Incidence, Risk Factors,

7/30/2019 Incidence, Risk Factors,

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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


2/15

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

Second malignancies in patients with NHL 1483


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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

1484 J. Tward et al.


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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



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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)



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.



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



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



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



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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