median 57)
Number of cycles no info
Randomised 124 a 60 b 64
Evaluable 124 a 60 b 64
Interventions a (CT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily
b (ICT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily IFN-alpha 5 mIUm2 D1 week4 and 5
mIUm2 D1 D3 D5 week 5 IL-2 10 mIUm2 D1 D3 D5
(each five weeks)
Outcomes 1 Response rates
2 Overall survival
3 Progression free survival
Notes Multicentric yes
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Bajetta 1994
Methods D parallel group (three groups)
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding pharmaceutic
Participants PS lt= 2
Brain mets no
16Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Bajetta 1994 (Continued)
Age 18 to 70 (median 53)
Number of cycles 8
Randomised 266 a 88 b 86 c 92
Evaluable 242 a 82 b 76 c 84
Interventions a (CT) DTIC 800 mgm2 D1
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU 3xweek
c (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU D1 to 3 6 mIU D4 to 6 9 mIU daily
(each 21 days)
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Overall survival
Notes Multicentric yes
Withdrawals a six b ten c eight
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Danson 2003
Methods D parallel group
AC independent allocation
RS permuted blocks
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets yes Age 16 to 88 (median 58)
Number of cycles six
Randomised 125 a 59 b 62
Evaluable 121 a 55 b 62
Interventions a (CT) temozolomide 200 mgm2 88 h (5 doses)
b (ICT) Temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIU 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
17Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Danson 2003 (Continued)
Notes Multicentric no
Withdrawals a 4 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Del Vecchio 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no Age 19 to 70 (median 50)
Number of cycles no info
Randomised 151 a 75 b 76
Evaluable 145 a 72 b 73
Interventions a (CT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250 mgm2 D1 to
3
b (ICT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250m gm2 D1 to
3 IFN-alpha 5 mIUm2 D1 to 5 IL-2 9 mIUday x 5 daysweek x 2 weeks with a week of
rest
(each 21 days)
Outcomes 1 Response rates
2 Time to Progression
2 Overall Survival
Notes Multicentric yes
Withdrawals a three b three
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
18Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Eton 2002
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding pharm
Participants PS lt= 3
Brain mets yes Age median 49
Number of cycles no info
Randomised 190
Evaluable 183 a 92 b 91
Interventions a (CT) cisplatin 20m gm2 D1 to 4 vimblastin 2 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1 to 4 vinblastin 15 mgm2 D1 to 4 DTIC 800 mgm2
D1 IFN-alpha 5mIUm2 D5 to 9 D17-21 IL-2 9 mIUm2 D5 to 8 D17 to 20
(each 21 days)
Outcomes 1 Response rates
2 Time to progression
3 Overall survival
Notes Multicentric no
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1991
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size no
ITT no
Placebo no
Funding both
Participants PS lt= 1
Brain mets no
Age 22 to 79
(median 57)
Number of cycles at least two
19Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1991 (Continued)
Randomised 73 Evaluable 68 a 34 b 34
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Time to treatment failure
3 Median survival
4 Toxicity
Notes Multicentric no
Withdrawals a three b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1998
Methods D 2 x 2 factorial design
AC independent allocation
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 18 to 84
Number of cycles no info
Randomised 271 Evaluable 263 a 68 b 65 c 63 d 67
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
c (CT) DTIC 200m gm2 D1 to 5 tamoxifen 20 mgdaily
d (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek tamoxifen 20 mgdaily
(each 28 days)
Outcomes 1 Response rates
2 Toxicity rates
20Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1998 (Continued)
3 Overall survival
4 Time to treatment failure
Notes Multicentric yes
Withdrawals a one b three c three d one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Gorbonova 2000
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no
Age 23 to 75
Number of cycles no info
Randomised 30 Evaluable 28 a 14 b 14
Interventions a (CT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2
b (ICT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2 IFN-alpha 3 mIU D5 7
9 11 13 15 17 19
(each 28 days)
Outcomes 1 Response rates
Notes Multicentric no
Withdrawals a two b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
21Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Johnston 1998
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age 18 to 70
(median 45)
Number of cycles no info
Randomised 65 Evaluable 65 a 30 b 35
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to 3
Tamoxifen 40 mg daily
b (ICT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to
3 Tamoxifen 40 mg daily IFN-alpha 9 mIU D1 to 3 IL-2 18 mIU D-2 IL-2 9 mIU D-
1 and 0
(each 28 days)
Outcomes 1 Response rates
2 Time to disease progression
3 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Kirkwood 1990
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding pharm
22Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Kirkwood 1990 (Continued)
Participants PS no info
Brain mets no info
Age no info
Number of cycles no info
Randomised 74 Evaluable 68 a 24 b 23 c 21
Interventions a (CT) DTIC 250 mgm2 D1 to 5 (each 21 days)
b (I) IFN-alpha 3 mIU d1 to 5 every week for 3 weeks than 3 mIUm2 3 xweek
c (ICT) DTIC 250 mgm2 D1 to 5 (each 21 days) IFN-alpha 3 mIU d1 to 5 every week
for 3 weeks than 3 mIUm2 3 xweek
Outcomes 1 Response rates
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Middleton 2000
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets no
Age 24 to 71
(median 51)
Number of cycles six
Randomised 105 Evaluable 96 a 46 b 50
Interventions a (CT) DTIC 800 mgm2 D1 cisplatin 25 mgm2 D1 to 3 BCNU 150 mgm2 D1
tamoxifen 20 mgdaily
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 9 mIU 3 xweek
(each 21 days)
Outcomes 1 Response rates
2 One year survival
3 Median survival
23Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Middleton 2000 (Continued)
4 Toxicity
4 Time spent in hospital
Notes Multicentric no
Withdrawals a seven b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Ridolfi 2002
Methods D parallel group
AC independent allocation by telephone
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 25 to 77
Number of cycles six
Randomised 178 Evaluable 176 a 89 b 87
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1
b (ICT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1 IFN-
alpha 3 mIU 3 xweek IL-2 45 mIU D3 to 5 D8 to 12
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
3 Time to progression
4 Toxicity
Notes Multicentric yes
Withdrawals a one b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
24Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Atkins 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding public
Participants PS lt= 1
Brain mets no info
Age 20 to 80 (median 50)
Number of cycles no info
Randomised 416 a 206 b 210
Evaluable 405 a 201 b 204
Interventions a (CT) cisplatin 20mgm2 D1 to 4 vinblastin 12 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1-4 vimblastin 12 mgm2 D1-4 DTIC 800 mgm2 D1
IFN-alpha 5 mIU D1-5 D8 D10 D12 IL-2 9 mIU D1-4
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
Notes Multicentric yes
Withdrawals a five b six
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
15Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Atzpodien 2002
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding both (pharmaceutic and public)
Participants PS lt= 1
Brain mets yes Age 28 to 77 (median 57)
Number of cycles no info
Randomised 124 a 60 b 64
Evaluable 124 a 60 b 64
Interventions a (CT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily
b (ICT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily IFN-alpha 5 mIUm2 D1 week4 and 5
mIUm2 D1 D3 D5 week 5 IL-2 10 mIUm2 D1 D3 D5
(each five weeks)
Outcomes 1 Response rates
2 Overall survival
3 Progression free survival
Notes Multicentric yes
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Bajetta 1994
Methods D parallel group (three groups)
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding pharmaceutic
Participants PS lt= 2
Brain mets no
16Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Bajetta 1994 (Continued)
Age 18 to 70 (median 53)
Number of cycles 8
Randomised 266 a 88 b 86 c 92
Evaluable 242 a 82 b 76 c 84
Interventions a (CT) DTIC 800 mgm2 D1
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU 3xweek
c (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU D1 to 3 6 mIU D4 to 6 9 mIU daily
(each 21 days)
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Overall survival
Notes Multicentric yes
Withdrawals a six b ten c eight
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Danson 2003
Methods D parallel group
AC independent allocation
RS permuted blocks
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets yes Age 16 to 88 (median 58)
Number of cycles six
Randomised 125 a 59 b 62
Evaluable 121 a 55 b 62
Interventions a (CT) temozolomide 200 mgm2 88 h (5 doses)
b (ICT) Temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIU 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
17Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Danson 2003 (Continued)
Notes Multicentric no
Withdrawals a 4 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Del Vecchio 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no Age 19 to 70 (median 50)
Number of cycles no info
Randomised 151 a 75 b 76
Evaluable 145 a 72 b 73
Interventions a (CT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250 mgm2 D1 to
