IHIC 2014 Panel #1: INVESTMENT OUTLOOK - BLUE SKIES? (Tom Oakden)
Surgery combined with intraoperative hyperthermic intraperitoneal chemotherapy (IHIC) for gastric...
Transcript of Surgery combined with intraoperative hyperthermic intraperitoneal chemotherapy (IHIC) for gastric...
2013
Int. J. Hyperthermia, March 2013; 29(2): 156–167
RESEARCH ARTICLE
Surgery combined with intraoperative hyperthermic intraperitonealchemotherapy (IHIC) for gastric cancer: A systematic review andmeta-analysis of randomised controlled trials
DENG-HAI MI1,2,3, ZHENG LI1,2,3, KE-HU YANG1,2, NONG CAO1,2,
ANNE LETHABY1,4, JIN-HUI TIAN1, NANCY SANTESSO1,5, BIN MA1,
YAO-LONG CHEN1, & YA-LI LIU1
1Evidence-Based Medicine Centre of Lanzhou University, Lanzhou, Gansu Province, China, 2Department of General
Surgery, First Clinical Medicine College of Lanzhou University, Lanzhou, Gansu Province, China, 3Department of
Oncology, Second People’s Hospital of Gansu Province, Lanzhou, Gansu Province, China, 4Department of Obstetrics
and Gynecology, Auckland City Hospital, Auckland, New Zealand, and 5McMaster University Health Sciences Centre,
Hamilton, Ontario, Canada
(Received 27 May 2012; Revised 9 January 2013; Accepted 15 January 2013)
AbstractBackground: Adjuvant intraoperative hyperthermic intraperitoneal chemotherapy (IHIC) is a therapy which combinesthermotherapy and intraperitoneal chemotherapy. It is theoretically powerful for patients with advanced gastric cancer(AGC), but is there evident advantage in clinical practice? We need evidence to guide our decision-making.Objectives: Meta-analysis was performed to assess the effectiveness and safety of adjuvant intraoperative hyperthermicintraperitoneal chemotherapy (IHIC) for patients with resectable locally advanced gastric cancer, and to provide thereference for clinical practice and study.Methods: We searched the Cochrane Library, PubMed, Embase, Web of Science and Chinese databases (ChineseBioMedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI) and Wanfang) electronicallyand also retrieved papers from other sources (tracing related references and communication with other authors). All relevantrandomised controlled trials (RCTs) were collected to compare surgery combined with IHIC to surgery without IHIC forAGC. There were no language restrictions. After independent quality assessment and data extraction by two reviewers,meta-analysis was conducted by RevMan 5.1 software.Results: 16 RCTs involving 1,906 patients were included. Compared with surgery alone, combination therapy (surgery plusIHIC) was associated with a signiEcant improvement in survival rate at 1 year (hazard ratio (HR)¼ 2.99; 95% confidenceinterval (CI)¼ 2.21 to 4.05; p< 0.00001), 2 years (HR¼ 2.43; 95%CI¼ 1.81 to 3.26; p< 0.00001), 3 years (HR¼ 2.63;95%CI¼ 2.17 to 3.20; p< 0.00001), 5 years (HR¼ 2.49; 95%CI¼ 1.97 to 3.14; p< 0.00001), and 9 years (HR¼ 2.14;95%CI¼ 1.38 to 3.32; p¼ 0.0007). Compared with surgery alone, combination therapy was associated with a signiEcantreduction in recurrence rate at 2 years (RR¼ 0.42; 95%CI¼ 0.29 to 0.61; p< 0.00001), 3 years (RR¼ 0.35; 95%CI¼ 0.24to 0.51; p< 0.00001) and 5 years (RR¼ 0.47; 95%CI¼ 0.39 to 0.56; p< 0.00001). IHIC was not found to be associatedwith higher risks of anastomotic leakage, ileus, bowel perforation, myelosuppression, gastrointestinal reaction andhypohepatia, but it increased the incidence of abdominal pain (RR¼ 21.46; 95%CI¼ 5.24 to 87.78; p< 0.00001).Conclusions: Compared with surgery alone, surgery combined with IHIC can improve survival rate and reduce the recurrencerate, with acceptable safety. However, safety outcomes should be further evaluated by larger samples and high qualitystudies. Additionally, hyperthermia for the intraperitoneal chemotherapy needs more clinical research.
Keywords: gastric cancer, radical surgery, hyperthermia, intraperitoneal chemotherapy, meta-analysis
Correspondence: Ke-Hu Yang, Professor of Oncology, Evidence Based Medicine Center of Lanzhou University, 199 Donggang West Road, Chengguan
District, Lanzhou City, Gansu Province, 730000, China. Tel: þ86-931-8912767. Fax: þ86-931-8915076. E-mail: [email protected] &
ISSN 0265–6736 print/ISSN 1464–5157 online � 2013 Informa UK Ltd.
