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REVIEW
Incidence, risk factors, and pathogenesis of second malignancies inpatients with non-Hodgkin lymphoma
JONATHAN TWARD, MARTHA GLENN, MICHAEL PULSIPHER, PHILLIP BARNETTE, &
DAVID GAFFNEY
Huntsman Cancer Hospital, University of Utah, UT, USA
(Received 28 February 2007; revised 10 May 2007; accepted 11 May 2007)
Abstract
Most Non-Hodgkins Lymphoma patients will survive their diagnosis. High dose chemotherapy and autologous stem celltransplantation, and radiation therapy have all been implicated as risk factors to secondary cancer development. Herein, wewill review the molecular biology, examine the epidemiologic findings, discuss the impact of both chemotherapy andradiotherapy, and focus on the special populations of pediatrics and high dose chemotherapy and autologous stem celltransplantation with regard to secondary cancer development.
Keywords: Secondary malignancies, non-Hodkin lymphoma, radiation, epidemiology
Introduction
Most patients with a diagnosis of NHL will survivetheir malignancy, with a reported five year relative
survival rate of 61.7% [1]. Annually in the United
States, approximately 56 300 new cases of non-
Hodgkins lymphoma will be diagnosed with an
estimated 19 200 deaths due to NHL [2]. Improve-
ments in multimodality therapy have all contributed
to an increase in survival. Along with our increasing
success in treating NHL, there has also been a
concomitant increase in secondary neoplasms which
are likely related to therapy. Many studies [3 20]
have demonstrated that NHL patients are at sig-
nificantly elevated risk for secondary cancers, despite
earlier reports to the contrary [21 25].Population-based data is well-powered but ham-
pered by a lack of histologic treatment, and patient
specific details that would allow for subgroup
analyses. Very few studies control for the effect of
treatment on the risk of secondary malignancy.
Therefore, while these studies in general confirm
the increased risk of secondary malignancies in
NHL, specific evidence supporting mechanisms of
carcinogenesis is lacking for many of the observed
cancers.
Using the current WHO lymphoma classification,there are over 20 different histologic types of non-
Hodgkins lymphoma described [26]. Clinicians tend
to simplify this system into two broad categories
based upon natural history and treatment appro-
aches, and consider them either low grade or
intermediate/high grade lymphomas based upon the
Working Formulation [27,28].
The low grade lymphomas are those that tend to
grow slowly over months or years, often causing little
or no symptoms and for which a watch and wait
approach may be appropriate for patients with stage
III and IV disease. Median age at presentation is
65 years. When treatment becomes necessary,prompted by symptoms, rapid progression of disease
or organ compromise, many different approaches are
available. There is no accepted standard approach for
initial or subsequent treatment of these patients, and
patients may receive immunotherapy, chemotherapy,
radioimmunotherapy, radiation or combinations
thereof for initial treatment. As there is no curative
approach at this time and although most patients
Correspondence: Dr. Jonathan D. Tward, Department of Radiation Oncology, Huntsman Cancer Hospital, University of Utah, 1950 Circle of Hope. Salt Lake
City, Utah, 84112-5560, USA. Tel: 801-581-3119. Fax: 801-585-2666. E-mail: [email protected]
Leukemia & Lymphoma, August 2007; 48(8): 1482 1495
ISSN 1042-8194 print/ISSN 1029-2403 online 2007 Informa UK Ltd.
DOI: 10.1080/10428190701447346
7/30/2019 Incidence, Risk Factors,
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respond well to initial therapy with response dura-
tions of months or years, recurrence or progression of
disease will necessitate multiple treatments in most
patients. And while response to these future treat-
ments, again selected with an individualized
approach, tends to be excellent, quality, and duration
of response decreases with each treatment.
Eventually, patients succumb from bone marrow
failure, infection or progressive lymphoma. There-
fore, the secondary malignancies seen in these
patients may be related to prolonged, repeated
exposure to chemotherapy agents, interaction be-
tween sequential exposures to chemotherapy, and
other treatment modalities such as radiation or
radioimmunotherapy, prolonged immunosuppres-
sion due to the underlying disease and repeated
treatments, and advanced age.
The intermediate/high grade lymphomas are more
aggressive, progress rapidly, and require immediatetreatment. The median age at presentation is younger
than for low grade lymphomas. Treatment for
these lymphomas tends to be more standardized and
intensive than that for the low grade lymphomas.
General cure rates are approximately 45 50% with
current standard first-line therapy, although some
relapsed/refractory patients can be cured with salvage
chemotherapy and high dose chemotherapy with stem
cell rescue [29,30]. Therefore, in contrast to those
seen in low grade lymphomas, secondary malignancies
would be expected to have a greater impact on the
patients overall survival and quality of life given they
might be lymphoma-free and diagnosed at ayounger age. The etiology of these malignancies might
be related more to dose intensity/density and addi-
tional risk of treatment with definitive radiotherapy
rather than from repeated or continuous exposure to
treatment as for the low grade lymphomas. Prolonged
immunosuppression is less likely to play a role.
Chemotherapy [4,14,19,31,32], high dose che-
motherapy and autologous stem cell transplantation
[12,15,17,20], and radiation therapy [3,6,16,33,34]
have all been implicated as risk factors to secondary
cancer development. Herein, we will review the
molecular biology, examine the epidemiologic find-
ings, discuss the impact of both chemotherapy andradiotherapy, and focus on the special populations of
pediatrics and high dose chemotherapy and auto-
logous stem cell transplantation with regard to
secondary cancer development.
Molecular biology of carcinogenesis
Chemotherapy related carcinogenesis
Chemotherapy has been used to treat NHL for
decades. The type of agent, cumulative dose, exp-
osure time, mode of administration, and interactions
with other treatments and patient characteristics all
seem to play a role in secondary cancer development
[35 37]. Most of the chemotherapy agents used
historically and currently for NHL are alkylators,
methylators, topoisomerase inhibitors, and purine
analogs. These all could contribute to secondary
malignancies by various pathways, as outlined below.