3
b (ICT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250m gm2 D1 to
3 IFN-alpha 5 mIUm2 D1 to 5 IL-2 9 mIUday x 5 daysweek x 2 weeks with a week of
rest
(each 21 days)
Outcomes 1 Response rates
2 Time to Progression
2 Overall Survival
Notes Multicentric yes
Withdrawals a three b three
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
18Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Eton 2002
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding pharm
Participants PS lt= 3
Brain mets yes Age median 49
Number of cycles no info
Randomised 190
Evaluable 183 a 92 b 91
Interventions a (CT) cisplatin 20m gm2 D1 to 4 vimblastin 2 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1 to 4 vinblastin 15 mgm2 D1 to 4 DTIC 800 mgm2
D1 IFN-alpha 5mIUm2 D5 to 9 D17-21 IL-2 9 mIUm2 D5 to 8 D17 to 20
(each 21 days)
Outcomes 1 Response rates
2 Time to progression
3 Overall survival
Notes Multicentric no
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1991
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size no
ITT no
Placebo no
Funding both
Participants PS lt= 1
Brain mets no
Age 22 to 79
(median 57)
Number of cycles at least two
19Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1991 (Continued)
Randomised 73 Evaluable 68 a 34 b 34
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Time to treatment failure
3 Median survival
4 Toxicity
Notes Multicentric no
Withdrawals a three b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1998
Methods D 2 x 2 factorial design
AC independent allocation
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 18 to 84
Number of cycles no info
Randomised 271 Evaluable 263 a 68 b 65 c 63 d 67
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
c (CT) DTIC 200m gm2 D1 to 5 tamoxifen 20 mgdaily
d (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek tamoxifen 20 mgdaily
(each 28 days)
Outcomes 1 Response rates
2 Toxicity rates
20Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1998 (Continued)
3 Overall survival
4 Time to treatment failure
Notes Multicentric yes
Withdrawals a one b three c three d one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Gorbonova 2000
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no
Age 23 to 75
Number of cycles no info
Randomised 30 Evaluable 28 a 14 b 14
Interventions a (CT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2
b (ICT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2 IFN-alpha 3 mIU D5 7
9 11 13 15 17 19
(each 28 days)
Outcomes 1 Response rates
Notes Multicentric no
Withdrawals a two b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
21Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Johnston 1998
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age 18 to 70
(median 45)
Number of cycles no info
Randomised 65 Evaluable 65 a 30 b 35
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to 3
Tamoxifen 40 mg daily
b (ICT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to
3 Tamoxifen 40 mg daily IFN-alpha 9 mIU D1 to 3 IL-2 18 mIU D-2 IL-2 9 mIU D-
1 and 0
(each 28 days)
Outcomes 1 Response rates
2 Time to disease progression
3 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Kirkwood 1990
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding pharm
22Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Kirkwood 1990 (Continued)
Participants PS no info
Brain mets no info
Age no info
Number of cycles no info
Randomised 74 Evaluable 68 a 24 b 23 c 21
Interventions a (CT) DTIC 250 mgm2 D1 to 5 (each 21 days)
b (I) IFN-alpha 3 mIU d1 to 5 every week for 3 weeks than 3 mIUm2 3 xweek
c (ICT) DTIC 250 mgm2 D1 to 5 (each 21 days) IFN-alpha 3 mIU d1 to 5 every week
for 3 weeks than 3 mIUm2 3 xweek
Outcomes 1 Response rates
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Middleton 2000
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets no
Age 24 to 71
(median 51)
Number of cycles six
Randomised 105 Evaluable 96 a 46 b 50
Interventions a (CT) DTIC 800 mgm2 D1 cisplatin 25 mgm2 D1 to 3 BCNU 150 mgm2 D1
tamoxifen 20 mgdaily
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 9 mIU 3 xweek
(each 21 days)
Outcomes 1 Response rates
2 One year survival
3 Median survival
23Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Middleton 2000 (Continued)
4 Toxicity
4 Time spent in hospital
Notes Multicentric no
Withdrawals a seven b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Ridolfi 2002
Methods D parallel group
AC independent allocation by telephone
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 25 to 77
Number of cycles six
Randomised 178 Evaluable 176 a 89 b 87
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1
b (ICT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1 IFN-
alpha 3 mIU 3 xweek IL-2 45 mIU D3 to 5 D8 to 12
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
3 Time to progression
4 Toxicity
Notes Multicentric yes
Withdrawals a one b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
24Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Atzpodien 2002
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding both (pharmaceutic and public)
Participants PS lt= 1
Brain mets yes Age 28 to 77 (median 57)
Number of cycles no info
Randomised 124 a 60 b 64
Evaluable 124 a 60 b 64
Interventions a (CT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily
b (ICT) cisplatin 35 mgm2 D1 to 3 carmustine 150 mgm2 D1 (cycles 1 and 3) DTIC
220 mgm2 D1 to 3 tamoxifen 20 mgm2 daily IFN-alpha 5 mIUm2 D1 week4 and 5
mIUm2 D1 D3 D5 week 5 IL-2 10 mIUm2 D1 D3 D5
(each five weeks)
Outcomes 1 Response rates
2 Overall survival
3 Progression free survival
Notes Multicentric yes
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Bajetta 1994
Methods D parallel group (three groups)
AC independent allocation
RS centrally (unclear)
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding pharmaceutic
Participants PS lt= 2
Brain mets no
16Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Bajetta 1994 (Continued)
Age 18 to 70 (median 53)
Number of cycles 8
Randomised 266 a 88 b 86 c 92
Evaluable 242 a 82 b 76 c 84
Interventions a (CT) DTIC 800 mgm2 D1
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU 3xweek
c (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU D1 to 3 6 mIU D4 to 6 9 mIU daily
(each 21 days)
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Overall survival
Notes Multicentric yes
Withdrawals a six b ten c eight
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Danson 2003
Methods D parallel group
AC independent allocation
RS permuted blocks
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets yes Age 16 to 88 (median 58)
Number of cycles six
Randomised 125 a 59 b 62
Evaluable 121 a 55 b 62
Interventions a (CT) temozolomide 200 mgm2 88 h (5 doses)
b (ICT) Temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIU 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
17Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Danson 2003 (Continued)
Notes Multicentric no
Withdrawals a 4 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Del Vecchio 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no Age 19 to 70 (median 50)
Number of cycles no info
Randomised 151 a 75 b 76
Evaluable 145 a 72 b 73
Interventions a (CT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250 mgm2 D1 to
3
b (ICT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250m gm2 D1 to
3 IFN-alpha 5 mIUm2 D1 to 5 IL-2 9 mIUday x 5 daysweek x 2 weeks with a week of
rest
(each 21 days)
Outcomes 1 Response rates
2 Time to Progression
2 Overall Survival
Notes Multicentric yes
Withdrawals a three b three
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
18Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Eton 2002
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding pharm
Participants PS lt= 3
Brain mets yes Age median 49
Number of cycles no info
Randomised 190
Evaluable 183 a 92 b 91
Interventions a (CT) cisplatin 20m gm2 D1 to 4 vimblastin 2 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1 to 4 vinblastin 15 mgm2 D1 to 4 DTIC 800 mgm2
D1 IFN-alpha 5mIUm2 D5 to 9 D17-21 IL-2 9 mIUm2 D5 to 8 D17 to 20
(each 21 days)
Outcomes 1 Response rates
2 Time to progression
3 Overall survival
Notes Multicentric no
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1991
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size no
ITT no
Placebo no
Funding both
Participants PS lt= 1
Brain mets no
Age 22 to 79
(median 57)
Number of cycles at least two
19Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1991 (Continued)
Randomised 73 Evaluable 68 a 34 b 34
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Time to treatment failure
3 Median survival
4 Toxicity
Notes Multicentric no
Withdrawals a three b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1998
Methods D 2 x 2 factorial design
AC independent allocation
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 18 to 84
Number of cycles no info
Randomised 271 Evaluable 263 a 68 b 65 c 63 d 67
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
c (CT) DTIC 200m gm2 D1 to 5 tamoxifen 20 mgdaily
d (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek tamoxifen 20 mgdaily
(each 28 days)
Outcomes 1 Response rates
2 Toxicity rates
20Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1998 (Continued)
3 Overall survival
4 Time to treatment failure
Notes Multicentric yes
Withdrawals a one b three c three d one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Gorbonova 2000
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no
Age 23 to 75
Number of cycles no info
Randomised 30 Evaluable 28 a 14 b 14
Interventions a (CT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2
b (ICT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2 IFN-alpha 3 mIU D5 7
9 11 13 15 17 19
(each 28 days)
Outcomes 1 Response rates
Notes Multicentric no
