Review Article

Therapeutic Radiation and the Potential Risk of Second

Malignancies
Sophia C. Kamran, MD1; Amy Berrington de Gonzalez, DPhil2; Andrea Ng, MD, MPH3; Daphne Haas-Kogan, MD3; and
Akila N. Viswanathan, MD, MPH3

Radiation has long been associated with carcinogenesis. Nevertheless, it is an important part of multimodality therapy for many
malignancies. It is critical to assess the risk of secondary malignant neoplasms (SMNs) after radiation treatment. The authors reviewed
the literature with a focus on radiation and associated SMNs for primary hematologic, breast, gynecologic, and pediatric tumors.
Radiation appeared to increase the risk of SMN in all of these; however, this risk was found to be associated with age, hormonal influ-
ences, chemotherapy use, environmental influences, genetic predisposition, infection, and immunosuppression. The risk also appears
to be altered with modern radiotherapy techniques. Practitioners of all specialties who treat cancer survivors in follow-up should be
aware of this potential risk. Cancer 2016;122:1809-21. V C 2016 American Cancer Society.

KEYWORDS: carcinogenesis, neoplasm, radiotherapy, risk, second primary, survivors.

INTRODUCTION
As innovations in cancer prevention, detection, and treatment have emerged over the past century, survival has improved.
However, longer survival also results in a longer interval in which to experience potential treatment sequelae. Secondary
malignant neoplasms (SMNs) are among the most serious consequences of cancer treatment, and are a major cause of
morbidity and mortality. In the Statistics, Epidemiology, and End Results (SEER) database, cancer survivors were found
to have a 14% increased risk of developing a malignancy compared with the general population.1
Radiation has long been known to be a carcinogen, based on data from survivors of the atomic bomb and reports of
the elevated cancer risk associated with occupational radiation exposure.2 However, it is also used to treat cancer. In recent
years, radiotherapy techniques have evolved from the use of large fields, kilovoltage x-rays, and cobalt-60 machines to
highly conformal therapy and high-energy linear accelerators, which may alter the risk of developing SMNs. It may not be
appropriate to extrapolate from data from a previous era to estimate radiation-related SMN risk for patients treated with
newer technologies.
Multiple studies have sought to define the dose-response relationship for the development of an SMN after radio-
therapy. However, many other factors can affect whether an SMN will occur, including age, environmental factors, the
presence of a cancer-prone syndrome, exposure to cytotoxic drugs, certain infections, immunosuppression, and hormonal
factors.3 Survivors of childhood cancer have a 6-fold relative risk (RR) (when compared with the general population and
stratified by age) of developing an SMN (Fig. 1). Risks for an SMN may be highest within the first 5 years after a primary
cancer diagnosis, possibly due in part to increased medical surveillance during that period. Nevertheless, recognition of
the risk, detection, and (if feasible) early treatment are crucial for this unique population.
In this review, we describe the biology of radiation carcinogenesis and discuss the SMN risks that may be associated
with radiotherapy for specific primary tumors.

RADIATION BIOLOGY
Cancer cell survival may decrease exponentially with increasing doses of radiation, but to our knowledge the biologic rela-
tionship with cancer formation is not fully understood. Cancer risk at low to moderate doses has been studied extensively

Corresponding author: Akila N. Viswanathan, MD, MPH, Department of Radiation Oncology, Brigham and Womens Hospital, 75 Francis St, ASB 1, L2, Boston,
MA 02115; Fax: (617) 278-6988; aviswanathan@lroc.harvard.edu
1
Harvard Radiation Oncology Program, Harvard Medical School, Boston, Massachusetts; 2Radiation Epidemiology Branch, Division of Cancer Epidemiology and
Genetics, National Cancer Institute, Bethesda, Maryland; 3Department of Radiation Oncology, Brigham and Womens Hospital, Harvard Medical School, Boston,
Massachusetts

DOI: 10.1002/cncr.29841, Received: September 10, 2015; Revised: November 3, 2015; Accepted: November 4, 2015, Published online March 7, 2016 in Wiley
Online Library (wileyonlinelibrary.com)

Cancer June 15, 2016 1809

Review Article

Figure 1. Irradiation may increase the risk of developing a secondary malignant neoplasm. This figure indicates initial radiation
fields (person on the left) and potential sites of subsequent second malignancies resulting from that treatment (person on the
right). CNS indicates central nervous system; GI, gastrointestinal; GYN, gynecologic.