DOI: 10.3109/02656736.2013.768359
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Introduction
A total of 989 600 new stomach cancer cases and
738 000 deaths are estimated to have occurred in
2008, accounting for 8% of the total cases and 10%
of total deaths worldwide. Over 70% of new cases
and deaths occur in developing countries. Generally,
stomach cancer rates are about twice as high in men
as in women [1]. Currently, surgical resection is
the mainstay of treatment for gastric cancer, but the
therapeutic effect after operation is reduced immen-
sely because of recurrence and metastasis. Despite
the use of radiotherapy or adjuvant or neoadjuvant
systemic chemotherapy, the long-term survival in
patients with locally advanced gastric cancer remains
limited. We need to search for more effective
adjuvant treatment regimens to change the current
situation.
There are many adjuvant treatments being inves-
tigated to reduce the recurrence rate and metastasis
rate. Intraoperative hyperthermic intraperitoneal
chemotherapy (IHIC) is the synthesis of thermo-
therapy, chemotherapy and peritoneal perfusion,
which as a targeted adjuvant treatment after surgery
may be considered a rational prophylactic and
therapeutic approach. Although the theoretical ratio-
nale is very appealing, the real situation in clinical
practice is unclear. Is there any signiEcant impact of
adjuvant IHIC on the outcomes of patients with
AGC? A systematic review [2] has proved that IHIC
has a positive effect on gastric cancer with peritoneal
metastasis, but what about the effect on patients
without peritoneal metastasis who have undergone
radical surgery? The current randomised controlled
trials (RCTs) have mostly small sample sizes and
have shown inconclusive results. So we performed
this meta-analysis of RCTs to reliably assess the
effectiveness and safety of adjuvant IHIC in the
treatment of resectable AGC without peritoneal
metastasis, and to provide the reference for further
clinical practice and study.
Methods
Study selection criteria
The studies were selected for review if they fulElled
the following inclusion criteria:
1. Study type: RCTs regardless of use of blinding.
2. Participants: Patients with histologically diag-
nosed primary cancer of the stomach having
radical resection. Studies of patients having non-
radical resection were excluded. Locally advanced
gastric cancer was defined as macroscopic serosal
invasion, excluding peritoneal or distant
metastases.
3. Intervention and comparison: Trials testing the
efEcacy and safety of radical surgery (RS)
combined with IHIC versus RS without IHIC,
no matter whether to implement post-operative
chemotherapy.
4. Outcomes: The primary end point of this meta-
analysis was overall survival, deEned as the time
from random assignment to the last follow-up or
death.
There were no language restrictions. When multi-
ple publications from the same institution were
identified as duplicates, only the most recent
update with the largest number of patients or
longer follow-up group was included.
Literature search strategy
We performed literature searches of the Cochrane
Library, PubMed, Embase, Web of Science, the
Chinese Biomedical Literature Database, Chinese
Journal Full Text Database and the Chinese
Wanfang Literature Database. The search terms
contained the target disease group and intervention
group, and all searches used a topic search combined
with a non-topic search. The search had no language
restrictions and the period of searching was from the
inception of databases to October, 2012. All relevant
RCTs were collected to evaluate the effectiveness
and safety of adjuvant IHIC for patients with
resectable locally advanced gastric cancer. The
reference lists of articles identified were reviewed
for further identiEcation of potentially relevant
studies. We also used Google Scholar and Medical
Matrix to search for relevant papers. Both published
and unpublished trials were sought to limit publica-
tion bias. We also communicated with some experts
to ask whether they knew about any unpublished
trials.
Literature screening
Studies were selected according to the inclusion and
exclusion criteria. The title and abstract were
assessed and if potentially relevant the publication
was retrieved to assess the full text. If necessary, we
contacted authors for missing data. All steps were
completed by two investigators (Zheng Li and Deng-
hai Mi) independently, and all steps were cross-
checked. We address discrepancies in the discussion.
Problems with discrepancies were judged by the
senior investigator (Ke-hu Yang) if they could not be
resolved by the two investigators. The Enal results
were reviewed by all three senior investigators.
Data extraction and critical appraisal
Two investigators (Zheng Li and Deng-hai
Mi) independently read each article included.
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Data extracted included the study design, year of
publication, number of patients, methodology, qual-
ity criteria, completeness of cytoreduction, criteria
used to define IHIC, IHIC protocol, treatment
outcomes, and prognostic factors associated with
outcomes. All data were extracted from texts, tables,
and figures of the articles and then tabulated.
The quality of studies was appraised indepen-
dently using the following criteria: (1) whether the
method of allocation was truly random; (2) whether
there was proper concealment of allocation;
(3) whether the groups were similar at baseline in
terms of prognostic features; (4) whether loss to
follow-up in each treatment group was speciEed and
(5) whether intention-to-treat (ITT) analysis was
conducted. When studies did not report adequate
information to determine the above-mentioned
assessment criteria, we tried to obtain additional
data direct from the investigators.
Discrepancies between the two investigators
were resolved by discussion and consensus with a
senior investigator (Nong Cao). The Enal results
were reviewed by all three senior investigators to
avoid bias.