Withdrawals a two b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
21Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Johnston 1998
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age 18 to 70
(median 45)
Number of cycles no info
Randomised 65 Evaluable 65 a 30 b 35
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to 3
Tamoxifen 40 mg daily
b (ICT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to
3 Tamoxifen 40 mg daily IFN-alpha 9 mIU D1 to 3 IL-2 18 mIU D-2 IL-2 9 mIU D-
1 and 0
(each 28 days)
Outcomes 1 Response rates
2 Time to disease progression
3 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Kirkwood 1990
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding pharm
22Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Kirkwood 1990 (Continued)
Participants PS no info
Brain mets no info
Age no info
Number of cycles no info
Randomised 74 Evaluable 68 a 24 b 23 c 21
Interventions a (CT) DTIC 250 mgm2 D1 to 5 (each 21 days)
b (I) IFN-alpha 3 mIU d1 to 5 every week for 3 weeks than 3 mIUm2 3 xweek
c (ICT) DTIC 250 mgm2 D1 to 5 (each 21 days) IFN-alpha 3 mIU d1 to 5 every week
for 3 weeks than 3 mIUm2 3 xweek
Outcomes 1 Response rates
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Middleton 2000
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets no
Age 24 to 71
(median 51)
Number of cycles six
Randomised 105 Evaluable 96 a 46 b 50
Interventions a (CT) DTIC 800 mgm2 D1 cisplatin 25 mgm2 D1 to 3 BCNU 150 mgm2 D1
tamoxifen 20 mgdaily
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 9 mIU 3 xweek
(each 21 days)
Outcomes 1 Response rates
2 One year survival
3 Median survival
23Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Middleton 2000 (Continued)
4 Toxicity
4 Time spent in hospital
Notes Multicentric no
Withdrawals a seven b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Ridolfi 2002
Methods D parallel group
AC independent allocation by telephone
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 25 to 77
Number of cycles six
Randomised 178 Evaluable 176 a 89 b 87
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1
b (ICT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1 IFN-
alpha 3 mIU 3 xweek IL-2 45 mIU D3 to 5 D8 to 12
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
3 Time to progression
4 Toxicity
Notes Multicentric yes
Withdrawals a one b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
24Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Bajetta 1994 (Continued)
Age 18 to 70 (median 53)
Number of cycles 8
Randomised 266 a 88 b 86 c 92
Evaluable 242 a 82 b 76 c 84
Interventions a (CT) DTIC 800 mgm2 D1
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU 3xweek
c (ICT) DTIC 800 mgm2 D1 IFN-alpha 3 mIU D1 to 3 6 mIU D4 to 6 9 mIU daily
(each 21 days)
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Overall survival
Notes Multicentric yes
Withdrawals a six b ten c eight
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Danson 2003
Methods D parallel group
AC independent allocation
RS permuted blocks
B participant no clinician no outcome assessor no
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets yes Age 16 to 88 (median 58)
Number of cycles six
Randomised 125 a 59 b 62
Evaluable 121 a 55 b 62
Interventions a (CT) temozolomide 200 mgm2 88 h (5 doses)
b (ICT) Temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIU 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
17Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Danson 2003 (Continued)
Notes Multicentric no
Withdrawals a 4 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Del Vecchio 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no Age 19 to 70 (median 50)
Number of cycles no info
Randomised 151 a 75 b 76
Evaluable 145 a 72 b 73
Interventions a (CT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250 mgm2 D1 to
3
b (ICT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250m gm2 D1 to
3 IFN-alpha 5 mIUm2 D1 to 5 IL-2 9 mIUday x 5 daysweek x 2 weeks with a week of
rest
(each 21 days)
Outcomes 1 Response rates
2 Time to Progression
2 Overall Survival
Notes Multicentric yes
Withdrawals a three b three
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
18Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Eton 2002
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding pharm
Participants PS lt= 3
Brain mets yes Age median 49
Number of cycles no info
Randomised 190
Evaluable 183 a 92 b 91
Interventions a (CT) cisplatin 20m gm2 D1 to 4 vimblastin 2 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1 to 4 vinblastin 15 mgm2 D1 to 4 DTIC 800 mgm2
D1 IFN-alpha 5mIUm2 D5 to 9 D17-21 IL-2 9 mIUm2 D5 to 8 D17 to 20
(each 21 days)
Outcomes 1 Response rates
2 Time to progression
3 Overall survival
Notes Multicentric no
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1991
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size no
ITT no
Placebo no
Funding both
Participants PS lt= 1
Brain mets no
Age 22 to 79
(median 57)
Number of cycles at least two
19Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1991 (Continued)
Randomised 73 Evaluable 68 a 34 b 34
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Time to treatment failure
3 Median survival
4 Toxicity
Notes Multicentric no
Withdrawals a three b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1998
Methods D 2 x 2 factorial design
AC independent allocation
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 18 to 84
Number of cycles no info
Randomised 271 Evaluable 263 a 68 b 65 c 63 d 67
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
c (CT) DTIC 200m gm2 D1 to 5 tamoxifen 20 mgdaily
d (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek tamoxifen 20 mgdaily
(each 28 days)
Outcomes 1 Response rates
2 Toxicity rates
20Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1998 (Continued)
3 Overall survival
4 Time to treatment failure
Notes Multicentric yes
Withdrawals a one b three c three d one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Gorbonova 2000
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no
Age 23 to 75
Number of cycles no info
Randomised 30 Evaluable 28 a 14 b 14
Interventions a (CT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2
b (ICT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2 IFN-alpha 3 mIU D5 7
9 11 13 15 17 19
(each 28 days)
Outcomes 1 Response rates
Notes Multicentric no
Withdrawals a two b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
21Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Johnston 1998
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age 18 to 70
(median 45)
Number of cycles no info
Randomised 65 Evaluable 65 a 30 b 35
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to 3
Tamoxifen 40 mg daily
b (ICT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to
3 Tamoxifen 40 mg daily IFN-alpha 9 mIU D1 to 3 IL-2 18 mIU D-2 IL-2 9 mIU D-
1 and 0
(each 28 days)
Outcomes 1 Response rates
2 Time to disease progression
3 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Kirkwood 1990
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding pharm
22Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Kirkwood 1990 (Continued)
Participants PS no info
Brain mets no info
Age no info
Number of cycles no info
Randomised 74 Evaluable 68 a 24 b 23 c 21
Interventions a (CT) DTIC 250 mgm2 D1 to 5 (each 21 days)
b (I) IFN-alpha 3 mIU d1 to 5 every week for 3 weeks than 3 mIUm2 3 xweek
c (ICT) DTIC 250 mgm2 D1 to 5 (each 21 days) IFN-alpha 3 mIU d1 to 5 every week
for 3 weeks than 3 mIUm2 3 xweek
Outcomes 1 Response rates
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Middleton 2000
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets no
Age 24 to 71
(median 51)
Number of cycles six
Randomised 105 Evaluable 96 a 46 b 50
Interventions a (CT) DTIC 800 mgm2 D1 cisplatin 25 mgm2 D1 to 3 BCNU 150 mgm2 D1
tamoxifen 20 mgdaily
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 9 mIU 3 xweek
(each 21 days)
Outcomes 1 Response rates
2 One year survival
3 Median survival
23Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Middleton 2000 (Continued)
4 Toxicity
4 Time spent in hospital
Notes Multicentric no
Withdrawals a seven b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Ridolfi 2002
Methods D parallel group
AC independent allocation by telephone
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 25 to 77
Number of cycles six
Randomised 178 Evaluable 176 a 89 b 87
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1
b (ICT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1 IFN-
alpha 3 mIU 3 xweek IL-2 45 mIU D3 to 5 D8 to 12
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
3 Time to progression
4 Toxicity
Notes Multicentric yes
Withdrawals a one b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
24Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Danson 2003 (Continued)
Notes Multicentric no
Withdrawals a 4 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Del Vecchio 2003
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no Age 19 to 70 (median 50)
Number of cycles no info
Randomised 151 a 75 b 76
Evaluable 145 a 72 b 73
Interventions a (CT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250 mgm2 D1 to
3
b (ICT) cisplatin 30 mgm2 D1 to 3 vindesine 25 mgm2 D1 DTIC 250m gm2 D1 to
3 IFN-alpha 5 mIUm2 D1 to 5 IL-2 9 mIUday x 5 daysweek x 2 weeks with a week of
rest
(each 21 days)
Outcomes 1 Response rates
2 Time to Progression
2 Overall Survival
Notes Multicentric yes
Withdrawals a three b three
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
18Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Eton 2002
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding pharm
Participants PS lt= 3
Brain mets yes Age median 49
Number of cycles no info
Randomised 190
Evaluable 183 a 92 b 91