These are typically used in combination, often
followed by radiotherapy, so assigning risk to specific
agents is difficult. Unfortunately, there are few
specific markers, molecular or otherwise, for
chemotherapy-induced cancers, although some cyto-
genetic abnormalities seen in secondary myelo-
dysplastic syndrome (MDS)/AML are more
prevalent than in de novo MDS/AML, and some
preliminary studies have begun to elucidate specific
point mutations that might be seen more frequently
in secondary malignancies [38 41].Alkylators and methylators such as cyclopho-
sphamide, procarbazine, dacarbazine, and thiogua-
nine are included in most NHL regimens. They
alkylate DNA, transferring an alkyl group, such as a
methyl group, to DNA, causing DNA mismatch,
inhibition of DNA replication and transcription, and
if not repaired, apoptosis. Secondary acute myelo-
genous leukemia, thought to arise from exposure of
bone marrow stem cells to these agents, is char-
acterized by a relatively long latency of 2 10 years,
a preceding myelodysplastic syndrome, and complex
karyotypic abnormalities. These features point to a
multihit pathway of leukemogenesis due to chromo-somal instability and mutations of multiple genes
responsible for cell cycle regulation [42]. These
agents methylate DNA including O6-guanine which
is typically repaired by O6-methylguanine methyl-
transferase (MGMT). If the cell is deficient in
MGMT, then the mismatch must be repaired by the
cells DNA mismatch repair mechanism (DNA-
MMR) or apoptosis occurs. If DNA-MMR is
defective in the cell, these point mutations are
tolerated, accumulate and eventually contribute to
carcinogenesis. Therefore, cells with defective or low
level expression of MGMT may be more susceptible
to these effects. Recent findings showing diminishedMGMT levels in bone marrow stem cells may
explain the unique sensitivity to the carcinogenic
effects of these agents [42]. In addition, alkylating
agents are often associated with nonrandom loss
of genetic material from chromosomes 5 and 7
[16,43].
Topoisomerase inhibitors, which include anthra-
cyclines such as doxorubicin and epidopophyllo-
toxins like etoposide, are also very commonly
used for treatment of NHL. In fact, anthracyclines
are considered a crucial component in virtually every
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front-line regimen for intermediate/aggressive lym-
phomas. These medications inhibit the religation of
DNA cleaved by topoisomerases, causing multiple
double strand breaks and ultimately initiating apop-
tosis in cancer cells. If the cell does not die, these
double strand breaks may be mistakenly ligated to
other loci, causing the common translocations
detected in tAML [42,44]. These translocations
can result in incorrectly regulated expression of key
genes or in chimeric proteins with lost or aberrant
functions in the affected bone marrow cells which,
possibly combined with other mutations, lead to
leukemia [45]. This hypothesis is supported by the
short latency of these leukemias of months to 5 years
and by the presence of characteristic translocations
detected by karyotyping [36,46]. Certain loci are
commonly involved in these translocations and many
have been mapped to topoisomerase cleavage sites,
most often the MLL gene at chromosome 11q23,AF4, and AF9, t(8;21) causing juxtaposition of the
RUNXand ETO loci, and t(15;7) involving the PML
and RAR loci.
Genetic susceptibility may also play a role by means
of genetic polymorphisms, in which certain indivi-
duals may metabolize environmental or therapeutic
agents to different degrees, either activating or
inactivating these agents, which may lead to increased
production of carcinogenic intermediates. Examples
include an NAD(P)H:quinine oxidoreductase1 poly-
morphism which may render an individual suscep-
tible to therapy-related myelodysplasia and leukemia
[47,48], and a glutathione S-transferase-P1 poly-morphism which may increase ones risk of develop-
ing therapy-related leukemia [49].
Radioimmunotherapy (RIT) is emerging as an
important therapy in relapsed NHL. Although the
secondary malignancy risk specifically due to the RIT
component of therapy has not been well described,
case series have suggested a correlation between RIT
containing regimens and secondary MDS and AML
[50]. The secondary cancer burden due to RIT will
only be elucidated as experience with RIT containing
regimens matures.
Radiotherapy related carcinogenesis
Radiotherapy is a known mutagen and carcinogen.
In contrast to chemotherapy carcinogenesis, radio-
therapy can induce multiple mutations with an
extended latency. This may implicate a multistage
mechanism of carcinogenesis, and suggest that
some form of genomic instability is operative [42].
Radiotherapy has not been implicated in specific
molecular alterations leading to secondary cancers.
However, radiotherapy and ionizing radiation
have long been known to induce specific cancers
especially leukemias and solid tumors, namely
sarcomas.
Ionizing radiation refers to radiation of sufficient
energy to break covalent bonds. X-rays of both
diagnostic and therapeutic energies are sparsely
ionizing, indicating there are few ionizing events
per path of a photon. In contrast, certain forms of
radiation are densely ionizing, such as neutrons and
particle radiation [51]. Radiation is known to inter-
act with proteins, lipids and reducing agents
(glutathione) in cells and the extracellular matrix;
however, the dominant target molecule in cells is
DNA [52]. Approximately one third of DNA damage
from radiotherapy is believed to be directly attribu-
table to incoming photons, while two thirds of the
damage is believed to be radiation induced splitting
of water molecules (radiolysis) which generate
hydroxyl radical and free electrons. Hydroxyl radical
reacts with the heterocyclic bases in DNA byaddition [53]. This results in both single and double
strand DNA breaks that may be either sublethal or
lethal to the cell by the formation of chromosomal
mutations, translocations, dicentrics, rings, acentric
fragments, and anaphase bridging. For a more
thorough account of radiation carcinogenesis and
radiobiology, the interested reader should review
Dr. Eric Halls excellent textbook [54].