Statistical analysis
Data were synthesised using RevMan 5.1 provided
by the Cochrane organisation. The heterogeneity
between the results of the research included was
examined by the chi-square test. Chi-square tests
were used to study heterogeneity between trials. The
I-squared value was used to estimate the percentage
of total variation across studies.
When the homogeneity of statistics between
studies was considered adequate (P40.1,
I2< 50%), we used the fixed effects model; if there
was obvious heterogeneity between the studies
(P< 0.1, I2450%), we analysed the sources of
heterogeneity, and then performed subgroup analysis
according to factors accounting for the heterogeneity.
When there was enough similarity between the
studies within the group or between the groups
(P40.1, I2< 50%) we used the fixed effects model to
perform meta-analysis. If there was statistical hetero-
geneity but no clinical and methodological hetero-
geneity between the subgroups we used the random
effects model. If the heterogeneity was substantial
between the studies included we used descriptive
analysis. We performed sensitivity analysis to exam-
ine the stability of the results where necessary.
The primary end point of this meta-analysis was
overall survival, deEned as the time from random
assignment to the last follow-up or death. Secondary
end points were the incidence of recurrence and
quality of life. Safety was also assessed, although the
frequency of important long-term adverse events may
not be adequately captured by the information
provided in RCTs. Results regarding the overall
survival were expressed as hazard ratios (HR) with
95% conEdence intervals (CI). Other indicators
used relative risk (RR) with 95%CI. All p-values
were two-sided. All statistical analysis was conducted
by Cochrane Review Manager 5.1.
Results
Results of the search and identified studies
There were 491 references identified through elec-
tronic database and other searches. A total of 113
articles were excluded as duplicates by Endnote and
seven articles were excluded as duplicates by
reviewers. The titles and abstracts of 371 potentially
appropriate articles were read by the reviewers, and
326 were excluded because they did not meet the
inclusion criteria. A total of 45 articles were
appraised by full text to confirm the studies included.
Articles were also excluded where patients had
peritoneal metastasis or had palliative surgery.
Finally, 16 RCTs [3–18] were included for appraisal
and data extraction for meta-analysis. The 16 RCTs
had a total sample of 1906 patients. The full details
are listed in Figure 1).
Characteristics of studies included
In these 16 studies [3–18], 1906 patients were
randomly assigned, of whom 935 patients were to
receive radical resection with adjuvant IHIC and 909
patients were to receive radical resection without
IHIC. A total of 62 patients with intraoperative
normothermic intraperitoneal chemotherapy (INIC)
were randomly assigned in two studies [7, 15]. Two
trials were reported in one article [5], and we used
the one in which the patients underwent radical
resection, with the exclusion of the other trial where
patients had palliative surgery. All of the 16 studies
[3–18] had RS with IHIC and RS alone, but
only some of them implemented post-operative
chemotherapy. Although there was a difference,
it was irrelevant to our analysis because the post-
operative treatment was balanced in the two com-
parative groups of every study. The full details are
listed in Table I.
Quality of trials
There was good agreement between the reviewers on
the eligibility and quality of the studies. Table II
demonstrates the quality of all 16 RCTs included in
the systematic review [3–18]. An attempt was made
to contact the corresponding authors of RCTs, where
necessary, to obtain missing details relating to
methodological quality.
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Eight RCTs [3, 6–8, 14–17] used an adequate
approach to sequence generation using computer-
generated random numbers or random-number
tables. The adequacy of randomisation was unclear
in the remaining eight RCTs. In the same eight
RCTs [3, 6–8, 14–17], the method of allocation
concealment was adequate; randomisation was
performed on a central site and transmitted to
treatment providers by telephone, fax or sealed
opaque envelopes. In the remaining eight RCTs
[4, 5, 9–13, 18], the information regarding
approaches to allocation concealment could not be
determined. The baseline features were similar
between treatment groups in all 16 RCTs. Four
RCTs [3, 10, 13, 16] had no loss to follow-up, two
RCTs [4, 17] speciEed numbers lost to follow-up in
each treatment group, and this was unclear in the
remaining 10 RCTs. Six [6–8,14,15,17] RCTs
analysed the data on an intention-to-treat (ITT)
basis, whereby participants were analysed in the
groups to which they were initially randomised; and
10 RCTs [3–5, 9–13, 16, 18] did not perform ITT
analysis. Blinding after allocation was impossible
because of the nature of the trials. The full details
are listed in Table II.
Assessment of overall survival
Subgroup analysis was used to evaluate total survival
of different follow-up years. A signiEcant survival
improvement was found in favour of IHIC: 1 year
(HR¼ 2.99; 95%CI¼ 2.21 to 4.05; p< 0.00001), 2
years (HR¼ 2.43; 95%CI¼ 1.81 to 3.26;
p< 0.00001), 3 years (HR¼ 2.63; 95%CI¼ 2.17 to
3.20; p< 0.00001), 5 years (HR¼ 2.49;
95%CI¼ 1.97 to 3.14; p< 0.00001), 9 years
(HR¼ 2.14; 95%CI¼ 1.38 to 3.32; p¼ 0.0007).