Interventions a (CT) cisplatin 20m gm2 D1 to 4 vimblastin 2 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1 to 4 vinblastin 15 mgm2 D1 to 4 DTIC 800 mgm2
D1 IFN-alpha 5mIUm2 D5 to 9 D17-21 IL-2 9 mIUm2 D5 to 8 D17 to 20
(each 21 days)
Outcomes 1 Response rates
2 Time to progression
3 Overall survival
Notes Multicentric no
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1991
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size no
ITT no
Placebo no
Funding both
Participants PS lt= 1
Brain mets no
Age 22 to 79
(median 57)
Number of cycles at least two
19Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1991 (Continued)
Randomised 73 Evaluable 68 a 34 b 34
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Time to treatment failure
3 Median survival
4 Toxicity
Notes Multicentric no
Withdrawals a three b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1998
Methods D 2 x 2 factorial design
AC independent allocation
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 18 to 84
Number of cycles no info
Randomised 271 Evaluable 263 a 68 b 65 c 63 d 67
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
c (CT) DTIC 200m gm2 D1 to 5 tamoxifen 20 mgdaily
d (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek tamoxifen 20 mgdaily
(each 28 days)
Outcomes 1 Response rates
2 Toxicity rates
20Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1998 (Continued)
3 Overall survival
4 Time to treatment failure
Notes Multicentric yes
Withdrawals a one b three c three d one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Gorbonova 2000
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no
Age 23 to 75
Number of cycles no info
Randomised 30 Evaluable 28 a 14 b 14
Interventions a (CT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2
b (ICT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2 IFN-alpha 3 mIU D5 7
9 11 13 15 17 19
(each 28 days)
Outcomes 1 Response rates
Notes Multicentric no
Withdrawals a two b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
21Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Johnston 1998
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age 18 to 70
(median 45)
Number of cycles no info
Randomised 65 Evaluable 65 a 30 b 35
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to 3
Tamoxifen 40 mg daily
b (ICT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to
3 Tamoxifen 40 mg daily IFN-alpha 9 mIU D1 to 3 IL-2 18 mIU D-2 IL-2 9 mIU D-
1 and 0
(each 28 days)
Outcomes 1 Response rates
2 Time to disease progression
3 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Kirkwood 1990
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding pharm
22Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Kirkwood 1990 (Continued)
Participants PS no info
Brain mets no info
Age no info
Number of cycles no info
Randomised 74 Evaluable 68 a 24 b 23 c 21
Interventions a (CT) DTIC 250 mgm2 D1 to 5 (each 21 days)
b (I) IFN-alpha 3 mIU d1 to 5 every week for 3 weeks than 3 mIUm2 3 xweek
c (ICT) DTIC 250 mgm2 D1 to 5 (each 21 days) IFN-alpha 3 mIU d1 to 5 every week
for 3 weeks than 3 mIUm2 3 xweek
Outcomes 1 Response rates
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Middleton 2000
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets no
Age 24 to 71
(median 51)
Number of cycles six
Randomised 105 Evaluable 96 a 46 b 50
Interventions a (CT) DTIC 800 mgm2 D1 cisplatin 25 mgm2 D1 to 3 BCNU 150 mgm2 D1
tamoxifen 20 mgdaily
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 9 mIU 3 xweek
(each 21 days)
Outcomes 1 Response rates
2 One year survival
3 Median survival
23Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Middleton 2000 (Continued)
4 Toxicity
4 Time spent in hospital
Notes Multicentric no
Withdrawals a seven b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Ridolfi 2002
Methods D parallel group
AC independent allocation by telephone
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 25 to 77
Number of cycles six
Randomised 178 Evaluable 176 a 89 b 87
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1
b (ICT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1 IFN-
alpha 3 mIU 3 xweek IL-2 45 mIU D3 to 5 D8 to 12
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
3 Time to progression
4 Toxicity
Notes Multicentric yes
Withdrawals a one b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
24Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Eton 2002
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size yes
ITT no
Placebo no
Funding pharm
Participants PS lt= 3
Brain mets yes Age median 49
Number of cycles no info
Randomised 190
Evaluable 183 a 92 b 91
Interventions a (CT) cisplatin 20m gm2 D1 to 4 vimblastin 2 mgm2 D1 to 4 DTIC 800 mgm2 D1
b (ICT) cisplatin 20 mgm2 D1 to 4 vinblastin 15 mgm2 D1 to 4 DTIC 800 mgm2
D1 IFN-alpha 5mIUm2 D5 to 9 D17-21 IL-2 9 mIUm2 D5 to 8 D17 to 20
(each 21 days)
Outcomes 1 Response rates
2 Time to progression
3 Overall survival
Notes Multicentric no
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1991
Methods D parallel group
AC unclear
RS unclear
B participant no clinician no outcome assessor no
Size no
ITT no
Placebo no
Funding both
Participants PS lt= 1
Brain mets no
Age 22 to 79
(median 57)
Number of cycles at least two
19Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1991 (Continued)
Randomised 73 Evaluable 68 a 34 b 34
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Time to treatment failure
3 Median survival
4 Toxicity
Notes Multicentric no
Withdrawals a three b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1998
Methods D 2 x 2 factorial design
AC independent allocation
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 18 to 84
Number of cycles no info
Randomised 271 Evaluable 263 a 68 b 65 c 63 d 67
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
c (CT) DTIC 200m gm2 D1 to 5 tamoxifen 20 mgdaily
d (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek tamoxifen 20 mgdaily
(each 28 days)
Outcomes 1 Response rates
2 Toxicity rates
20Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1998 (Continued)
3 Overall survival
4 Time to treatment failure
Notes Multicentric yes
Withdrawals a one b three c three d one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Gorbonova 2000
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no
Age 23 to 75
Number of cycles no info
Randomised 30 Evaluable 28 a 14 b 14
Interventions a (CT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2
b (ICT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2 IFN-alpha 3 mIU D5 7
9 11 13 15 17 19
(each 28 days)
Outcomes 1 Response rates
Notes Multicentric no
Withdrawals a two b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
21Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Johnston 1998
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age 18 to 70
(median 45)
Number of cycles no info
Randomised 65 Evaluable 65 a 30 b 35
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to 3
Tamoxifen 40 mg daily
b (ICT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to
3 Tamoxifen 40 mg daily IFN-alpha 9 mIU D1 to 3 IL-2 18 mIU D-2 IL-2 9 mIU D-
1 and 0
(each 28 days)
Outcomes 1 Response rates
2 Time to disease progression
3 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Kirkwood 1990
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding pharm
22Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Kirkwood 1990 (Continued)
Participants PS no info
Brain mets no info
Age no info
Number of cycles no info
Randomised 74 Evaluable 68 a 24 b 23 c 21
Interventions a (CT) DTIC 250 mgm2 D1 to 5 (each 21 days)
b (I) IFN-alpha 3 mIU d1 to 5 every week for 3 weeks than 3 mIUm2 3 xweek
c (ICT) DTIC 250 mgm2 D1 to 5 (each 21 days) IFN-alpha 3 mIU d1 to 5 every week
for 3 weeks than 3 mIUm2 3 xweek
Outcomes 1 Response rates
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Middleton 2000
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets no
Age 24 to 71
(median 51)
Number of cycles six
Randomised 105 Evaluable 96 a 46 b 50
Interventions a (CT) DTIC 800 mgm2 D1 cisplatin 25 mgm2 D1 to 3 BCNU 150 mgm2 D1
tamoxifen 20 mgdaily
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 9 mIU 3 xweek
(each 21 days)
Outcomes 1 Response rates
2 One year survival
3 Median survival
23Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Middleton 2000 (Continued)
4 Toxicity
4 Time spent in hospital
Notes Multicentric no
Withdrawals a seven b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Ridolfi 2002
Methods D parallel group
AC independent allocation by telephone
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 25 to 77
Number of cycles six
Randomised 178 Evaluable 176 a 89 b 87
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1
b (ICT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1 IFN-
alpha 3 mIU 3 xweek IL-2 45 mIU D3 to 5 D8 to 12
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
3 Time to progression
4 Toxicity
Notes Multicentric yes
Withdrawals a one b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
24Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1991 (Continued)
Randomised 73 Evaluable 68 a 34 b 34
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
(each 28 days)
Outcomes 1 Response rates
2 Time to treatment failure
3 Median survival
4 Toxicity
Notes Multicentric no
Withdrawals a three b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Falkson 1998
Methods D 2 x 2 factorial design
AC independent allocation
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 18 to 84
Number of cycles no info
Randomised 271 Evaluable 263 a 68 b 65 c 63 d 67
Interventions a (CT) DTIC 200 mgm2 D1 to 5
b (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek
c (CT) DTIC 200m gm2 D1 to 5 tamoxifen 20 mgdaily
d (ICT) DTIC 200 mgm2 D1 to 5 IFN-alpha 15 mIUm2 5 daysweek for 3 weeks
IFN-alpha 10 mIUm2 3 xweek tamoxifen 20 mgdaily
(each 28 days)