Epidemiologic findings
Population statistics
Several recent large population based studies have
used cancer registry data to examine secondary can-
cer risk in patients with NHL [3,8,9,55]. The studies
support an increased relative risk of secondary malig-
nancy of about 1.14 to 1.47 over the general
population.
The epidemiologic literature relies upon the
standardized incidence ratio (SIR) and absolute
excess risk (AER) as two complimentary measures
of the incidence of an event of interest (in this case
secondary cancer) in a subpopulation as compared to
the entire population. Both are based on comparing
the observed number of events in the subpopulationO with the number of events E expected if the risk
profile of the subpopulation were identical to that of
the full population. As a person ages his or her risk of
an event typically changes due to both attained age
and attained calendar year. The calculation of the
expected number of events is adjusted for these
variables. Additionally, fixed characteristics affecting
event rates, such as gender and race, are incorpo-
rated in the calculation of the expected number of
events. These adjustments make subpopulations of
different structures comparable: for example, longer
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follow-up in one group. SIR and AER differ in
the way they combine O and E: SIR measures the
fold-difference between the observed and expected
number of events (SIRO/E), while AER measures
the actual number of excess events normalized to
the number of person-years observed (AER
(O-E)/PY). Thus, SIR measures the relative risk of
the event on an individual levelit does not depend
on the frequency of the event in the population, while
AER measures the population impactsmall in-
creases in the relative risk of a common event affects
more people than a large increase in a rare event. It
should be noted that the length of follow-up does not
affect either measure: the number of observed events
O increases, but so do the number of expected events
E and the number person-years PY [3]. In this
review, the AER is expressed as number of events per
10 000 person-years.
We recently reported on the risk of secondarycancer development in 77 823 survivors of NHL from
the United States SEER data base [3]. Over 2000
twenty-plus year survivors were included, allowing us
to evaluate cancer risk over three decades. Second
cancers developed in 5638 people. In some cases,
more than one secondary cancer was diagnosed; thus,
6188 additional malignancies were observed. Details
of our study are reviewed below.
Overall, for NHL survivors second malignancies
occurred at a higher rate than that expected in the
general population (O/E 1.14, 95% CI 1.11 1.17,
AER 20.12,). There was a significantly increased
risk for cancers of the head and neck, melanoma,lung, colon, bladder, kidney, Hodgkins disease,
leukemia, and Kaposis sarcoma versus the general
population. External beam radiation did not signifi-
cantly alter the overall risk for secondary cancers
versus unirradiated patients with NHL (all sites: O/E
1.18 vs. 1.13, AER 23.36 vs. 19.36,). However, when
comparing specific cancer subtypes between the
irradiated and nonirradiated cohorts, radiation ther-
apy resulted in significantly more soft tissues cancers
(sarcomas), female breast cancers, and mesothelio-
mas (p5 0.05), Table I.
Age at diagnosis
The overall O/E risk of secondary malignancies was
highest for the youngest patients and trended down-
ward with increasing age. NHL diagnosed after age
75 carried a similar relative risk of secondary
malignancies to that of the general population. The
O/E risk of secondary cancers is greatest for the
youngest cohort, while the absolute excess risk for
secondary cancers peaks for people aged 25 49 years
of age at the time of their initial NHL diagnosis and
then declines with advancing age. This held true for
both the irradiated and unirradiated patient cohorts
(Table II).
Gender
In general, the O/E risk of all secondary cancers was
similar in men and women (O/E 1.15 vs. 1.12;
RR 1.02 p 0.92). Lung and mediastinal cancers
accounted for the greatest AER in both men and
women (6.36 and 7.19, respectively). When exclud-
ing sex-specific malignancies, we discovered that
women had a relative risk of 1.29 for secondary
cancers over the general population.
Latency period
Often the incidence of secondary cancers increase
with time; however, our data did not conclusively
demonstrate that [3]. At first glance, it appears thatwith increased latency the standardized incidence
ratio increases: for all cancers SIR 1.12, 1.21, and
1.50 for latencies 510, 10 20, and420 years, res-
pectively; for a test of linear trend, p-value50.0001.
However such an analysis is misleading, as age at
diagnosis affects both the risk of secondary cancers
and the probability of surviving 10 or 20 years past
diagnosis. After adjusting for age at diagnosis, the
effect of latency disappears.
Reduction in cancer risk
A significantly decreased risk of female breast,prostate, and myeloma was also observed in NHL
survivors. Although the unirradiated persons had a
significantly decreased risk of developing female
breast cancer across all age cohorts (O/E 0.79,
AER73.57), the risk for the irradiated group was
equivalent to the endemic rate (O/E 1.00,
AER 0.01). Female breast cancer accounted for
the greatest number of observed secondary malig-
nancies (548 persons) in women, yet NHL survivors
are protected from this malignancy versus the general
population. It has been hypothesized that lowered
estrogen levels due to ablation of ovarian function
from chemotherapy may explain this decline. ForHodgkins disease, patients that receive ovarian
ablative therapy with either chemotherapy of radio-
therapy, a decrease in breast cancer has been
observed [56,57]. Prostate cancer risk was also
significantly lower for unirradiated persons than the
standard population (O/E 0.89, AER73.11).
Several hypotheses could explain the reduced risk
for prostate cancer in NHL survivors. Therapy for
NHL may eradicate or delay the clinically detectable
progression of occult prostate cancers [58,59].
Another speculative hypothesis is that men who
Second malignancies in patients with NHL 1485
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have been diagnosed with a prior malignancy may bemore conscientious of their health resulting in
lifestyle changes impacting their prostate cancer risk
[60 62]. The above two arguments may also
account for the decline observed in the diagnosis of
myeloma after treatment for NHL.