in survivors of the atomic bomb and in occupational
cohorts with diagnostic medical exposures.2 Cancer treat-
ment increasingly uses high-dose (>5 gray [Gy]) radiation
to treat solid malignancies, and the risk of a second solid
malignancy is to our knowledge not well established.
Berrington de Gonzalez et al systematically reviewed
epidemiologic studies that assessed the dose-response rela-
tionship for SNM after high-dose fractionated radiation.4
A linear dose-response curve was supported in the direc-
tion of a reduction in risk at high doses, with the exception
of patients with thyroid cancer, for whom there was a pla-
teau and then a decrease in risk noted at doses >20 Gy.
Sachs et al suggested a model to explain these observations
that posits that significant levels of radiation-induced
stem cell repopulation counteract comparably large levels
of cell killing induced by radiation, so that the response
(and risk) remain nearly linear.5 Another theoretical
model6 analyzed the effects of inflammation and prolifer-
ative stress risks from fractionated radiotherapy. Tissue
injury due to high doses of radiation may be secondary to

1810 Cancer June 15, 2016


enhanced cell proliferation, escaping senescence and apo-
ptosis, and reentering the cell cycle, thus triggering
enhanced carcinogenesis. An acceleration model parame-
ter p was introduced and affects the dose-response
model at large doses.6
A SEER database study evaluated a cohort of
647,672 patients with cancer. Of those, 9% of 5-year sur-
vivors developed a second solid cancer. In their analysis,
of all the patients treated with radiotherapy, approxi-
mately 8% of second malignancies could be attributed to
radiotherapy for the first cancer.7 These SMNs were
defined as malignancies occurring !5 years after radiation
and within the radiation field, because at least a 5-year lag
has been demonstrated between radiation exposure and
solid cancer induction.8 In a dose-response analysis, the
relative risk (RR) was higher for SMN sites that received
>5 Gy compared with sites that received "5 Gy (inten-
sity-modulated radiotherapy [IMRT] vs stereotactic body
radiotherapy not analyzed).7 Clarification of dose-risk
curves that predict SMN risks in the era of high-dose irra-
diation and newer treatment modalities is needed.
Age and Its Role
Age plays a significant role in carcinogenesis after irradia-
tion, irrespective of the technology used.2 For children,
who are known to be more radiosensitive, radiation-
related cancer risks increase indefinitely after exposure
and the cumulative lifetime risks are higher. A case-
control study of survivors of childhood cancer (matched
by age at the time of the cancer diagnosis and survival)
performed by Inskip et al evaluated breast-cancer risk
related to doses received in early childhood, when devel-
oping breast tissue is of most concern, and found that the
odds ratio for breast cancer increased linearly with radia-
tion dose, reaching 11-fold for breast doses of approxi-
mately 40 Gy compared with no radiation.9 Other
modifying factors, such as chemotherapy agents received
and hormonal status, appear to alter this risk. In a study of
the SMN risk among patients with Hodgkin lymphoma
(HL) treated with radiotherapy, the RR of developing any
SMN increased with a lower age at the time of diagnosis,
compared with an age-matched and sex-matched general
population.10 SMNs were defined as any leukemia, lym-
phoma, or secondary solid malignancy identified from
retrospective chart review or from contact with surveilling
physicians. The RR was 2.4 for patients diagnosed and
treated at age >50 years, 4.9 for patients aged 20 to 50
years at the time of diagnosis and treatment, and 10.7 for
patients aged < 20 years at the time of diagnosis and treat-
ment. These results must be interpreted with caution
Cancer June 15, 2016
Radiation and Secondary Malignancies/Kamran et al
because the absolute excess risk for those 3 age groups
(youngest to oldest) were 71.0, 88.5, and 211.0 per
10,000 person-years, respectively, because elders have a
much greater risk of developing cancer in general. In addi-
tion, caution must be taken when interpreting risk using
the general population as a control, because these controls
presumably have not had the additional exposure to diag-
nostic low-dose radiation from staging and surveillance
that cancer survivors have. However, the overall conclu-
sion from the study by Inskip et al9 was that survivors of
HL on average have a 2.3% to 4.0% excess risk of SMN
per person per year at 15 to 20 years or more after initial
therapy. Therefore, the continued long-term follow-up of
survivors of childhood cancer is critical.
Radiation Field Size
The risk of SMN increases with increasing radiation field
size. For patients with HL, the RR was 2.1 for patients
treated with mantle radiation alone, 4.2 for patients
treated with subtotal lymph node irradiation, and 5.1 for
patients treated with total lymph node irradiation com-
pared with the age-matched and sex-matched general pop-
ulation.10 Concurrent chemoradiation significantly raised
the risk in all cases; for the same fields combined with
chemotherapy, the RRs were 4.7, 5.9, and 13.5, respec-
tively (P 5 .03). De Bruin et al examined the effect of
radiation field size on the risk of breast cancer in long-
term survivors of HL.11 In a cohort of 1,112 female 5-
year survivors who were treated before the age of 41 years,
full mantle irradiation was associated with a 2.7-fold
increased risk of breast cancer compared with mediastinal
irradiation alone (hazard ratio [HR], 2.7; 95% confidence
interval [95% CI], 1.1%-6.9%).11 All breast cancers
occurred within the initial radiation fields. This supports
the hypothesis that reducing the amount of breast tissue
exposed to radiation decreases the long-term risk of breast
cancer, and that smaller radiation fields overall may
reduce the long-term risk of SMN, with less irradiation to