Outcomes 1 Response rates
2 Toxicity rates
20Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1998 (Continued)
3 Overall survival
4 Time to treatment failure
Notes Multicentric yes
Withdrawals a one b three c three d one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Gorbonova 2000
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no
Age 23 to 75
Number of cycles no info
Randomised 30 Evaluable 28 a 14 b 14
Interventions a (CT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2
b (ICT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2 IFN-alpha 3 mIU D5 7
9 11 13 15 17 19
(each 28 days)
Outcomes 1 Response rates
Notes Multicentric no
Withdrawals a two b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
21Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Johnston 1998
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age 18 to 70
(median 45)
Number of cycles no info
Randomised 65 Evaluable 65 a 30 b 35
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to 3
Tamoxifen 40 mg daily
b (ICT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to
3 Tamoxifen 40 mg daily IFN-alpha 9 mIU D1 to 3 IL-2 18 mIU D-2 IL-2 9 mIU D-
1 and 0
(each 28 days)
Outcomes 1 Response rates
2 Time to disease progression
3 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Kirkwood 1990
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding pharm
22Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Kirkwood 1990 (Continued)
Participants PS no info
Brain mets no info
Age no info
Number of cycles no info
Randomised 74 Evaluable 68 a 24 b 23 c 21
Interventions a (CT) DTIC 250 mgm2 D1 to 5 (each 21 days)
b (I) IFN-alpha 3 mIU d1 to 5 every week for 3 weeks than 3 mIUm2 3 xweek
c (ICT) DTIC 250 mgm2 D1 to 5 (each 21 days) IFN-alpha 3 mIU d1 to 5 every week
for 3 weeks than 3 mIUm2 3 xweek
Outcomes 1 Response rates
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Middleton 2000
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets no
Age 24 to 71
(median 51)
Number of cycles six
Randomised 105 Evaluable 96 a 46 b 50
Interventions a (CT) DTIC 800 mgm2 D1 cisplatin 25 mgm2 D1 to 3 BCNU 150 mgm2 D1
tamoxifen 20 mgdaily
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 9 mIU 3 xweek
(each 21 days)
Outcomes 1 Response rates
2 One year survival
3 Median survival
23Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Middleton 2000 (Continued)
4 Toxicity
4 Time spent in hospital
Notes Multicentric no
Withdrawals a seven b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Ridolfi 2002
Methods D parallel group
AC independent allocation by telephone
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 25 to 77
Number of cycles six
Randomised 178 Evaluable 176 a 89 b 87
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1
b (ICT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1 IFN-
alpha 3 mIU 3 xweek IL-2 45 mIU D3 to 5 D8 to 12
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
3 Time to progression
4 Toxicity
Notes Multicentric yes
Withdrawals a one b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
24Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Falkson 1998 (Continued)
3 Overall survival
4 Time to treatment failure
Notes Multicentric yes
Withdrawals a one b three c three d one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Gorbonova 2000
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no
Age 23 to 75
Number of cycles no info
Randomised 30 Evaluable 28 a 14 b 14
Interventions a (CT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2
b (ICT) cisplatin 100 mgm2 D3 aranoza 600 mgm2 D1 to 2 IFN-alpha 3 mIU D5 7
9 11 13 15 17 19
(each 28 days)
Outcomes 1 Response rates
Notes Multicentric no
Withdrawals a two b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
21Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Johnston 1998
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age 18 to 70
(median 45)
Number of cycles no info
Randomised 65 Evaluable 65 a 30 b 35
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to 3
Tamoxifen 40 mg daily
b (ICT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to
3 Tamoxifen 40 mg daily IFN-alpha 9 mIU D1 to 3 IL-2 18 mIU D-2 IL-2 9 mIU D-
1 and 0
(each 28 days)
Outcomes 1 Response rates
2 Time to disease progression
3 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Kirkwood 1990
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding pharm
22Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Kirkwood 1990 (Continued)
Participants PS no info
Brain mets no info
Age no info
Number of cycles no info
Randomised 74 Evaluable 68 a 24 b 23 c 21
Interventions a (CT) DTIC 250 mgm2 D1 to 5 (each 21 days)
b (I) IFN-alpha 3 mIU d1 to 5 every week for 3 weeks than 3 mIUm2 3 xweek
c (ICT) DTIC 250 mgm2 D1 to 5 (each 21 days) IFN-alpha 3 mIU d1 to 5 every week
for 3 weeks than 3 mIUm2 3 xweek
Outcomes 1 Response rates
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Middleton 2000
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets no
Age 24 to 71
(median 51)
Number of cycles six
Randomised 105 Evaluable 96 a 46 b 50
Interventions a (CT) DTIC 800 mgm2 D1 cisplatin 25 mgm2 D1 to 3 BCNU 150 mgm2 D1
tamoxifen 20 mgdaily
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 9 mIU 3 xweek
(each 21 days)
Outcomes 1 Response rates
2 One year survival
3 Median survival
23Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Middleton 2000 (Continued)
4 Toxicity
4 Time spent in hospital
Notes Multicentric no
Withdrawals a seven b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Ridolfi 2002
Methods D parallel group
AC independent allocation by telephone
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 25 to 77
Number of cycles six
Randomised 178 Evaluable 176 a 89 b 87
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1
b (ICT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1 IFN-
alpha 3 mIU 3 xweek IL-2 45 mIU D3 to 5 D8 to 12
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
3 Time to progression
4 Toxicity
Notes Multicentric yes
Withdrawals a one b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
24Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Johnston 1998
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age 18 to 70
(median 45)
Number of cycles no info
Randomised 65 Evaluable 65 a 30 b 35
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to 3
Tamoxifen 40 mg daily
b (ICT) BCNU 100 mgm2 D1 cisplatin 25 mgm2 D1 to 3 DTIC 220 mgm2 D1 to
3 Tamoxifen 40 mg daily IFN-alpha 9 mIU D1 to 3 IL-2 18 mIU D-2 IL-2 9 mIU D-
1 and 0
(each 28 days)
Outcomes 1 Response rates
2 Time to disease progression
3 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Kirkwood 1990
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding pharm
22Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Kirkwood 1990 (Continued)
Participants PS no info
Brain mets no info
Age no info
Number of cycles no info
Randomised 74 Evaluable 68 a 24 b 23 c 21
Interventions a (CT) DTIC 250 mgm2 D1 to 5 (each 21 days)
b (I) IFN-alpha 3 mIU d1 to 5 every week for 3 weeks than 3 mIUm2 3 xweek
c (ICT) DTIC 250 mgm2 D1 to 5 (each 21 days) IFN-alpha 3 mIU d1 to 5 every week
for 3 weeks than 3 mIUm2 3 xweek
Outcomes 1 Response rates
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Middleton 2000
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets no
Age 24 to 71
(median 51)
Number of cycles six
Randomised 105 Evaluable 96 a 46 b 50
Interventions a (CT) DTIC 800 mgm2 D1 cisplatin 25 mgm2 D1 to 3 BCNU 150 mgm2 D1
tamoxifen 20 mgdaily
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 9 mIU 3 xweek
(each 21 days)
Outcomes 1 Response rates
2 One year survival
3 Median survival
23Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Middleton 2000 (Continued)
4 Toxicity
4 Time spent in hospital
Notes Multicentric no
Withdrawals a seven b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Ridolfi 2002
Methods D parallel group
AC independent allocation by telephone
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 25 to 77
Number of cycles six
Randomised 178 Evaluable 176 a 89 b 87
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1
b (ICT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1 IFN-
alpha 3 mIU 3 xweek IL-2 45 mIU D3 to 5 D8 to 12
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
3 Time to progression
4 Toxicity
Notes Multicentric yes
Withdrawals a one b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
24Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Kirkwood 1990 (Continued)
Participants PS no info
Brain mets no info
Age no info
Number of cycles no info
Randomised 74 Evaluable 68 a 24 b 23 c 21
Interventions a (CT) DTIC 250 mgm2 D1 to 5 (each 21 days)
b (I) IFN-alpha 3 mIU d1 to 5 every week for 3 weeks than 3 mIUm2 3 xweek
c (ICT) DTIC 250 mgm2 D1 to 5 (each 21 days) IFN-alpha 3 mIU d1 to 5 every week
for 3 weeks than 3 mIUm2 3 xweek
Outcomes 1 Response rates
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Middleton 2000
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 3
Brain mets no
Age 24 to 71
(median 51)
Number of cycles six
Randomised 105 Evaluable 96 a 46 b 50
Interventions a (CT) DTIC 800 mgm2 D1 cisplatin 25 mgm2 D1 to 3 BCNU 150 mgm2 D1
tamoxifen 20 mgdaily
b (ICT) DTIC 800 mgm2 D1 IFN-alpha 9 mIU 3 xweek
(each 21 days)
Outcomes 1 Response rates
2 One year survival
3 Median survival
23Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Middleton 2000 (Continued)
4 Toxicity
4 Time spent in hospital
Notes Multicentric no
Withdrawals a seven b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Ridolfi 2002
Methods D parallel group
AC independent allocation by telephone
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 25 to 77
Number of cycles six
Randomised 178 Evaluable 176 a 89 b 87
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1