Many clinical and pathological data known to be of
prognostic significance are not available in the SEER
database. Specifically lacking is information regard-
ing lymphoma staging, details about type or amounts
of chemotherapy, or if they received bone marrow
transplant, the proportion of individuals who had
HIV, or who were otherwise immunocompromised,or the specifics of radiotherapy dose, treatment fields,
and fractionation schemes [1]. In addition, the SEER
database does not record history of treatment failure
or time of relapse. Therefore, we were unable to
adjust for these factors in our analyses.
Radiation induced second malignancies
There are several well characterized scenarios where
radiation has been clearly linked to induction of neo-
plasia. The best characterized episodes of ionizing
Table I. Comparison of standardized incidence ratios and absolute excess risk for patients by treatment modality.
No radiation radiation#
Persons 55 392
Person years at risk
261 545 Persons 21 111
Person years at risk
112 281
Observed Excess risk O/E 95% CI Observed Excess risk O/E 95% CI
All sites 4334 19.36 1.13 1.1 1.17 1752 23.36 1.18 1.12 1.23
All sites excluding NHL 4191 19.14 1.14 1.1 1.17 1671 20.9 1.16 1.11 1.22
All solid tumors{ 3752 12.84 1.1 1.06 1.13 1521 17.06 1.14 1.09 1.2
Gyn malignancies 173 70.55 0.92 0.79 1.07 80 0.36 1.05 0.84 1.31
Head and neck 159 1.42 1.3 1.11 1.52 61 1.1 1.25 0.96 1.61
Melanoma 145 1.75 1.46 1.23 1.72 61 1.96 1.56 1.2 2.01
Lung and mediastinum 782 7.28 1.32 1.23 1.42 300 6.25 1.31 1.16 1.46
Soft tissues{ 27 0.31 1.42 0.94 2.07 20 1.11 2.65 1.62 4.1
Esophagus 38 70.07 0.95 0.67 1.31 11 70.39 0.72 0 .36 1 .28
Stomach 87 0.31 1.1 0.88 1.36 39 0.67 1.24 0.88 1.69
Colon excluding rectum 440 2.12 1.14 1.04 1.26 152 0.21 1.02 0.86 1.19
Rectum and rectosigmoid junction 130 70.34 0.94 0.78 1.11 50 70.45 0.91 0.67 1.2
Anus, anal canal and anorectum 10 0.06 1.2 0.58 2.21 5 0.15 1.53 0.49 3.57
Liver, gallbladder, and billary 54 70.2 0.91 0.68 1.19 24 0.05 1.02 0.66 1.52
Pancreas 827
0.75 0.81 0.64 1 43 0.31 1.09 0.79 1.46Breast{ 360 73.58 0.79 0.71 0.88 183 0.22 1.01 0.87 1.17
Female breast{ 356 73.57 0.79 0.71 0.88 179 0.01 1 0.86 1.16
Male breast 4 70.01 0.94 0.25 2.4 4 0.21 2.45 0.66 6.28
Prostate 627 73.11 0.89 0.82 0.96 243 71.9 0.92 0.81 1.04
Testis 5 0.02 1.1 0.36 2.58 0 70.2 0 0 1.66
Penis 6 0.11 1.86 0.68 4.05 1 70.02 0.8 0.01 4.45
Urinary bladder 284 3 1.38 1.22 1.55 95 1.42 1.2 0.97 1.47
Kidney and renal pelvis 134 1.87 1.58 1.32 1.87 52 1.69 1.58 1.18 2.07
Brain 38 0.02 1.01 0.72 1.39 16 0.09 1.06 0.61 1.73
Thyroid 25 0.09 1.11 0.72 1.63 18 0.76 1.89 1.12 2.99
Hodgkin lymphoma 51 1.59 5.44 4.05 7.15 14 0.89 3.49 1.9 5.85
Myeloma 27 70.82 0.56 0.37 0.81 7 71.03 0.38 0 .15 0 .78
Leukemia 183 3.19 1.84 1.58 2.12 59 1.8 1.52 1.16 1.96
Mesothelioma{ 9 70.06 0.86 0.39 1.63 9 0.45 2.26 1.03 4.28
Kaposi sarcoma 83 2.93 13.24 10.54 16.41 30 2.43 11.09 7.48 15.83
Miscellaneous 153 1.78 1.44 1.22 1.69 57 1.38 1.37 1.04 1.78
Values in reverse typeface represent p50.05 or standardized incidence ratio versus general USA population.
Values with shaded background represent p50.05 for differences in SIR between the No Radiation and Radiation cohorts.
The number of patients entering the external beam radiation group was 9734 and the corresponding number of person years was 54 249.
Excess Risk is #cases/10 000 person years.#Includes patients whose radiotherapy as encoded was External Beam only.{Excludes lymphohematopoietic disorders.{p0.05 for differences in SIR between NHL patients who did, or did not receive radiotherapy.{p0.01 for differences in SIR between NHL patients who did, or did not receive radiotherapy.For female specific sites, the number of patients entering the no radiation group was 25 460 and the corresponding number of person years
was 12 7398.
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TableII.Theageatdiagnosiso
fNHLalterstheriskprofileforsecondarymalignancies.