normal tissue. Modern radiotherapy techniques are trend-
ing toward the use of smaller radiation fields for the ma-
jority of solid malignancies to decrease the risk of SMN
and normal-tissue toxicity.
Delivery of Radiation
Newer radiation techniques expose less tissue to high
doses compared with older techniques. IMRT creates
highly conformal radiation treatment plans that avoid
most normal structures but conform around the macro-
scopic tumor, thus allowing for dose escalation in some
cancers.3 Because it has been used only relatively recently,
1811
Review Article
it will be important to follow patients who received
IMRT to adequately assess SMN risk.
Proton therapy has garnered interest given the physi-
cal characteristics of the beam. Protons are heavy charged
particles that exhibit rapidly increasing and large energy
losses near the end of their ranges, known as the Bragg
peak, thereby minimizing radiation exposure to surround-
ing nontarget tissues.12 This has made proton treatment
an attractive modality, especially for children. In one
study, patients treated at the Harvard Cyclotron with pro-
ton radiation with passive scattering were matched to
patients treated with photon therapy who were identified
in the SEER database.13 After adjusting for sex and age at
the time of treatment, proton treatment was not found to
be associated with an increased risk of SMN compared
with photon therapy (HR, 0.52; P<.009). However, me-
dian follow-up times were 6.0 years and 6.7 years, respec-
tively, in the photon and proton cohorts, and this is not a
time when the majority of radiation-related cancers are
expected to occur. Because proton therapy has only
recently been incorporated into the treatment of more
and more disease sites, it will be necessary to wait to per-
form epidemiologic studies with sufficient follow-up to
determine the risk of SMNs in populations treated with
protons.
HEMATOLOGIC MALIGNANCIES
The literature examining the late effects of radiation on
patients initially treated for HL is robust, because radia-
tion plays an important role in the treatment of these of-
ten young patients (Table 1).14-28 The cumulative
incidence of SMN after HL was found to be 16.1% at 25
years (95% CI, 15%-17.3%) in a SEER study of cancer
survivors.29 A study published in 2007 with data from
18,862 patients with HL who had survived 5 years esti-
mated the RR (compared with the general population)
and cumulative incidence for SMN relative to age at the
time of the diagnosis of HL.14 It found that for patients
diagnosed at age 30 years who survived to age 40 years,
the RRs were elevated for second cancers of the breast
(RR, 6.1), other supradiaphragmatic sites (RR, 6.0), and
infradiaphragmatic sites (RR, 3.7), all within prior radia-
tion fields (Table 2).10,14,15,25,30 There was an observed
20-fold risk of malignant mesothelioma. For patients of
both sexes diagnosed with HL at age 30 years, the 30-year
cumulative risks of SMN were 18% for men and 26% for
women, compared with 7% and 9%, respectively, for age-
matched controls in the general population. In addition,
that study found that the excess cumulative incidence of
SMN was highly dependent on age at the time of the diag-
1812
nosis of HL, particularly for women. Women diagnosed
with HL at age 20 years were estimated to have a 30-year
cumulative incidence of SMN that was 20% higher than
that of age-matched controls in the general population.
These trends have implications for screening recommen-
dations in this population. For example, in the United
States, colorectal screening typically commences at age 50
years. However, the absolute risk of colorectal cancer for a
survivor of HL at ages 35 to 40 years has been found to be
comparable to that of an average individual aged 50 to 54
years in the general population. Similarly, breast cancer
screening typically begins at age 40 years. However, the
absolute risk of breast cancer among young female survi-
vors of HL has been shown to be comparable to that of an
average 50-year-old woman within 5 to 10 years of their
HL diagnosis.
Lung cancer after radiotherapy for HL is a major
concern given recent growing evidence for and interest in
radiation-induced lung tumors. A study by Gilbert et al
matched 227 survivors of HL who subsequently devel-
oped lung cancer with 455 controls (survivors of HL with-
out lung cancer), finding the estimated excess RR per Gy
received was 0.15 (95% CI, 0.06-0.39). The effects of
radiotherapy and chemotherapy were additive, whereas
the interaction of radiation and smoking was multiplica-
tive. The excess RR per Gy was 4 times higher for males
than for females.16
Stomach cancer is another cause of morbidity and
mortality among survivors of HL. The risk of stomach
cancer after treatment of HL was examined in a study by
Morton et al in which 89 cases were matched with 190
controls (survivors of HL). The risk of stomach cancer
was found to increase with increasing radiation dose and
with increasing number of alkylating chemotherapy
cycles.17 Another study found that in survivors of testicu-
lar cancer or HL, mean stomach radiation doses >20 Gy
were associated with a RR of malignancy of 9.9 compared
with doses of <11 Gy; the risk of gastric cancer increased
significantly with increasing estimated stomach dose.31
The above-mentioned risks may not apply to
modern-day survivors of HL, given the use of smaller radi-
ation fields and newer techniques. However, because
many long-term survivors of HL were treated in the older
era, and given the above-mentioned risks of lung and
stomach cancer, it is especially important for practitioners
to counsel survivors of HL concerning the risks of smok-
ing, as well as to evaluate gastrointestinal (GI) symptoms
promptly with appropriate workup, particularly if the
patient received infradiaphragmatic radiotherapy along
with alkylating chemotherapy.
Cancer June 15, 2016
 Radiation and Secondary Malignancies/Kamran et al