b (ICT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1 IFN-
alpha 3 mIU 3 xweek IL-2 45 mIU D3 to 5 D8 to 12
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
3 Time to progression
4 Toxicity
Notes Multicentric yes
Withdrawals a one b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
24Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Middleton 2000 (Continued)
4 Toxicity
4 Time spent in hospital
Notes Multicentric no
Withdrawals a seven b two
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Ridolfi 2002
Methods D parallel group
AC independent allocation by telephone
RS permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding public
Participants PS lt= 2
Brain mets no
Age 25 to 77
Number of cycles six
Randomised 178 Evaluable 176 a 89 b 87
Interventions a (CT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1
b (ICT) BCNU 100 mgm2 D1 cisplatin 75 mgm2 D1 DTIC 800 mgm2 D1 IFN-
alpha 3 mIU 3 xweek IL-2 45 mIU D3 to 5 D8 to 12
(each 21 days)
Outcomes 1 Overall survival
2 Response rates
3 Time to progression
4 Toxicity
Notes Multicentric yes
Withdrawals a one b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
24Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Rosenberg 1999
Methods D parallel group
AC independent allocation
RS centrally (unclear)
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding unknown
Participants PS lt= 1
Brain mets no
Age no info
Number of cycles four
Randomised 102 Evaluable 102 a 52 b 50
Interventions a(CT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29
b (ICT) cisplatin 25 mgm2 D2 to 4 D23 to 35 DTIC 220 mgm2 D2 to 4 D23 to 25
tamoxifen 40 mg D1 10 mg D2 to 29 IFN-alpha 6 mIUm2 D5 to 8 D 26 to 29 IL-2
720000 IUkg 88 hours to tolerance D5 to 8 D 26 to 29
(each 58 days)
Outcomes 1 Response rate
2 Overall survival
Notes Multicentric no
Withdrawals a 0 b 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Spieth 2003
Methods D parallel group
AC unclear
RS unclear
B participant N clinician N outcome assessor N
Size no
ITT no
Placebo no
Funding unknown
Participants PS no info
Brain mets no info
Age no info
25Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Spieth 2003 (Continued)
Number of cycles no info
Randomised 294 Evaluable 280 a 138 b 142
Interventions a (CT) temozolomide 200 mgm2 D1 to 5
b (ICT) temozolomide 200 mgm2 D1 to 5 IFN-alpha 5 mIUm2 daily for week 1
thereafter on D1 3 5
(each 28 days)
Outcomes 1 Response rates
2 Overall survival
3 Toxicity
Notes Multicentric yes
Withdrawals not described
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Thomson 1993
Methods D parallel group
AC independent allocation
RS centrally dynamic technique
B participant N clinician N outcome assessor N
Size yes
ITT no
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age 18 to 75
Number of cycles no info
Randomised 176 Evaluable 170 a 83 b 87
Interventions a (CT) DTIC 800 mgm2 D1
(each 21 days)
b (ICT) DTIC 800 mgm2 D1 (each 21 days) IFN-alpha 3 mIU D1 to 3 9 mIU D4 to
67 thereafter 9 mIU 3 xweek
Outcomes 1 Response rates
2 Response duration
3 Time to progression
4 Quality of life
5 Toxicity
26Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Thomson 1993 (Continued)
6 Overall survival
Notes Multicentric yes
Withdrawals a five b one
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Vorobiof 1994
Methods D parallel group
AC closed envelope
RS closed envelope random number technique
B participant N clinician N outcome assessor N
Size no
ITT yes
Placebo no
Funding unknown
Participants PS lt= 2
Brain mets no
Age no info
Number of cycles no info
Randomised 60 Evaluable 60 a 20 b 20 c 20
Interventions a (CT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days
b (I) IFN-alpha 6 mIUm2 3 xweek
c (ICT) Vindesine 3 mgm2 weekly for 3 weeks followed by Vindesine 4 mgm2 each 21
days IFN-alpha 6 mIUm2 3 xweek
Outcomes 1 Response rates
2 Overall Survival
Notes Multicentric no
Withdrawals a 0 b 0 c 0
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
27Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Young 2001
Methods D parallel group
AC independent allocation by telephone
RS centrally random permuted blocks
B participant N clinician N outcome assessor N
Size yes
ITT yes
Placebo no
Funding both
Participants PS lt= 2
Brain mets no
Age 31 to 80 (median 57)
Number of cycles 6
Randomised 61 Evaluable 59 a 31 b 28
Interventions a (CT) DTIC 950 mgm2 D1 (each 28 days)
b (ICT) DTIC 950 mgm2 D1 (each 28 days) IFN-alpha 45 mIU 3 xweek
Outcomes 1 Median survival
2 Response rates
3 Toxicity
4 Quality of life
Notes Multicentric yes
Withdrawals a 0 b 2
Risk of bias
Bias Authorsrsquo judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
D = design AC = allocation concealment RS = randomization system B = blindness Size = population size calculated ITT = intention
to treat analysis Funding = source of funding PS = Eastern Cooperative Oncology Group definition of performance status mets =
metastasis CT = chemotherapy ICT - chemoimmunotherapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Bajetta 2001 Immunotherapy on both arms
Legha 1996 Not randomized
28Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Richtig 2004 Immunotherapy on both arms
Sertoli 1999 Immunotherapy on three arms
Sparano 1993 Comparison of iFN with IL-2 immunotherapy on both arms
Vuoristo 2005 Immunotherapy on both arms
29Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall Survival 8 1355 Peto Odds Ratio (95 CI) 089 [072 111]
11 ICT with interferon-alpha 4 526 Peto Odds Ratio (95 CI) 074 [049 112]
12 ICT with interferon-alpha
plus interleukin-2
4 829 Peto Odds Ratio (95 CI) 096 [074 124]
2 1 year survival 13 1803 Risk Ratio (M-H Random 95 CI) 106 [091 124]
21 ICT with interferon-alpha 7 1008 Risk Ratio (M-H Random 95 CI) 118 [093 150]
22 ICT with interferon-alpha
plus interleukin-2
6 795 Risk Ratio (M-H Random 95 CI) 097 [079 120]
3 2 year survival 11 1677 Risk Ratio (M-H Random 95 CI) 108 [086 136]
31 ICT with interferon-alpha 6 947 Risk Ratio (M-H Random 95 CI) 119 [084 167]
32 ICT with interferon-alpha
plus interleukin-2
5 730 Risk Ratio (M-H Random 95 CI) 097 [065 143]
4 5 year survival 2 307 Risk Ratio (M-H Random 95 CI) 234 [097 565]
Comparison 2 Response rates
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Overall response rate 17 2434 Risk Ratio (M-H Random 95 CI) 140 [120 163]
11 ICT with interferon-alpha 10 1331 Risk Ratio (M-H Random 95 CI) 132 [102 171]
12 ICT with interferon-alpha
plus interleukin-2
7 1103 Risk Ratio (M-H Random 95 CI) 146 [119 179]
2 Complete response rate 15 2109 Risk Ratio (M-H Random 95 CI) 158 [106 236]
3 Partial response rate 15 2110 Risk Ratio (M-H Random 95 CI) 131 [107 159]
Comparison 3 Progression free survival
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Progression free survival 3 424 Peto Odds Ratio (95 CI) 076 [057 102]
30Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Comparison 4 Toxicity
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 Hematological toxicity grade
gt=3
11 Risk Ratio (M-H Random 95 CI) Subtotals only
11 ICT with interferon-alpha 6 842 Risk Ratio (M-H Random 95 CI) 153 [042 552]
12 ICT with interferon-alpha
plus interleukin-2
5 892 Risk Ratio (M-H Random 95 CI) 186 [082 423]
2 Non-hematological toxicity
grade gt=3
6 858 Risk Ratio (M-H Random 95 CI) 274 [206 364]
21 ICT with interferon-alpha 2 332 Risk Ratio (M-H Random 95 CI) 289 [146 573]
22 ICT with interferon-alpha
plus interleukin-2
4 526 Risk Ratio (M-H Random 95 CI) 263 [178 390]
3 Treatment related mortality 11 1883 Risk Ratio (M-H Random 95 CI) 078 [026 232]
Analysis 11 Comparison 1 Survival Outcome 1 Overall Survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 1 Overall Survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
1 ICT with interferon-alpha
Danson 2003 1062 859 49 082 [ 030 222 ]
Falkson 1991 1232 932 45 066 [ 023 185 ]
Spieth 2003 42142 34138 175 078 [ 046 132 ]
Young 2001 330 131 12 034 [ 005 253 ]
Subtotal (95 CI) 266 260 280 074 [ 049 112 ]
Heterogeneity Chi2 = 071 df = 3 (P = 087) I2 =00
Test for overall effect Z = 143 (P = 015)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 46204 54201 237 126 [ 080 198 ]
Eton 2002 1391 692 54 044 [ 017 113 ]
Johnston 1998 735 730 35 122 [ 037 395 ]
005 02 1 5 20
Favours ICT Favours CT (control)
(Continued )
31Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Ridolfi 2002 2987 2289 394 089 [ 063 126 ]
Subtotal (95 CI) 417 412 720 096 [ 074 124 ]
Heterogeneity Chi2 = 441 df = 3 (P = 022) I2 =32
Test for overall effect Z = 031 (P = 076)
Total (95 CI) 1000 089 [ 072 111 ]
Heterogeneity Chi2 = 622 df = 7 (P = 051) I2 =00
Test for overall effect Z = 102 (P = 031)
Test for subgroup differences Chi2 = 111 df = 1 (P = 029) I2 =10
005 02 1 5 20
Favours ICT Favours CT (control)
Analysis 12 Comparison 1 Survival Outcome 2 1 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 2 1 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 58160 2482 92 124 [ 084 184 ]
Danson 2003 1662 1055 40 142 [ 070 286 ]
Falkson 1991 1830 931 49 207 [ 111 385 ]
Falkson 1998 53131 48132 121 111 [ 082 151 ]
Middleton 2000 1550 1046 41 138 [ 069 276 ]
Thomson 1993 1987 2783 67 067 [ 041 111 ]
Young 2001 728 731 26 111 [ 044 276 ]
Subtotal (95 CI) 548 460 437 118 [ 093 150 ]
05 07 1 15 2
Favours CT (control) Favours ICT
(Continued )
32Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 186 (ICT) 135 (CT)
Heterogeneity Tau2 = 003 Chi2 = 857 df = 6 (P = 020) I2 =30
Test for overall effect Z = 135 (P = 018)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 3264 3160 107 097 [ 068 137 ]
Del Vecchio 2003 3673 3672 113 099 [ 071 137 ]
Eton 2002 4691 3792 115 126 [ 091 173 ]
Johnston 1998 1035 1730 51 050 [ 027 093 ]
Ridolfi 2002 2987 2489 78 124 [ 079 194 ]
Rosenberg 1999 2450 3052 99 083 [ 057 121 ]
Subtotal (95 CI) 400 395 563 097 [ 079 120 ]
Total events 177 (ICT) 175 (CT)