Noradiation
radiation
#
525
2549
5074
75
525
2549
5074
75
Persons
1752
Person
years
atrisk
12288
O/E
Persons
11061
Person
yearsat
risk
65442
O/E
Persons
29549
Person
yearsat
risk
148890
O/E
Persons
12989
Person
yearsat
risk
34453
O/E
Persons
1041
Person
yearsat
risk
8842
O/E
Persons
5104
Person
yearsat
risk
31744
O/E
Persons
10737
Person
yearsat
risk
59811
O/E
Persons
4218
Person
yearsat
risk
11624
O/E
Excess
risk
Excess
risk
Excess
risk
Excess
risk
Excess
risk
Excess
risk
Excess
risk
Excess
risk
Allsites
5.11
2.1
33.55
1.81
22.24
1.12
715.77
0.94
19.36
4.51
44.72
2.01
20.14
1.11
717.06
0.93
Allsites
excluding
NHL
3.03
1.71
32.06
1.81
22.49
1.13
714.74
0.94
17.5
4.42
39.39
1.93
18.66
1.11
716.48
0.93
Allsolidtumors
{
1.35
1.38
26.33
1.71
14.66
1.09
716.83
0.92
11.52
3.67
35.15
1.88
14.21
1.09
714.85
0.93
Gyn malignancies
70.32
0
1.76
1.59
71.22
0.86
72.09
0.81
0.71
2.7
1.76
1.59
71.13
0.87
3.23
1.28
Headandneck
70.11
0
1.64
1.87
1.37
1.23
1.88
1.33
70.14
0
0.81
1.4
1.56
1.26
0.58
1.11
Melanoma
70.51
0
1.62
1.69
1.87
1.43
2.37
1.46
1.63
3.61
2.32
1.97
2.17
1.52
0.3
1.06
Lungand
mediastinum
70.12
0
6.82
2.3
11.04
1.37
75.85
0.82
70.15
0
8.58
2.45
8.88
1.31
78.02
0.74
Softtissues
0.6
3.74
0.26
1.75
0.2
1.25
0.77
1.61
0.92
5.26
2.17
7.13
0.71
1.88
0.49
1.4
Esophagus
70.01
0
0.05
1.12
70.26
0.86
0.53
1.22
70.01
0
0.5
2.11
70.88
0.53
70.52
0.77
Stomach
70.03
0
0.49
1.85
70.34
0.9
2.97
1.43
70.04
0
0.61
1.93
0.79
1.22
0.88
1.13
Colonexcluding
rectum
0.71
8.12
0.66
1.27
3.4
1.2
70.12
1
70.13
0
0.49
1.18
1.58
1.09
78.63
0.75
Rectumand
rectosigmoid
junction
70.06
0
70.04
0.97
70.04
0.99
72.18
0.78
70.07
0
70.14
0.9
70.14
0.98
73.07
0.69
Anus,analcanal
andanorectum
70.01
0
0.62
5.49
70.18
0.53
0.07
1.15
70.02
0
0.49
4.6
0.13
1.35
70.51
0
Liver,gallbladder,
bileducts
70.03
0
0.24
1.47
70.03
0.99
71.83
0.61
70.04
0
0.37
1.65
70.34
0.87
1.31
1.28
Pancreas
70.02
0
0.18
1.24
71.05
0.77
71.37
0.84
1.1
38.85
0.46
1.57
0.8
1.17
73.13
0.62
Breast
70.44
0
71.98
0.76
73.57
0.83
77.67
0.72
2.72
5.03
1.92
1.25
71.58
0.92
2.55
1.09
Femalebreast{
70.44
0
71.93
0.76
73.57
0.82
77.68
0.71
2.72
5.05
1.67
1.21
71.89
0.91
2.79
1.1
Malebreast
0
0
70.05
0
0
1.01
0.02
1.07
0
0
0.26
5.38
0.31
2.58
70.24
0
Prostate
70.02
0
70.9
0.8
73.7
0.9
76.18
0.86
70.04
0
0.39
1.07
73.93
0.88
0.74
1.02
Testis
0.35
1.74
0.06
1.14
70.01
0.85
70.04
0
70.52
0
70.39
0
70.08
0
70.04
0
Penis
0
0
0.12
4.47
0.12
1.85
0.05
1.2
0
0
0.28
8.2
70.15
0
70.22
0
Urinarybladder
70.06
0
2.79
2.87
3.75
1.4
1.13
1.07
70.08
0
2.37
2.38
1.88
1.2
72.15
0.86
Kidneyand
renalpelvis
70.07
0
1.6
2.4
2.45
1.6
0.66
1.14
70.09
0
3.19
3.62
1.41
1.36
70.32
0.93
Brain
0.54
3
70.08
0.89
70.02
0.99
0.2
1.11
0.85
4.07
0.23
1.32
70.24
0.86
0.83
1.47
(continued)
Second malignancies in patients with NHL 1487
7/30/2019 Incidence, Risk Factors,
7/15
TableII.(Continued).
Noradiation
radiation
#
525
2549
5074
75
525
2549
5074
75
Persons
1752
Person
years
atrisk
12288
O/E
Persons
11061
Person
yearsat
risk
65442
O/E
Persons
29549
Person
yearsat
risk
148890
O/E
Persons
12989
Person
yearsat
risk
34453
O/E
Persons
1041
Person
yearsat
risk
8842
O/E
Persons
5104
Person
yearsat
risk
31744
O/E
Persons
10737
Person
yearsat
risk
59811
O/E
Persons
4218
Person
yearsat
risk
11624
O/E
Excess
risk
Excess
risk
Excess
risk
Excess
risk
Excess
risk
Excess
risk
Excess
risk
Excess
risk
Thyroid
70.34
0
0.37
1.43
0.02
1.02
0.07
1.08
3
8.69
1.04
2.21
0.09
1.09
1.76
3.15
Hodgkin
lymphoma
1.26
4.39
1.68
6.52
1.78
5.86
0.74
2.77
0.74
2.89
0.96
4.15
0.8
3.17
1.3
4.12
Myeloma
70.01
0
0.05
1.13
71.02
0.54
71.91
0.48
70.02
0
70.12
0.73
71.18
0.46
73.51
0
Leukemia
0.53
2.92
3.04
4.28
3.88
1.9
1.54
1.18
4.24
16.21
2.47
3.47
1.55
1.36
70.44
0.95
Mesothelioma
0
0
70.07
0
70.16
0.67
0.42
1.56
0
0
0.23
3.56
0.85
2.74
70.67
0
Kaposisarcoma
1.4
7.17
10.04
21.02
0.55
5.55
0.32
2.23
70.26
0
7.41
16.97
0.72
7.03
70.25
0
Miscellaneous
70.05
0
0.64
1.87
2.67
1.6
0.29
1.03
1.07
19.91
1.09
2.36
2.02
1.45
70.72
0.93
Valuesinreversetypefacerepresentp5
0.05forstandardizedincidenceratioversusgeneralUSApopulation.