There was no substantial statistical heterogeneity
among the trials, and the meta-analysis was per-
formed using the fixed effects model in all sub-
groups. We did not synthesise the subgroups of
different years because it was inapposite. All the
details are shown in Figure 2.
Assessment of disease recurrence
Two RCTs [6, 17], three [6, 9, 16], five [3, 6, 7, 12,
17], and eight RCTs [3, 6, 8, 10–13, 15] documen-
ted the incidence of 1-year, 2-year, 3-year and 5-year
recurrence respectively; we performed the subgroup
meta-analysis for these different follow-up years.
There was no substantial statistical heterogeneity
Potential studies evaluating IHIC for gastric cancer (N = 491) in: The Cochrane Library (n = 50) PubMed (n = 89) Embase (n = 78) Web of Science (n = 61) The Chinese Biomedical Literature Database (n = 103) The Chinese Journal Full Text Database (n = 63) The Chinese WanFang Literature Database (n = 47)
Duplicated studies (n = 113) were excluded by Endnote software
Potential appropriate studies to be included in the systematic review (n = 371)
Studies excluded (n = 154) because: Review (n = 33) Editorial (n = 6) Cohort study (n = 13) Case controlled study (n = 45) Animal experiment (n = 31) Case report (n = 26)
Studies excluded (n = 172) because: Not gastric cancer (n = 71) Not radical surgery (n = 18) Not IHIC intervention (n = 83)
Potential appropriate studies selected for full text evaluation (n = 45)
Studies excluded (n = 8) because: Duplicate publications (n = 3) No outcomes of interest (n = 2) The loss to follow-up is greater than 20% (n = 3)
Potential appropriate studies for final analysis (16 studies with 1,906 patients)
Duplicated studies (n = 7) were excluded by investigators
Studies excluded (n = 21) because: Not random trial (n = 2) Not the befitting patients (n = 6) Not real IHIC (n = 8) Not radical surgery (n = 5)
Figure 1. Selection process for RCTs of RS combined with IHIC for resectable AGC.
Meta-analysis of IHIC for AGC 159
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Tab
leI.
Tri
ald
esig
nan
db
asel
ine
char
acte
rist
ics
of
stu
die
sin
clu
ded
.
Stu
dy
and
year
NS
tud
yty
pe
Gas
tric
can
cer
Ch
arac
teri
stic
s
of
pat
ien
tsS
urg
ery
Tre
atm
ent
of
exp
erim
enta
lgro
up
Tre
atm
ent
of
con
tro
l
Ch
enet
al.,
20
06
[3]
14
0R
CT
Pri
mar
yA
GC
Wit
hse
rosa
lin
vasi
on
bu
tw
ith
ou
tp
erit
on
eal
met
asta
sis
Rad
ical
IHIC
wit
hC
DD
Pan
d5
-Fu
RS
alo
ne
Ch
enet
al.,
20
05
[4]
60
RC
TP
rim
ary
AG
CW
ith
sero
sal
inva
sio
nb
ut
wit
ho
ut
per
ito
nea
lm
etas
tasi
sR
adic
alIH
ICw
ith
CD
DP
and
5-F
uR
Sal
on
e
Ch
enet
al.,
20
01
[5]
60
RC
TP
rim
ary
AG
CW
ith
sero
sal
inva
sio
nb
ut
wit
ho
ut
per
ito
nea
lm
etas
tasi
sR
adic
alIH
ICw
ith
CD
DP
RS
alo
ne
Fu
jim
oto
etal
.,1
99
9[6
]1
41
RC
TP
rim
ary
AG
CW
ith
sero
sal
inva
sio
nb
ut
wit
ho
ut
per
ito
nea
lm
etas
tasi
sR
adic
alIH
ICw
ith
MM
CR
Sal
on
e
Fu
jim
ura
etal
.,1
99
4[7
]5
8R
CT
Pri
mar
yA
GC
Wit
hse
rosa
lin
vasi
on
bu
tw
ith
ou
tp
erit
on
eal
met
asta
sis
Rad
ical
IHIC
wit
hC
DD
Pan
dM
MC
RS
alo
ne
Ham
azo
eet
al.,
19
94
[8]
82
RC
TP
rim
ary
AG
CW
ith
sero
sal
inva
sio
nb
ut
wit
ho
ut
per
ito
nea
lm
etas
tasi
sR
adic
alIH
ICw
ith
MM
CR
Sal
on
e
Jin
,2
00
7[9
]1
16
RC
TP
rim
ary
AG
CW
ith
sero
sal
inva
sio
nb
ut
wit
ho
ut
per
ito
nea
lm
etas
tasi
sR
adic
alIH
ICw
ith
CD
DP
and
MM
CR
Sal
on
e
Wan
get
al.,
20
06
[10
]6
8R
CT
Pri
mar
yA
GC
Wit
hse
rosa
lin
vasi
on
bu
tw
ith
ou
tp
erit
on
eal
met
asta
sis
Rad
ical
IHIC
wit
hC
DD
PR
Sal
on
e
Wan
get
al.,
20
02
[11
]2
28
RC
TP
rim
ary
AG
CW
ith