Heterogeneity Tau2 = 003 Chi2 = 860 df = 5 (P = 013) I2 =42
Test for overall effect Z = 025 (P = 080)
Total (95 CI) 948 855 1000 106 [ 091 124 ]
Total events 363 (ICT) 310 (CT)
Heterogeneity Tau2 = 003 Chi2 = 1883 df = 12 (P = 009) I2 =36
Test for overall effect Z = 071 (P = 048)
Test for subgroup differences Chi2 = 141 df = 1 (P = 024) I2 =29
05 07 1 15 2
Favours CT (control) Favours ICT
33Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 13 Comparison 1 Survival Outcome 3 2 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 3 2 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 18160 882 83 115 [ 052 254 ]
Danson 2003 662 455 35 133 [ 040 447 ]
Falkson 1998 21131 24132 182 088 [ 052 150 ]
Middleton 2000 1150 446 45 253 [ 087 739 ]
Thomson 1993 1487 983 85 148 [ 068 324 ]
Young 2001 228 231 15 111 [ 017 734 ]
Subtotal (95 CI) 518 429 446 119 [ 084 167 ]
Total events 72 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 348 df = 5 (P = 063) I2 =00
Test for overall effect Z = 098 (P = 033)
2 ICT with interferon-alpha plus interleukin-2
Atzpodien 2002 1764 1560 145 106 [ 058 193 ]
Del Vecchio 2003 1973 1472 140 134 [ 073 246 ]
Eton 2002 2291 1992 177 117 [ 068 201 ]
Ridolfi 2002 187 389 10 034 [ 004 322 ]
Rosenberg 1999 750 1652 81 046 [ 020 101 ]
Subtotal (95 CI) 365 365 554 097 [ 065 143 ]
Total events 66 (ICT) 67 (CT)
Heterogeneity Tau2 = 006 Chi2 = 589 df = 4 (P = 021) I2 =32
Test for overall effect Z = 017 (P = 086)
Total (95 CI) 883 794 1000 108 [ 086 136 ]
Total events 138 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 983 df = 10 (P = 046) I2 =00
Test for overall effect Z = 067 (P = 050)
Test for subgroup differences Chi2 = 060 df = 1 (P = 044) I2 =00
005 02 1 5 20
Favours CT (control) Favours ICT
34Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 14 Comparison 1 Survival Outcome 4 5 year survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 1 Survival
Outcome 4 5 year survival
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atzpodien 2002 264 060 86 469 [ 023 9579 ]
Eton 2002 1391 692 914 219 [ 087 551 ]
Total (95 CI) 155 152 1000 234 [ 097 565 ]
Total events 15 (ICT) 6 (CT)
Heterogeneity Tau2 = 00 Chi2 = 023 df = 1 (P = 063) I2 =00
Test for overall effect Z = 189 (P = 0059)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
35Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 21 Comparison 2 Response rates Outcome 1 Overall response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 1 Overall response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 40160 1682 83 128 [ 077 214 ]
Danson 2003 1362 555 25 231 [ 088 606 ]
Falkson 1991 1630 631 36 276 [ 125 609 ]
Falkson 1998 27122 22128 86 129 [ 078 213 ]
Gorbonova 2000 414 414 17 100 [ 031 323 ]
Kirkwood 1990 421 524 17 091 [ 028 297 ]
Middleton 2000 950 1446 42 059 [ 028 123 ]
Spieth 2003 34142 19138 84 174 [ 104 290 ]
Thomson 1993 1882 1482 57 129 [ 069 241 ]
Young 2001 422 626 18 079 [ 025 244 ]
Subtotal (95 CI) 705 626 462 132 [ 102 171 ]
Total events 169 (ICT) 111 (CT)
Heterogeneity Tau2 = 004 Chi2 = 1172 df = 9 (P = 023) I2 =23
Test for overall effect Z = 210 (P = 0036)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 25136 21172 77 151 [ 088 257 ]
Atzpodien 2002 2264 1860 83 115 [ 069 192 ]
Del Vecchio 2003 2473 1672 75 148 [ 086 254 ]
Eton 2002 4491 2392 124 193 [ 128 292 ]
Johnston 1998 835 830 31 086 [ 037 201 ]
Ridolfi 2002 2287 1889 73 125 [ 072 216 ]
Rosenberg 1999 2250 1452 74 163 [ 095 282 ]
Subtotal (95 CI) 536 567 538 146 [ 119 179 ]
Total events 167 (ICT) 118 (CT)
Heterogeneity Tau2 = 00 Chi2 = 463 df = 6 (P = 059) I2 =00
Test for overall effect Z = 368 (P = 000023)
Total (95 CI) 1241 1193 1000 140 [ 120 163 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
36Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Total events 336 (ICT) 229 (CT)
Heterogeneity Tau2 = 000 Chi2 = 1670 df = 16 (P = 041) I2 =4
Test for overall effect Z = 429 (P = 0000018)
Test for subgroup differences Chi2 = 036 df = 1 (P = 055) I2 =00
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 22 Comparison 2 Response rates Outcome 2 Complete response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 2 Complete response rate
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 2136 6172 042 [ 009 206 ]
Atzpodien 2002 764 860 082 [ 032 212 ]
Bajetta 1994 12160 482 154 [ 051 462 ]
Danson 2003 262 055 444 [ 022 9061 ]
Del Vecchio 2003 373 172 296 [ 032 2778 ]
Eton 2002 691 292 303 [ 063 1463 ]
Falkson 1991 1230 231 620 [ 151 2540 ]
Falkson 1998 9122 4128 236 [ 075 747 ]
Gorbonova 2000 114 114 100 [ 007 1445 ]
Johnston 1998 135 030 258 [ 011 6116 ]
Middleton 2000 450 246 184 [ 035 958 ]
Ridolfi 2002 387 389 102 [ 021 493 ]
001 01 1 10 100
Favours CT (control) Favours ICT
(Continued )
37Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Rosenberg 1999 350 452 078 [ 018 331 ]
Thomson 1993 682 282 300 [ 062 1443 ]
Young 2001 022 026 00 [ 00 00 ]
Total (95 CI) 1078 1031 158 [ 106 236 ]
Total events 71 (ICT) 39 (CT)
Heterogeneity Tau2 = 00 Chi2 = 1215 df = 13 (P = 052) I2 =00
Test for overall effect Z = 224 (P = 0025)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours CT (control) Favours ICT
Analysis 23 Comparison 2 Response rates Outcome 3 Partial response rate
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 2 Response rates
Outcome 3 Partial response rate
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 23136 15172 89 194 [ 105 357 ]
Atzpodien 2002 1564 1060 67 141 [ 069 288 ]
Bajetta 1994 28160 1282 86 120 [ 064 223 ]
Danson 2003 1162 555 37 195 [ 072 527 ]
Del Vecchio 2003 2173 1572 98 138 [ 078 246 ]
Eton 2002 3891 2192 147 183 [ 117 286 ]
Falkson 1991 430 431 22 103 [ 028 376 ]
Falkson 1998 18122 18128 90 105 [ 057 192 ]
Gorbonova 2000 314 314 19 100 [ 024 413 ]
02 05 1 2 5
Favours CT (control) Favours ICT
(Continued )
38Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Johnston 1998 735 830 45 075 [ 031 183 ]
Middleton 2000 550 1246 39 038 [ 015 100 ]
Ridolfi 2002 1987 1589 89 130 [ 070 238 ]
Rosenberg 1999 1950 1052 78 198 [ 102 382 ]
Thomson 1993 1282 1283 64 101 [ 048 212 ]
Young 2001 422 626 29 079 [ 025 244 ]
Total (95 CI) 1078 1032 1000 131 [ 107 159 ]
Total events 227 (ICT) 166 (CT)
Heterogeneity Tau2 = 002 Chi2 = 1579 df = 14 (P = 033) I2 =11
Test for overall effect Z = 265 (P = 00081)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours CT (control) Favours ICT
Analysis 31 Comparison 3 Progression free survival Outcome 1 Progression free survival
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 3 Progression free survival
Outcome 1 Progression free survival
Study or subgroup ICT CTPeto
Odds Ratio WeightPeto
Odds Ratio
nN nN
Exp[(O-E)V]Fixed95
CI
Exp[(O-E)V]Fixed95
CI
Eton 2002 1391 792 98 051 [ 020 128 ]
Johnston 1998 235 230 21 117 [ 016 875 ]
Ridolfi 2002 287 189 881 079 [ 058 108 ]
Total (95 CI) 1000 076 [ 057 102 ]
Heterogeneity Chi2 = 098 df = 2 (P = 061) I2 =00
Test for overall effect Z = 182 (P = 0068)
Test for subgroup differences Not applicable
02 05 1 2 5
Favours ICT Favours control (CT)
39Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 41 Comparison 4 Toxicity Outcome 1 Hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 1 Hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Bajetta 1994 3160 182 124 154 [ 016 1455 ]
Danson 2003 1462 1955 192 065 [ 036 118 ]
Falkson 1991 1634 234 162 800 [ 199 3215 ]
Falkson 1998 25136 5135 181 496 [ 196 1258 ]
Middleton 2000 650 3546 186 016 [ 007 034 ]
Young 2001 522 226 155 295 [ 063 1376 ]
Subtotal (95 CI) 464 378 1000 153 [ 042 552 ]
Total events 69 (ICT) 64 (CT)
Heterogeneity Tau2 = 216 Chi2 = 4632 df = 5 (Plt000001) I2 =89
Test for overall effect Z = 064 (P = 052)
2 ICT with interferon-alpha plus interleukin-2
Atkins 2003 95173 70193 219 151 [ 120 191 ]
Eton 2002 9191 8892 223 105 [ 100 110 ]
Johnston 1998 1335 530 175 223 [ 090 553 ]
Ridolfi 2002 3087 3389 212 093 [ 063 138 ]
Rosenberg 1999 3950 452 171 1014 [ 391 2630 ]
Subtotal (95 CI) 436 456 1000 186 [ 082 423 ]
Total events 268 (ICT) 200 (CT)
Heterogeneity Tau2 = 079 Chi2 = 16211 df = 4 (Plt000001) I2 =98
Test for overall effect Z = 149 (P = 014)
005 02 1 5 20
Favours ICT Favours CT (control
40Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 42 Comparison 4 Toxicity Outcome 2 Non-hematological toxicity grade gt=3
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 2 Non-hematological toxicity grade gt=3
Study or subgroup ICT CT Risk Ratio Weight Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
1 ICT with interferon-alpha
Falkson 1991 330 131 17 310 [ 034 2817 ]
Falkson 1998 26136 9135 156 287 [ 140 589 ]
Subtotal (95 CI) 166 166 173 289 [ 146 573 ]
Total events 29 (ICT) 10 (CT)
Heterogeneity Tau2 = 00 Chi2 = 000 df = 1 (P = 095) I2 =00
Test for overall effect Z = 304 (P = 00024)
2 ICT with interferon-alpha plus interleukin-2
Eton 2002 3691 1292 236 303 [ 169 545 ]
Johnston 1998 935 430 70 193 [ 066 563 ]
Ridolfi 2002 2187 1389 207 165 [ 088 309 ]
Rosenberg 1999 4350 1252 313 373 [ 224 620 ]
Subtotal (95 CI) 263 263 827 263 [ 178 390 ]
Total events 109 (ICT) 41 (CT)
Heterogeneity Tau2 = 005 Chi2 = 444 df = 3 (P = 022) I2 =32
Test for overall effect Z = 482 (P lt 000001)
Total (95 CI) 429 429 1000 274 [ 206 364 ]
Total events 138 (ICT) 51 (CT)
Heterogeneity Tau2 = 00 Chi2 = 447 df = 5 (P = 048) I2 =00
Test for overall effect Z = 694 (P lt 000001)
Test for subgroup differences Chi2 = 005 df = 1 (P = 082) I2 =00
005 02 1 5 20
Favours ICT Favours CT (control
41Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 43 Comparison 4 Toxicity Outcome 3 Treatment related mortality
Review Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma
Comparison 4 Toxicity
Outcome 3 Treatment related mortality
Study or subgroup ICT CT Risk Ratio Risk Ratio
nN nN
M-HRandom95
CI
M-HRandom95
CI
Atkins 2003 3204 2201 148 [ 025 875 ]