TABLE 1. Studies Examining the Rates of Secondary Malignancy in Irradiated Populations

Study No. of Patients Secondary Malignancy Risk

Hematologic malignancy
Hodgson 200714 18,862 5-y survivors Breast 6.1 (RR)
Infradiaphragmatica 3.7
Supradiaphragmaticb 6.0
Thyroid 3.1
Soft tissue and bone 11.7
Travis 200515 3817 1-y survivors Breast 1.4%, 11.1%, 29%c
Gilbert 200316 19,046 1-y survivors Lung 5.8 (RR)d
Morton 201317 19,882 ! 5-y survivors Stomach 6.8 (OR)
Breast malignancy
Berrington de Gonzalez 201018 182,057 5-y survivors High-dose regione 1.45 (RR)
Contralateral breast 1.09
19
Stovall 2008 2017 survivors Contralateral breast 2.5 and 3.0 (RR)f
Inskip 199420 8976 survivors Lung 1.8 (RR) at 10 y
Grantzau 201421 23,627 survivors Lung 8.5% per Gyg
Morton 201222 289,748 ! 5-y survivors Esophagus 8.3 (OR)h
Gynecological malignancy
Wright 201023 199,268 6-mo survivors with primary tumors Leukemia 1.72 (HR)
of vulva, cervix, uterus, anus, and rectum Multiple myeloma 1.08 (NS)
Onsrud 201324 568 survivors of endometrial cancer Secondary malignancy, 2.02 (HR)
nonspecified
Wiltink 201525 2554 patients from TME, PORTEC-1, Any secondary malignancy 2.98 (SIR)
and PORTEC-2 trials
Lonn 201026 60,949 ! 1-y survivors of uterine cancer Any secondary malignancy 1.26, 1.15, 1.07 (IRR)i
Pediatric malignancy
Bowers 201327 >150,000 CNS neoplasms 8.1-52.3 (RR)
Friedman 201028 14,363 5-y survivors Meningioma 87.8 (SIR)
Osteosarcoma 30
Bone cancer 19
Thyroid cancer 10.9
Head and neck cancer 10.8
Breast cancer 9.8
AML 9.3