sero
sal
inva
sio
nb
ut
wit
ho
ut
per
ito
nea
lm
etas
tasi
sR
adic
alIH
ICw
ith
MM
Can
d5
-Fu
RS
alo
ne
Wan
g,
20
10
[12
]1
16
RC
TP
rim
ary
AG
CW
ith
sero
sal
inva
sio
nb
ut
wit
ho
ut
per
ito
nea
lm
etas
tasi
sR
adic
alIH
ICw
ith
CD
DP
and
5-F
uR
Sal
on
e
Ye
etal
.,2
00
7[1
3]
20
3R
CT
Pri
mar
yA
GC
Wit
hse
rosa
lin
vasi
on
bu
tw
ith
ou
tp
erit
on
eal
met
asta
sis
Rad
ical
IHIC
wit
hC
DD
Pan
d5
-Fu
RS
alo
ne
Yo
nem
ura
etal
.,1
99
5[1
4]
16
0R
CT
Pri
mar
yA
GC
Wit
hse
rosa
lin
vasi
on
bu
tw
ith
ou
tp
erit
on
eal
met
asta
sis
Rad
ical
IHIC
wit
hC
DD
Pan
dM
MC
RS
alo
ne
Yo
nem
ura
etal
.,2
00
1[1
5]
13
9R
CT
Pri
mar
yA
GC
Wit
hse
rosa
lin
vasi
on
bu
tw
ith
ou
tp
erit
on
eal
met
asta
sis
Rad
ical
IHIC
wit
hC
DD
Pan
dM
MC
RS
alo
ne
Zh
ang
etal
.,2
00
7[1
6]
21
2R
CT
Pri
mar
yA
GC
Wit
hse
rosa
lin
vasi
on
bu
tw
ith
ou
tp
erit
on
eal
met
asta
sis
Rad
ical
IHIC
wit
hC
DD
Pan
dM
MC
RS
alo
ne
Zh
anet
al.,
20
10
[17
]6
0R
CT
Pri
mar
yA
GC
Wit
hse
rosa
lin
vasi
on
bu
tw
ith
ou
tp
erit
on
eal
met
asta
sis
Rad
ical
IHIC
wit
hC
DD
PR
Sal
on
e
Zh
ang
etal
.,1
99
8[1
8]
63
RC
TP
rim
ary
AG
CW
ith
sero
sal
inva
sio
nb
ut
wit
ho
ut
per
ito
nea
lm
etas
tasi
sR
adic
alIH
ICw
ith
5-F
uan
dD
DW
RS
alo
ne
AG
C,
Ad
van
ced
gas
tric
can
cer;
CD
DP
,C
isp
lati
n;
DD
W,
Do
ub
led
isti
lled
wat
er;
IHIC
,In
trao
per
ativ
eh
yper
ther
mic
intr
aper
ito
nea
lch
emo
ther
apy;
MM
C,
Mit
om
ycin
;N
,N
um
ber
of
pat
ien
ts;
RC
T,
Ran
do
mis
edco
ntr
olled
tria
l;R
S,
Rad
ical
surg
ery;
5-F
u,
Flu
oro
ura
cil.
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among these RCTs and we performed the meta-
analysis using the fixed effects model in all sub-
groups. It was found that IHIC could reduce
recurrence rate signiEcantly: 2 years (RR¼ 0.42;
95%CI¼ 0.29 to 0.61; p< 0.00001), 3 years
(RR¼ 0.35; 95%CI¼ 0.24 to 0.51; p< 0.00001), 5
years (RR¼ 0.47; 95%CI¼ 0.39 to 0.56;
p< 0.00001). However, there was no signiEcant
difference in the 1-year recurrence rate (RR¼ 0.66;
95%CI¼ 0.25 to 1.78; p¼ 0.41) because of the
limited sample size. We did not combine the
subgroups of different years because it was inappo-
site. The full details are listed in Table III.
Assessment of safety
Four studies [3, 4, 9, 12] reported the incidence of
abdominal pain, comparing 212 patients in the IHIC
groups with 218 patients in the control groups. There
was statistical difference in the meta-analysis of the
incidence of abdominal pain between the two groups
and no substantial heterogeneity was identiEed
(RR¼ 21.46; 95%CI¼ 5.24 to 87.78; p< 0.00001).
But all the reports explained that pain naturally
resolved. There was no statistical heterogeneity in the
meta-analysis of anastomotic leakage, ileus, bowel
perforation, myelosuppression, gastrointestinal reac-
tion and hypohepatia between the two groups. We
used the fixed effects model, and the results of meta-
analysis showed no statistical differences in these
morbidity rates between the IHIC and without IHIC
groups. The full details are listed in Table III.
Analysis of publication bias
We used the funnel plot to examine the publication
bias in the outcome of meta-analysis with the most
RCTs contributing data. The horizontal axis of the
plot was the HR effect estimate and the vertical axis
of the plot was the standard error (SE) of the log
(HR). The funnel plot of 3-year survival rate suggests
that the quantity distribution of the RCTs is
generally balanced, so the influence of publication
bias is limited to the meta-analysis of the 3-year
survival rate. All the details are shown in Figure 3.