Forfemalespecificsites,thenumberofp
atientsenteringtheexternalbeamradiation
525,2549,5074,and75
ageintervals
was328,1778,5046,and2582andthecorrespondingnumberof
personyearswas3105,13444,30255,
and7445respectively.
Excessriskis#cases/10000personyears.
#Includespatientswhoseradiotherapyw
asencodedasExternalBeamonly.
{Excludeslymphohematopoieticdisorde
rs.
{Forfemalespecificsites,thenumberof
patientsenteringthenoradiation525,25
49,5074,and75
ageintervalswas592,
3944,13587,and7337andthecorrespond
ingnumberofperson
yearswas4294,27843,74561and20
701respectively.
1488 J. Tward et al.
7/30/2019 Incidence, Risk Factors,
8/15
radiation include atomic bomb survivors, patients
with tuberculosis treated with high doses secondary
to the use of fluoroscopy (dynamic X-ray use),
patients treated for anklosying spondilitis with
fluoroscopy, patients treated with superficial X-rays
for postpartum mastitis and tinea capitis, and
patients treated with radiotherapy [52]. The induc-
tion of second malignancies after radiotherapy have
clearly been related to patient age, radiation dose,
length of follow-up, site treated, and field size. Thus,
a common definition of a second malignancy from
radiotherapy is a tumor of new histologic type in a
previous radiotherapy field appearing ten years or
more after a course of radiotherapy. The statistical
probability is greatest when the above definition is
met; however, other data have implicated doses out
of field are sufficient to cause a statistically
significant increase in second cancers. Often when
discussing second cancers after radiotherapy, it isuseful to discuss in field versus out of field. In a
landmark paper by Travis et al., they documented the
dose response relationship for breast cancer induc-
tion in female survivors of Hodgkins disease indi-
cating that doses as low as 4 Gy yield a statistically
significant increase [57]. Both in field and out of
field radiation is likely operative in second cancers
after the treatment of NHL.
When interpreting population based studies, one
has to be mindful that radiotherapy techniques have
markedly improved over the past several decades. In
the pre-1970s era (prior to the widespread adoption
of megavoltage linear accelerators), patients mayhave received maximum and integral doses that
were greater than those using modern radiotherapy
techniques due to nonstandardized dose/fractiona-
tion regimens, the variability and lower peak
energies from historic radiotherapy equipment,
less rigorous quality assurance, an inability to
account for tissue inhomogeneities, and a lack of
computerized treatment planning. Nevertheless, an
increasingly popular form of radiotherapy is inten-
sity modulated radiotherapy (IMRT). In IMRT,
specific organs at risk typically receive a lower dose,
whereas the total body dose is higher. This is a
function of the small fraction of radiation leakagefrom the head of the linear-accelerator. IMRT
treatments require a longer time to deliver, and
hence result in more absorbed total dose for the
patient. Since radiation carcinogenesis is a stochas-
tic effect, how these advances in technology have
altered the pattern of secondary cancers is un-
known.
In our population-based study, radiation therapy
did not significantly increase the overall, solid tumor,
or hematologic cancer risk of secondary malignancies
versus the unirradiated group. The only significant
differences seen in irradiated versus unirradiated
patients were for the development of soft tissue
malignancies (sarcomas), female breast cancer, and
mesothelioma. The increased risk of sarcoma devel-
opment in irradiated patients is well known.
[63 65]. The aggregate absolute excess risk for soft
tissue malignancies, female breast cancer, and
mesothelioma in irradiated patients is 1.57 cases
per 10 000 person years. Nevertheless, our subgroup
of patients under 25 years at the time of NHL
diagnosis who had radiation therapy had a signifi-
cantly elevated risk for leukemia, thyroid, and female
breast cancer (O/E 16.21, 8.69, and 5.03, respec-
tively). These data highlight the importance of the
judicious use of radiotherapy in young patients, and
particularly in growing children.
Chemotherapy induced second malignancies
Two relatively large studies have looked at the impact
of chemotherapy specifically on secondary cancer
development. A British cohort study investigated
the risk of secondary malignancy in 2456 NHL
patients treated from 1974 2000 and included
analyses of risk depending upon treatment with
CHOP (cyclophosphamide, doxorubicin, vincristine
and prednisone) versus chlorambucil [11]. These two
groups probably represent aggressive NHL and low
grade NHL, respectively, and so include all the
inherent differences represented by those histologic
subtypes, but no striking differences were noted.
The marked overall increased risk of secondary AMLwas confirmed (RR 8.8). For those treated with
either CHOP or chlorambucil, the risk was higher
(RR 14.2 and 19.2, respectively), solidly implicating
chemotherapy in leukemogenesis. Overall risk for
developing subsequent lung cancer was also con-
firmed at 1.6. The risk for those treated with CHOP
but not chlorambucil was higher (RR 2.1). In an
analysis of 2837 patients treated on three
GELA protocols from 1984 1998 with ACBVP
(doxorubicin, cyclophosphamide, bleomycin, vinde-
sine and prednisone), a standard chemotherapeutic
regimen for aggressive NHL, increased risk was seen
only for secondary MDS/AML (males O/E, 5.65;females, O/E 19.89), and lung cancer in males only
with a O/E of 2.45 [13]. No increased overall risk for
secondary malignancies was detected. An EORTC
cohort study revealed that smoking significantly
increases the likelihood of developing secondary
lung cancer after chemotherapy and/or radiotherapy
for NHL [66]. Increased risk of bladder carcinoma
after treatment with cyclophosphamide for NHL
has also been noted in an earlier case-controlled
cohort study. A cumulative dose effect was reported,
with no significant increased risk in those treated
Second malignancies in patients with NHL 1489
7/30/2019 Incidence, Risk Factors,
9/15
with less than 20 g total, but sixfold after 20 49 g or
14.5-fold increased risk after 50 g or more [7].