Atzpodien 2002 064 060 00 [ 00 00 ]
Bajetta 1994 0160 082 00 [ 00 00 ]
Eton 2002 191 392 034 [ 004 318 ]
Falkson 1991 030 031 00 [ 00 00 ]
Falkson 1998 2132 0131 496 [ 024 10238 ]
Middleton 2000 050 246 018 [ 001 374 ]
Ridolfi 2002 087 089 00 [ 00 00 ]
Rosenberg 1999 050 052 00 [ 00 00 ]
Thomson 1993 087 083 00 [ 00 00 ]
Young 2001 030 131 034 [ 001 813 ]
Total (95 CI) 985 898 078 [ 026 232 ]
Total events 6 (ICT) 8 (CT)
Heterogeneity Tau2 = 00 Chi2 = 361 df = 4 (P = 046) I2 =00
Test for overall effect Z = 045 (P = 065)
Test for subgroup differences Not applicable
001 01 1 10 100
Favours ICT Favours CT (control)
A D D I T I O N A L T A B L E S
Table 1 Methodological quality analysis
Study ID Randomiza-
tion
Allocation
Conceal
Blind pat
clin
Blind
outcome
Lost to follow
up
ITT Funding
Atkins 2003 unclear unclear - unclear + - public
Atzpodien
2002
+ + - unclear + + both
42Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Methodological quality analysis (Continued)
Bajetta 1994 + + - unclear + + pharm
Danson 2003 + + - unclear + + unclear
Del Vecchio
2003
unclear unclear - unclear + + unclear
Eton 2002 unclear unclear - unclear + - pharm
Falkson 1991 unclear unclear - unclear + - both
Falkson 1998 + + - unclear + + public
Gorbonova
2000
unclear unclear - unclear + -
Johnston
1998
+ + - unclear + +
Kirkwood
1990
+ unclear - unclear + - pharm
Middleton
2000
+ + - unclear + + unclear
Ridolfi 2002 + + - unclear + + public
Rosenberg
1999
+ + - unclear + + unclear
Spieth 2003 unclear unclear - unclear + - unclear
Thomson
1993
+ + - unclear + - unclear
Vorobiof 1994 + + - unclear + + unclear
Young 2001 + + - unclear + + both
Table 2 Additional Quality Analysis
Study ID Biopsy Baseline Clearly defined Statistics
Atkins 2003 - - - +
Atzpodien 2002 + + + +
43Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 2 Additional Quality Analysis (Continued)
Bajetta 1994 + + + -
Danson 2003 + - + -
Del Vecchio 2003 + + - +
Eton 2002 + - + +
Falkson 1991 + + + -
Falkson 1998 + + + +
Gorbonova 2000 + - - -
Johnston 1998 - + + +
Kirkwood 1990 - - - -
Middleton 2000 - + + +
Ridolfi 2002 + + + +
Rosenberg 1999 + + + +
Spieth 2003 + - - -
Thompson 1993 + + - +
Vorobiof 1994 + + + -
Young 2001 + + + +
Table 3 Content of Quality Analysis List
Abbreviation Description
Randomization Was an adequate method of randomisation performed
Allocation Conceal Was the method of allocation concealment adequate
Blind patclin Were participants and clinicians blinded
Blind outcome Was the outcome assessor blinded
Lost to follow up Was there a description of withdrawals and drop-outs Was it adequate
ITT Did the analysis include an intention to treat analysis
44Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 3 Content of Quality Analysis List (Continued)
Funding What was the source of funding Public pharmaceutical industry or both
Biopsy Was it described the necessity of a biopsy proven melanoma
Baseline Were there baseline assessments of the participants for presence of liver and brain metastasis performance
status
Clear defined Were the aims interventions and outcome measures clearly defined
Statistical Were appropriate statistical analyses used Were alpha and beta errors pre-defined
A P P E N D I C E S
Appendix 1 Search strategy for MEDLINE (OVID)
1 RANDOMIZED CONTROLLED TRIALpt
2 CONTROLLED CLINICAL TRIALpt
3 RANDOMIZED CONTROLLED TRIALSsh
4 RANDOM ALLOCATIONsh
5 DOUBLE BLIND METHODsh
6 SINGLE-BLIND METHODsh
7 or1-6
8 animal not human
9 7 not 8
10 CLINICAL TRIALpt
11 exp CLINICAL TRIALS
12 (clin$ adj25 trial$)tiab
13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$))tiab
14 PLACEBOSsh
15 placebo$tiab
16 random$tiab
17 RESEARCH DESIGNsh
18 or10-17
19 18 not 8
20 19 not 9
21 COMPARATIVE STUDYsh
22 exp EVALUATION STUDIES
23 FOLLOW UP STUDIESsh
24 PROSPECTIVE STUDIESsh
25 (control$ or prospectiv$ or volunteer$)tiab
26 or21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 melanomamp or exp MELANOMA
45Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
31 29 and 30
32 cytokinesmp or exp CYTOKINES
33 interferonmp or exp Interferons
34 interleukinmp or exp Interleukins
35 chemotherapymp or exp Drug Therapy
36 exp Immunotherapy or chemoimmunotherapymp
37 32 or 33 or 34 or 35 or 36
38 31 and 37
39 limit 38 to yr=2003 - 2005
Appendix 2 Search strategies for electronic databases
The Cochrane Skin Group Specialised Register
This contains the results of a comprehensive program of ongoing handsearching of dermatological journals and conference proceedings
We searched this on 14th February 2006 using the following terms
MELANOMA and (cytokine or interleukin or interferon or chemotherap or immunotherap or chemoimmunotherap)
The Cochrane Central Register of Controlled Trials
We searched The Cochrane Library Issue 3 2005 using the following terms
1 (melanoma in Record Title and chemotherap in All Text)
2 (interferon in All Text or interleukin in All Text or immunotherapy in All Text)
3 (1 and 2)
Medline (PubMed)
We searched PubMed on 30th January 2006 using the following terms
((ldquoMelanomardquo [MeSH] OR melanoma) AND (ldquoCytokinesrdquo [MeSH] OR interfero OR interleuk) AND (ldquoDrug Therapyrdquo [MeSH] OR
chemotherap OR immunotherap OR chemoimmunotherap)) AND (randomized controlled trial [Publication Type] OR (random)
OR (randomized [TitleAbstract] AND trial [TitleAbstract])) was made on 30th January 2006 The lists of rsquorelated articlesrsquo obtained
for each relevant record were also searched
EMBASE
We searched EMBASE (from 2003 to 20th July 2005) using the following terms
melanoma AND (random AND trial) AND (cytokin or interleuk or interferon or immunotherap) AND (chemotherap)
LILACS (Latin American and Caribbean Health Science Information Database)
The LILACS search was made from 1982 to 20th February 2006 using the following terms
1 MELANOMA and INTERFERON
2 MELANOMA and INTERLEU$
3 1 or 2
46Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
F E E D B A C K
Comment from Douglas Grindlay 09 July 07
Summary
Date of Submission 09-Jul-2007
Name Douglas Grindlay
Personal Description Occupation NLH Dermatology Information Specialist
Feedback In the context of my role compiling uncertainties for the Database of Uncertainties of Effects of Treatments (DUETs) I
found it difficult to tell from this review whether the conclusion is that chemoimmunotherapy definitely has no advantage in terms
of survival over chemotherapy or whether there is still uncertainty over whether chemoimmunotherapy does work better Given that
18 trials were found and the meta-analysis showed significant effect on survival why would further research need to be done (see
conclusion that ldquoFurther use of combined immunotherapy and chemotherapy should only be done in the context of clinical trialsrdquo)
Submitter agrees with default conflict of interest statement I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback
Reply
Dear Sir
Thank you for your important comments Our review found differences in response rates but not in survival as described by Dr
Grindlay Therefore we concluded that there is not enough evidence that chemoimmunotherapy is more effective than chemotherapy
alone in terms of survival This conclusion is in conflict with some international guidelines recommendations (NCCN NCIetc)
which include chemoimmunotherapy as a valid option to treat melanoma patients
In addition to the need to demonstrate survival benefit for chemoimmunotherapy over chemotherapy we also suggest that chemoim-
munotherapy could be studied with different combinations of drugs and different doses other than those used in existing trials included
in the review These are the main reasons why we concluded that there are still uncertainties that require new trials in the future
Best wishes
Andre Sasse
Contributors
Author of comments Douglas Grindlay
Author responding Andre Sasse
W H A T rsquo S N E W
Last assessed as up-to-date 15 November 2006
Date Event Description
18 July 2013 Amended This review is going to be updated We have written a published note to say that this review will be
updated by incorporation into another broader Cochrane review The protocol of this is currently being
written
47Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
H I S T O R Y
Protocol first published Issue 3 2005
Review first published Issue 1 2007
Date Event Description
6 September 2008 Amended Converted to new review format
C O N T R I B U T I O N S O F A U T H O R S
draft the protocol ADS OAC ECS
search for trials (2 people) ADS ECS
obtain copies of trials ADS
select which trials to include (2 + 1 arbiter) ADS OAC ECS
extract data from trials (2 people) ADS ECS
enter data into RevMan ADS
carry out the analysis ADS OAC LGC
interpret the analysis ADS OAC ECS
draft the final review ADS LGC OAC
consumer review LU
update the review ADS
D E C L A R A T I O N S O F I N T E R E S T
None known
N O T E S
The Cochrane Skin Group has made the decision to allow another team to incorporate the subject of this review into the protocol that
they are currently writing in order to update another review that has been out of date for some years The other review title is rsquoSystemic
treatments for metastatic cutaneous melanomarsquo We feel it makes clinical sense to combine these two reviews
48Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
I N D E X T E R M SMedical Subject Headings (MeSH)
Antineoplastic Agents [lowasttherapeutic use] Combined Modality Therapy [methods] Immunotherapy [lowastmethods] Interferon-alpha
[therapeutic use] Interleukin-2 [therapeutic use] Melanoma [drug therapy secondary lowasttherapy] Randomized Controlled Trials as
Topic Skin Neoplasms [drug therapy lowasttherapy]
MeSH check words
Humans
49Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review)
Copyright copy 2013 The Cochrane Collaboration Published by John Wiley amp Sons Ltd