Discussion
Surgical treatment is still the main treatment for
stomach cancer, but 5-year survival rate after surgery
alone is very low. The main reason for death is post-
operative loco-regional (peritoneal) recurrence and
distant metastases. One of the long-term goals of
treatment is to reduce the recurrence rate of stomach
cancer, which is critical to improve overall survival.
IHIC is the organic combination of hyperthermia,
chemotherapy and intraperitoneal perfusion, which
can improve the sensitisation and antipersonnel force
for cancer. So theoretically, IHIC has a very obvious
advantage compared with conventional systemic
chemotherapy.
Effectiveness evaluation
The existing systematic review [2] has suggested that
IHIC has a positive effect on gastric cancer with
peritoneal metastasis, but what about the effect of
this treatment on patients without peritoneal metas-
tasis and undergoing radical surgery? There are only
a few available trials with small sample sizes for the
comparison of RS combined with IHIC and RS
alone, but the meta-analysis was still able to
demonstrate statistically signiEcant and clinically
Table II. Quality assessment of RCTs included for meta-analysis.
Study and year
Truly
random
Allocation
concealment
Baseline
features
Loss to
follow-up
ITT
analysis
Eligibility
criteria
Chen et al., 2006 [3] Yes Yes Adequate No No Adequate
Chen et al., 2005 [4] Unclear Unclear Adequate Yes (N¼ 4) No Adequate
Chen et al., 2001 [5] Unclear Unclear Adequate Unclear No Adequate
Fujimoto et al., 1999 [6] Yes Yes Adequate Unclear Yes Adequate
Fujimura et al., 1994 [7] Yes Yes Adequate Unclear Yes Adequate
Hamazoe et al., 1994 [8] Yes Yes Adequate Unclear Yes Adequate
Jin, 2007 [9] Unclear Unclear Adequate Unclear No Adequate
Wang et al., 2006 [10] Unclear Unclear Adequate No No Adequate
Wang et al., 2002 [11] Unclear Unclear Adequate Unclear No Adequate
Wang, 2010 [12] Unclear Unclear Adequate Unclear No Adequate
Ye et al., 2007 [13] Unclear Unclear Adequate No No Adequate
Yonemura et al., 1995 [14] Yes Yes Adequate Unclear Yes Adequate
Yonemura et al., 2001 [15] Yes Yes Adequate Unclear Yes Adequate
Zhang et al., 2007 [16] Yes Yes Adequate No No Adequate
Zhan et al., 2010 [17] Yes Yes Adequate Yes (N¼ 1) Yes Adequate
Zhang et al., 1998 [18] Unclear Unclear Adequate Unclear No Adequate
Meta-analysis of IHIC for AGC 161
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relevant differences. The results of this meta-analysis
indicate that compared with RS alone, RS combined
with IHIC is more beneficial and superior for
primary AGC without peritoneal metastasis, and is
associated with improving overall survival and redu-
cing recurrence.
To further clarify the effects of adjuvant IHIC and
explore variation among trials, we categorised the
trials according to the post-operative treatment with
or without chemotherapy. We performed both
subgroup analysis and sensitivity analysis. The results
of meta-analysis did not change, suggesting that
Figure 2. Meta-analysis of overall survival rate for patients in the two groups.
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these findings are robust. The data show that the
post-operative treatment is irrelevant to compare
effectiveness of RS combined with IHIC and RS
alone, which is because the post-operative treatments
are balanced between the two groups in each RCT.
There is no consistent method in the reports of
loco-regional peritoneal recurrence and distant
metastases, so we performed the meta-analysis
using the disease recurrence rate which contains
loco-regional peritoneal recurrence and distant
metastases. Although there is some clinical hetero-
geneity in the recurrence rate of different RCTs, it is
appropriate to combine studies and we can get the
general trend to evaluate IHIC.
Historical analyses of treatment failure after
curative resection for gastric cancer showed that
approximately half of patients had a Erst site of
recurrence in their peritoneal cavity and the devel-
opment of local-regional recurrence had a negative
impact on overall survival [19–21]. We searched for
the best combination treatment for the eradication of
carcinomatosis. IHIC can effectively prevent the
recurrence of cancer, especially for patients with
serosal invasion but without peritoneal metastasis,
who have undergone radical surgery [6, 8, 14]. It is
one of the reasons why IHIC can improve overall
survival. IHIC can improve survival rates mainly
through eradicating residual disease in the peritoneal
Figure 3. Funnel plot analysis.
Table III. Meta-analysis of recurrence rate and safety for patients in the two arms.