Abbreviations: AML, acute myeloid leukemia; CNS, central nervous system; Gy, gray; HR, hazard ratio; IRR, incidence rate ratios; NS, not significant; OR,
odds ratio; PORTEC, Post Operative Radiation Therapy in Endometrial Carcinoma; RR, relative risk; SIR, standardized incidence ratio; TME, Total Mesorectal
Excision.
a
Infradiaphragmatic solid tumors include those of the stomach, colon, rectum and anus, pancreas, urinary bladder, and kidney.
b
Supradiaphragmatic solid tumors include buccal, esophagus, lung, and pleura.
c
Cumulative absolute risk for a female treated with chest irradiation at age 25 years to a dose of 40 Gy without alkylating agents by age 35 years, 45 years,
and 55 years, respectively.
d
RR of 5.8 at the median dose of 32 Gy.
e
High-dose region defined as receiving !1 Gy, including esophagus, pleura, lung, bone, and soft tissue.
f
RR was 2.5 for women aged < 40 years who received > 1.0 Gy of absorbed dose and 3.0 for women aged < 40 years with follow-up of > 5 years.
g
Risk increased linearly by 8.5% per Gy among patients who developed a primary lung cancer !5 years after treatment for breast cancer.
h
In patients who received !35 Gy to the esophagus.
i
1.26 for combined external beam radiotherapy and brachytherapy, 1.16 for external beam radiotherapy alone, and 1.07 for brachytherapy alone.

Breast Cancer as a Second Malignancy
In 2005, Travis et al sought to estimate the cumulative
absolute risk of breast cancer among women diagnosed
with HL at age "30 years between 1965 and 1994.15
Risks were generated for different cohorts depending on
age and the use of alkylating chemotherapy, which has
been shown to reduce the risk of breast cancer (Table
2).10,14,15,25,30 For example, a patient treated for HL at
age 15 years with radiation alone (!40 Gy) without
chemotherapy had a risk of 10.3 at 30 years of follow-up
compared with the age-matched and sex-matched general
population. It is interesting to note that the study did not
account for competing breast cancer risk factors, and the
data may not be applicable to contemporary women who
are treated with smaller radiation fields.
Using the SEER database, Milano et al examined
the long-term survival of patients with HL who developed
a subsequent new breast primary tumor.32 They focused
on clinical presentation and overall outcome compared
with primary breast-cancer occurring within the general
population. On average, survivors of HL were younger at
the time of diagnosis (45 years vs 63 years) and were more
likely to have estrogen receptor-negative and progesterone
receptor-negative status. Survivors of HL were more likely

Cancer June 15, 2016 1813

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TABLE 2. Relative Risk Related to Absolute Risk

Primary Malignancy Factors That Alter Risk SMN RR Absolute Risk

Hodgkin lymphoma10 Any SMN

Age < 20 y 10.7 71.0a
Age 20-50 y 4.9 88.5
Age > 50 y 2.4 211.0
Radiation field: mantle 2.1 58.1
Radiation field: subtotal lymph node irradiation 4.2 78.9
Radiation field: total lymph node irradiation 5.1 94.7
Hodgkin lymphoma14 Breast cancer: 6.1 37a
Diagnosed at age 30 y, survived to age 40 y Supradiaphragmatic site: 6.0 5.9
Infradiaphragmatic site: 3.7 3.7
Hodgkin lymphoma15 Breast cancer
Diagnosed at age 15 y, no RT, plus chemotherapy, 30-y follow-up - 0.8b
Diagnosed at age 15 y, no RT, no chemotherapy, 30-y follow-up - 1.7
Diagnosed at age 15 y, RT of 20 to < 40 Gy, plus chemotherapy, 30-y follow-up - 4.1
Diagnosed at age 15 y, RT of 20 to < 40 Gy, no chemotherapy, 30-y follow-up - 8.5
Diagnosed age 15, RT ! 40 Gy plus chemotherapy, 30-y follow-up - 5.0
Diagnosed at age 15 y, RT ! 40 Gy, no chemotherapy, 30-y follow-up - 10.3
Rectal or endometrial cancer25 Any SMN 2.98c 154a
Pediatric malignancy30 CNS tumors
RT alone 11.2c 27.3a
RT plus chemotherapy 12.9 29.6