Finally, increases in risk of tAML were seen after
treatment with prednimustine, procarbazine, or
mechlorethamine (RR*13.0), and with chloram-
bucil in patients treated with 1300 mg total (RR
6.5) [67].
Therefore, it appears that chemotherapy used for
treatment of NHL increases the relative risk of
secondary MDS/AML, lung cancer, and bladder
cancer substantially. While there is an increased risk
of other secondary cancers after treatment for NHL,
these have not been directly linked to chemotherapy.
Future studies that carefully control for histology,
treatment, and patient-related factors are needed.
However, significant advancement in understanding
the pathogenesis of these cancers will be made when
molecular markers for specific exposures can be
measured [68].
Second malignancies after autologous and
allogeneic transplantation for NHL
For several decades, hematopoietic cell transplanta-
tion (HCT) has offered the ability to deliver high dose
chemotherapy with or without total body irradiation
(TBI) aimed at overcoming moderate chemotherapy
resistance in relapsed intermediate or high grade
NHL, high-risk NHL in first remission, or multiply
relapsed low-grade NHL [69]. Over the past few
years, these approaches have sometimes been com-
bined with antibodies such as rituximab [70] orradioconjugates such as bexxar or zevalin [71,72].
Recently, an increasing number of centers are turning
to allogeneic approaches with either standard or
reduced intensity preparative regimens to treat
NHL, taking advantage of an immunologic graft
versus lymphoma effect to overcome chemotherapy
resistance [73 75]. Risk factors for the development
of secondary malignancies after transplant differ by
type of secondary malignancy, with pretransplant
(previous therapy, genetic susceptibilities), transplant
specific (preparative regimen, graft manipulations),
and posttransplant (GVHD, immunodeficiency)
factors all contributing to the likelihood of a secondcancer.
Malignancies reported after transplant have been
broadly categorized as follows: (1) tMDS/t-AML
(2) LPD/lymphoma, and (3) solid tumors. Reported
incidences of all malignancies have ranged from
9.9 14% at 11 20 years after transplant [76 80].
Leukemias and lymphomas almost invariably develop
in the first 5 8 years following transplant, while solid
tumors have a longer latency period and do not
demonstrate a plateau in incidence (cumulative
incidence 2.2%, 5%, and 8.1% at 10, 15, and 20
TableIII.Riskfactorsassociatedwithsecondmalignanciesaftertran
splant.
tMDS/tAML
LPD/lymphoma
Solidtumors
EBV
Lympho-proliferativedisorders[74,87]
HodgkinDisease:[88]
LateOnsetLymphoma
Pre-transplanttherapy
Donortype/graftmanipulation
s
AcuteGVHD
ChronicGVHD[80]
Transplantrela
tedfactors
Chemotherapy
HLAmismatch
ChronicGVHD
TBI[74,80]
Numberofregimes[19]
Unrelateddonor
ChronicGVHD[80]
Otherfactors
Youngerage
attransplant[80,89]
Malesex[80
]
Useofalkylatingagents[13,81]
T-celldepletion
Pre-TransplantXRT[82,83]
Transplantrelatedfactors
UseofPBSCoverBM
[74,81,82,84]
TransplantusingTBI[13,14,81,85]
Numberoftransplants[85]
Fewercellsinfused[86]
Otherfactors
OlderageatBMT(435,38,or40)[
14,19,74]
Numberofrelapses[83]
IntervalfromdiagnosistoBMT[19,8
5]
LowplateletcountafterBMT[19]
ATGtherapy
Anti-CD3monoclonalantib
odytherapy
Pre-andPost-transplantImmu
odeficiencies
Primarydiagnosisofimmun
odeficiency
AcuteGVHD
ChronicGVHD
1490 J. Tward et al.
7/30/2019 Incidence, Risk Factors,
10/15
years respectively) [81]. Factors contributing to risk
are somewhat different for each of these three
categories of malignancies (Table III).
Therapy related MDS and AML (tMDS/tAML) is
most closely associated with intensity of treatment,
both pretransplant and during transplant. These
diseases most often occur after an autologous HCT
in a heavily pretreated individual, likely reflecting
DNA damage to marrow that is returned to the
patient. The finding that radiation involving signifi-
cant marrow exposure used prior to transplant and
higher dose TBI given as part of the transplant shows
that radiation damage to marrow and marrow stroma
contributes to risk. The increased risk of tMDS/
tAML noted with smaller amounts of marrow
infused, older donors (less marrow reserve), and
poor platelet counts after transplant further illustrate
the importance of healthy marrow function to cancer
prevention.Risks factors associated with the development of
posttransplant lymphoproliferative disorders (LPD)
and Hodgkins disease or NHL after transplant differ
significantly from tMDS/tAML. These cancers are
associated with immune deficiency created by
unrelated or mismatched grafts, T-cell depletion,
primary immunodeficiencies, immune suppressive
medications, or GVHD (Table II).
Secondary solid tumors after transplant occur
following both allogeneic and TBI-containing auto-
logous procedures. Tumors of the oral cavity, brain,
liver, uterus/cervix, thyroid, breast, bone, and con-
nective tissue, along with melanoma have beenreported and are thought to be associated with
radiation exposure [82]. Squamous cell cancers are
generally associated with tissue damage associated
with chronic GVHD [82]. Because of thelong lag-time
between transplant and the onset of these tumors,
younger age has been described as a risk factor for
solid tumors, but whether this is a true risk factor or
simply a product of the fact that a larger number of
younger patients live decades after allogeneic trans-
plants and are therefore susceptible is unknown.
Secondary malignancies after therapy fornon-Hodgkins lymphoma in pediatric
patients
The estimated cumulative probability of developing
any second malignancy after treatment of childhood
cancer is approximately 3% at 20 years, a 3- to
10-fold risk over the general population [49,83 85].