IHIC Control Heterogeneity
Statistical
Result of meta-analysis
Outcome Included studies n N n N I2 % P method RR (95%CI) P
1-year recurrence rate 2 [6, 17] 6 101 9 100 0 0.81 M-H, fixed 0.66 (0.25, 1.78) 0.41
2-year recurrence rate 3 [6, 9, 16] 31 221 84 248 0 0.78 M-H, fixed 0.42 (0.29, 0.61) <0.00001
3-year recurrence rate 5 [3, 6, 7, 12, 17] 30 249 84 248 0 0.45 M-H, fixed 0.35 (0.24, 0.51) <0.00001
5-year recurrence rate 8 [3, 6, 8, 10–13, 15] 111 555 228 518 0 0.45 M-H, fixed 0.47 (0.39, 0.56) <0.00001
Abdominal pain 4 [3, 4, 9, 12] 40 212 0 218 0 0.78 M-H, fixed 21.46 (5.24, 87.78) <0.00001
Anastomotic leakage 6 [6–8, 10, 14, 15] 10 299 11 287 0 0.98 M-H, fixed 0.86 (0.38, 1.95) 0.72
Ileus 2 [10, 15] 3 85 1 78 0 0.78 M-H, fixed 2.08 (0.32, 13.55) 0.45
Bowel perforation 2 [7, 15] 2 70 0 65 0 0.94 M-H, fixed 2.70 (0.29, 25.15) 0.38
Myelosuppression 3 [3, 12, 14] 13 205 12 211 0 0.79 M-H, fixed 1.10 (0.53, 2.29) 0.80
Gastrointestinal reaction 2 [3, 12] 26 126 22 130 0 0.94 M-H, fixed 1.23 (0.73, 2.05) 0.44
Hypohepatia 2 [3, 12] 4 126 1 130 0 0.57 M-H, fixed 3.09 (0.50, 18.87) 0.22
CI, Confidence interval; IHIC, Intraoperative hyperthermic intraperitoneal chemotherapy; M-H, Mantel-Haenszel; RR, Relative risk.
Meta-analysis of IHIC for AGC 163
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cavity, but the recurrence also occurred through
lymphatic and haematogenous dissemination, so
IHIC should be combined with post-operative
intravenous chemotherapy.
We should also pay attention to intraoperative
normothermic intraperitoneal chemotherapy (INIC)
versus IHIC. Hyperthermia is an effective treatment
modality to augment chemotherapy-based anti-
cancer treatments by various forms, which has been
demonstrated by experiments [22–23].
Hyperthermia also has been proven to modulate
directly or indirectly the cells of the innate and
adaptive immune system, thereby improving effec-
tiveness [24–26]. The data of two meta-analyses
[27–28] demonstrated a positive effect of INIC, and
the authors also emphasise that IHIC is superior
because hyperthermia has a synergistic and addi-
tional anti-tumour activity. Two [7, 15] included
RCTs of the present meta-analysis and Tan et al.’s
RCT [29] performed the comparison of IHIC and
INIC. The results indicate that IHIC is superior in
terms of signiEcantly improving overall survival and
reducing recurrence. The control group underwent
post-gastric resection lavage with saline only in every
RCT included, but the effectiveness was limited
compared to those with INIC or IHIC, as demon-
strated by the trials and this review.
Berardi et al.’s systematic review [30] indicates
that neoadjuvant chemotherapy (NAC) could
improve the global outcome of patients with locally
advanced gastric cancer allowing a radical resection.
Li et al.’s meta-analysis [31] suggests that NAC
could improve tumour stage and survival rate of
patients with AGC with reasonable safety. Three
meta-analyses [32–34] suggest that adjuvant che-
motherapy (AC) may produce a small survival
benefit in patients with curatively resected gastric
carcinoma. Chen et al.’s meta-analysis [35] recom-
mends that combined NAC and AC should be used
to improve the overall survival of AGC patients.
Comprehensive tumour treatment to improve
the curative effect is very important, so that in
the future there might also be the possibility of
NACþ surgeryþ IHICþAC as a potential therapy,
which suggests that gastric cancer would be treated
by an interdisciplinary approach in general.
Safety evaluation
There are two kinds of post-operative treatment in
the RCTs: with or without chemotherapy. Post-
operative factors were balanced in the two treatment
groups of every RCT, so the contrasts of overall
survival and recurrence rate were independent of
the post-operative chemotherapy (PC). And it is
appropriate to synthesise the data of all RCTs for
meta-analysis of overall survival and recurrence rate.
But the PC is relevant to the safety evaluation
because many complications and adverse effects were
caused by chemotherapy. For example, it is not
appropriate to compare myelosuppression between
the two groups of the RCTs without PC because only
the IHIC group had chemotherapy while the other
group had no chemotherapy. So the data from the
RCTs without PC could not be pooled together for
the meta-analysis of myelosuppression, gastrointest-
inal reaction, hypohepatia and renal dysfunction,
which were the side effects of chemotherapy.
The reports of safety evaluation are not consistent,
so we performed the meta-analysis using the data
discussed by the investigators. Although there is
some clinical heterogeneity in the safety evaluation
of different RCTs, it is appropriate to combine
studies and we can get the general trend to evaluate
the IHIC.