Abbreviations: CNS, central nervous system; Gy, gray; RR, relative risk; RT, radiotherapy; SMN, secondary malignant neoplasm.
a
Absolute excess risk per 10,000 person-years.
b
Cumulative absolute risk.
c
Standardized incidence ratios.

to undergo complete mastectomy, and 35% of those with
localized disease who underwent partial mastectomy did
not receive radiation. Survivors of HL were found to have
lower 15-year overall survival rates than those in the gen-
eral population who developed breast cancer (48% vs
58% for localized breast cancer; P<.0001). Mortality
from heart disease was significantly higher in the HL pop-
ulation as well. In a similar study by Elkin et al,33 survi-
vors of HL who developed breast cancer were more likely
than women in the general population to have their breast
cancer diagnosed by mammography (40% vs 33%), to be
diagnosed at an earlier stage (ductal carcinoma in situ or
stage I AJCC 7th Ed., 2010: 61% vs 42%), to present
with bilateral disease (6% vs 2%), to be postmenopausal
at the time of diagnosis, to not have axillary lymph node
involvement (25% vs 39%), and to undergo mastectomy.
In addition, the rate of metachronous contralateral
tumors was 4 times greater in survivors of HL compared
with the general population.
A variety of factors play a role in the subsequent de-
velopment of breast cancer after radiotherapy for HL. van
Leeuwen et al examined the role of radiation dose, chemo-
therapy use, and hormonal status in breast cancer develop-
ment.34 Using historical data sets, they found that
increasing the radiation dose led to an increased risk of
breast cancer (RR of 4.47 for doses between 38.5-56 Gy
compared with referent group doses between 0.26-3.9
Gy). The use of alkylating chemotherapy was found to be
protective because it often puts patients into menopause,
thereby decreasing breast tissue exposure to hormones
(RR of 0.33 for patients receiving < 6 cycles of alkylating
chemotherapy and 0.28 for those receiving ! 6 cycles,
compared with a referent group receiving no chemother-
apy). Early menopause (aged 19-30 years) was associated
with a decreased RR for breast cancer after radiation. Vol-
ume treated was also important, similar to the previously
cited study by De Bruin et al (Table 3).10,11,21,22,35
Screening this young population may be difficult
because mammography has been suggested to be less
sensitive in patients aged <40 years. Breast magnetic
resonance imaging (MRI) has emerged as the preferred
technology for screening high-risk women (eg, BRCA
carriers). Ng et al performed a prospective analysis using
breast MRI and mammography to screen female survi-
vors of HL who received chest radiation for HL at age
<35 years and were at least 8 years from the time of
their diagnosis.36 The sensitivity was 68% for mam-
mography and 67% for MRI; however, the combined
sensitivity of both modalities was 94%. Therefore, it
was concluded that using both modalities would be
more beneficial in the population of survivors of HL
than using either alone.
Overall, historically treated female survivors of HL
are at an increased risk of developing breast cancer,