Few studies report the specific rate of second cancers
after therapy for non-Hodgkins lymphoma, with
reported estimates ranging from.1.4% to 4.8% at
20 years [84 86]. Difficulties in accurate estimation
may result from small numbers of reported cases,
evolution of therapy over treatment generations, and
variability in secondary malignancy rates reported
for the three primary types of childhood NHL: the
lymphoblastic (10.9%), small, noncleaved (.5%),
and large cell histologies (5.8%) [86].
Secondary malignancies are of two major subtypes:
(1) therapy related acute myeloid leukemias and
myelodysplastic syndromes (t-AML/MDS), gener-
ally presenting 1 5 years following initial therapy
with topo-isomerase II inhibitors or alkylating agents
and (2) solid tumors such as breast, thyroid, and soft
tissue sarcomas, presenting 10 20 years after radia-
tion and alkylator therapy. Secondary leukemias,
breast, and thyroid carcinoma, and bone sarcomas
constitute approximately half of all second malignant
neoplasms following therapy for childhood NHL
[8385].
Host specific risk factors for the development of
secondary malignancies, not specific to NHL, in-clude a younger age at first cancer diagnosis
[85,87 90] and female gender [91,92]. The younger
age association is primarily due to increased risk of
radiation-induced solid tumor secondaries. This risk
may be conferred by increased susceptibility in
tissues undergoing rapid proliferation and differen-
tiation in the younger patient. Although data specific
to NHL is lacking, extrapolated data from radiation
exposure in HD demonstrates age association, with
patients receiving mantle irradiation during puberty
having a 75-fold increase in breast cancer [93], and
patients treated after age 30 having no increased risk
[94]. It is also likely that given the longer latencyperiod until solid tumor development, the pediatric
patient has an increased period of relative suscept-
ibility. Female sex was an independent risk factor in
developing a secondary malignancy after therapy for
NHL, presumably due to increased thyroid and
breast carcinoma [85].
Therapy related risk factor research focuses on
relative attribution of therapy modalities to the
development of secondary malignancies. Radiation
therapy is clearly implicated in the development of
secondary solid tumors, exhibiting dose response,
increased effect on younger patients, and tumor
development usually within or at the periphery of theprior radiation field [84,95 97]. Radiation therapy
has not been significantly implicated in the develop-
ment of leukemia or myelodysplastic syndrome
[3,16,32,98,99].
The rare studies that have concluded no in-
creased risk of second malignancy attributed to
chemotherapy alone have an acknowledged limitation
of small sample size and low doses of alkylators and
topoisomerase II inhibitors [84,100]. Other studies
have detailed a synergistic carcinogenic effect
between chemotherapy and radiotherapy, especially
Second malignancies in patients with NHL 1491
7/30/2019 Incidence, Risk Factors,
11/15
in the development of soft tissue sarcomas [83 85].
Several groups report a linear association between
alkylator dose and soft tissue sarcoma development,
independent of radiation therapy [95,97], with
Hawkins et al. reporting a relative risk of 31 for
patients treated for NHL developing a second bone
cancer.
Many studies support the association between
chemotherapeutic agents and secondary acute
myeloid leukemia and myelodysplasia [101].
Alkylator associated hematopoietic malignancy often
occurs after a prolonged latent period, presumably
allowing for the accumulation of additional muta-
genic events that lead to transformation. Data support
a linear dose relationship between alkylating agent
and the development of secondary myelodysplasia
and leukemia [12]. It does not appear that pediatric
patients are at greater risk for alkylating agent related
MDS or leukemia than adult patients [102].This contrasts with the topoisomerase-II inhibitor
associated myeloid leukemias, which tend to occur
within five years of exposure, without preceding
myelodysplasia, and are a result of translocations
involving the Mixed Lineage Leukemia gene on
chromosome band 11q23 [43,103 105]. Although a
dose response relationship between epipodo-
phyllotoxin use and secondary leukemia was not
observed in a 12-trial review by the National Cancer
Insitutute [106], other studies have supported in-
creasing risk with cumulative exposure, with the most
notable reporting an O/E of 200 for a cohort of
patients developing acute myeloid leukemia afterepipodophyllotoxin therapy for NHL [86].
The concept of genetic host susceptibility to
malignancy, although not unique to the pediatric
population, is often raised due to the earlier onset of
these malignancies. This susceptibility may manifest
in a patient who has a specific tumor predisposition
syndrome, in which both primary and secondary
malignancies may be overrepresented. Patients with
Bloom syndrome are at increased risk for lymphomas
early in life, with an increasing risk of carcinoma
with advancing age, with an unclear increased risk
secondary to treatment for the initial malignancy
[107,108]. Therapy for a primary lymphoma in apatient with altered tumor suppression mechanisms
may lead to even greater susceptibility to a second
malignancy, such as in the therapeutic use of
chemotherapy and/or radiation therapy in patients
with ataxia telangiectasia [109,110].
Conclusion
The population-based data clearly demonstrate that
NHL survivors are at higher risk for developing both
solid tumors and hematologic secondary malignan-
cies than the general population. These risks are
altered by the type of second cancer, age at diagnosis
of NHL, effect of radiation therapy, effect of chemo-
therapy, and gender. Overall, radiation therapy does
not cause a significant increase in excess risk of
secondary malignancies for patients with NHL.
Nevertheless, certain solid tumors (sarcomas, meso-
thelioma, and female breast cancer) are significantly
elevated in irradiated patients. Additionally, certain
subgroups, such as young patients, are at a markedly
elevated relative risk of secondary cancers (notably
breast and thyroid) related to radiotherapy. Further
investigations with more robust data bases that in-
corporate the specifics of histology, staging, treatment
delivery, genetics, and other prognostic variables will
be crucial to our understanding of this growing patient
population. With continued studies, we can refine our
treatments to make them safer for patients.
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