The meta-analysis showed that IHIC does not
increase the incidence of anastomotic leakage, ileus,
bowel perforation, myelosuppression, gastrointest-
inal reaction and hypohepatia. Abdominal pain was
increased by IHIC but all the reports explained that it
disappears naturally. So we suggest that surgery
combined with IHIC for advanced gastric cancer is a
feasible treatment.
Study limitations
Only acceptable RCTs were included in order to
ensure the quality of the meta-analysis, but the data
in some types of trials have also investigated this
issue. One study [36] of 174 patients was excluded
because it was a retrospective study. Three RCTs
[37–39] were excluded because the rate of loss to
follow-up was more than 20%, which might cause
bias. All of these studies indicated that IHIC has
superior curative effects and is feasible.
The quality of some of the RCTs included was not
adequate in this meta-analysis as they did not report
the detailed method of random sequence generation
and concealment of allocation. Recurrence and
safety were not reported in a unified standard
throughout the trials, thus there may be lack of
precision in the meta-analysis; however, the sensitiv-
ity analysis indicated that findings were not markedly
changed. The data were insufficient to evaluate the
safety of IHIC adequately. In addition, economic
outcomes and quality of life were not reported in any
of the RCTs included. Although the surgical
methods in some RCTs are not currently acceptable
anymore, they are irrelevant to the results of this
meta-analysis because the surgical factors were
balanced in the two groups of every RCT.
Because of the reasons above, we suggest that
prospective trials should be well-designed, well-
executed and well-reported, in order to adequately
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evaluate the role of IHIC. We also need to collect the
data of non-randomised studies to adequately assess
the safety of IHIC.
The conclusion and the prospect of thermatology
Compared with RS alone, RS combined with IHIC
for AGC without peritoneal metastasis can reduce
post-operative recurrence rates and improve overall
survival without increasing the risk of anastomotic
leakage, ileus, bowel perforation, myelosuppression,
gastrointestinal reaction and hypohepatia. Although
IHIC increased the incidence of abdominal pain, this
disappeared naturally. The safety of IHIC can be
generally accepted. There are also some problems
with IHIC, which should be improved by clinical
practice and study. Some of these include the best
temperature for perfusion, the dosage and compat-
ibility of medicines for perfusion, and other issues.
In addition, we should pay attention to try to prevent
and reduce adverse reactions and complications.
Hyperthermia therapy has positive clinical value
for the tumour. There have been many evidence-
based studies for hyperthermia therapy. Two reviews
[40–41], from Lancet Oncology and the International
Journal of Hyperthermia, have introduced various
clinical applications of hyperthermia, and have
summarised the clinical trials comprehensively
regarding hyperthermia combined with radiotherapy
and chemotherapy for various tumours.
Chua et al.’s study [42] demonstrated a superior
effect in patients with advanced ovarian cancer who
received cytoreductive surgery and IHIC, when
compared with the traditional standard of care.
Two Cochrane systematic reviews [43–44] investi-
gated hyperthermia treatment for cervical cancer and
rectal cancer respectively, and suggested there were
positive effects of hyperthermia therapy. Two trials
[45–46] indicated that radiotherapy combined with
hyperthermia had significant benefits compared to
radiotherapy alone for the lung or nasopharyngeal
cancer. Two trials [47–48] suggested that che-
motherapy combined with hyperthermia had signifi-
cant benefits for lung or pancreatic cancer. Bergs
et al.’s review [49] suggested that trimodality therapy
consisting of hyperthermia, cisplatin and radiation is
effective and feasible in patients and seems to be
promising. Mi et al.’s meta-analysis [50] indicated
that chemoradiotherapy combined with hyperther-
mia for non-small-cell lung cancer had superior
effects. Three trials [51–53] indicated that neo-
adjuvant chemoradiation combined with regional
hyperthermia followed by oesophageal resection for
patients with oesophageal cancer resulted in good
loco-regional control and overall survival. Kang
et al.’s trial [54] indicated that hyperthermia
seemed to increase the response of both primary
tumour and lymph nodes to preoperative radio-
chemotherapy in patients with locally advanced rectal
cancer. All these studies have demonstrated the value
of hyperthermia therapy for cancer, and provided the
reference for clinical practice and research of
hyperthermia at the same time.
Non-invasive temperature measurement, targeted
therapy and control of thermal dose are the crux of
hyperthermia treatment. Two studies [55–56] sug-
gested that targeted hyperthermia by nanoparticles
has great value and is promising. Three studies
[57–59] researching the method of non-invasive
temperature measurement are valuable for the
improvement of the efficacy of hyperthermia treat-
ment. We hope that there will be more high quality
experiments and clinical trials researching hyperther-
mia therapy for tumours, and breaking through the
technical bottleneck of hyperthermia treatment,
which is critical to popularise this treatment.
We hope that hyperthermia therapy for tumours
can play an increasing role in clinical practice.
Acknowledgements
We wish to thank Qi Zhou, of the Department of
Clinical Epidemiology and Biostatistics, McMaster
University, for her valuable guidance in data analysis.
Declaration of interest: The authors report no
conflicts of interest. The authors alone are respon-
sible for the content and writing of the paper.
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