1814 Cancer June 15, 2016


TABLE 3. Factors That May Reduce the Risk of
SMN in Irradiated Populations
SMN by Factors That Have Been
Primary Site Shown To Reduce Risk
Hematologic primary
Breast Alkylating chemotherapy, menopause11
Lung Reduced radiation field size for all others10
Stomach
Thyroid
Soft tissue and bone
Others
Breast primary
Lung Smoking cessation21
Esophagus Reduced use of supraclavicular and
internal mammary lymph node irradiation22
Pediatric primary
Any SMN Proton therapy35
Abbreviation: SMN, secondary malignant neoplasm.
particularly if they were treated at a young age. This risk is
altered by modern radiotherapy techniques, as well as hor-
monal status, use of alkylating chemotherapy, and genet-
ics; nevertheless, it is important to recognize. Breast
cancer occurring after HL appears to differ from de novo
breast cancer, with a younger age at presentation and
poorer biologic characteristics. Overall and cause-specific
survival rates are worse in survivors of HL, and therefore it
is important to develop rigorous screening and educa-
tional awareness programs to detect cancers earlier.
BREAST MALIGNANCY
Due to notable improvements in the diagnosis and treat-
ment of de novo primary breast cancer, >90% of survivors
survive for !5 years.18 Long-term health consequences
due to treatment, including radiotherapy, are an impor-
tant issue, particularly the development of SMNs (Table
1).14-28 In 2006, using SEER registries, Curtis et al29
found that breast-cancer survivors had an 18% increased
risk of any SMN compared with the general population
(ratio of observed/expected of 1.18; 95% CI, 1.17-1.20).
The cumulative incidence of developing any second can-
cer after breast cancer was 17.6% at 25 years (95% CI,
17.4%-17.8%). Berrington de Gonzalez et al evaluated
long-term cancer risks of breast-cancer survivors between
1973 and 2000 using the SEER database.18 The RR for
SMN in a high-dose site (defined in that study as !1 Gy)
was 1.45 (95% CI, 1.33-1.58) compared with the age-
matched and sex-matched general population. There was
no excess risk for sites that received <1 Gy. Risks were
lower for modern treatment periods (1993 or more
recent) and higher for patients who were of a younger age
at the time of treatment. SMNs that were greatly increased
Cancer June 15, 2016
Radiation and Secondary Malignancies/Kamran et al
(>2-fold standard incidence ratios) included esophageal,
pleural, bone, soft tissue, and contralateral breast tumors.
The RR of lung cancer was also significantly increased,
and was higher for ipsilateral compared with contralateral
lung cancer (1.54 vs 1.18). For patients diagnosed with
breast cancer in 1983 or later, the risk of lung cancer was
higher after mastectomy than after breast-conserving ther-
apy. The RR for esophageal cancers was 1.99, and that of
soft-tissue cancers was 2.52; the risk for angiosarcomas
was found to be especially elevated (RR, 13.7). Rubino
et al demonstrated a dose-response relation between breast
irradiation and soft-tissue or bone sarcoma.37 All sarco-
mas were relatively rare in that cohort, with a 15-year inci-
dence estimate of 0.3%. Women who received > 14 Gy
were found to have a higher risk than women who
received <14 Gy; the odds ratios were 1.6 and 30.6,
respectively, for women who received 14 to 44 Gy and
!45 Gy at the site of sarcoma.
Stovall et al addressed the risk of contralateral breast
cancer after radiotherapy for a first breast cancer using in-
formation from the Womens Environmental, Cancer,
and Radiation Epidemiology (WECARE) study, with
708 cases of bilateral breast cancer (asynchronous) and
1399 controls (women with unilateral breast cancer) who
were countermatched based on radiation treatment.19
Dose estimates to the contralateral breast were measured
with a thermoluminescent dosimeter in tissue-equivalent
phantoms. The mean radiation dose to the specific quad-
rant of the contralateral breast cancer was 1.1 Gy. Younger
women (those aged < 40 years) who received > 1.0 Gy of
absorbed dose to the quadrant of contralateral breast can-
cer were found to have a 2.5-fold greater risk of develop-
ing cancer than unexposed women. Women aged < 40
years with a follow-up of > 5 years had an RR of 3.0
(95% CI, 1.1-8.1) with a significant dose dependence (an
excess RR per Gy of 1.0). However, no excess risk was
observed in women treated at age >45 years, which is typ-
ically when women experience their first breast cancer.
Hence, practitioners must remain vigilant about follow-
up for their younger patients.
The risk of lung cancer after radiotherapy for breast
cancer has been addressed by groups from the United
States and the Netherlands. The US-based group used a
cohort of 8,976 women treated for invasive breast cancer
between 1935 and 1971 and followed for ! 10 years.
Sixty-one lung cancer cases were identified that met entry
criteria and were matched to 120 reference subjects from
the same registry.20 The RR of lung cancer associated with
radiation for breast cancer was 1.8 (95% CI, 0.8-3.8) and
was found to increase with time (RR of 2.8 ! 15 years
1815
Review Article
after treatment). Risk was also associated with dose; the
excess RR was 0.08 per Gy. The mean lung dose was 9.8
Gy for both lungs combined. Nine cases of radiation-
induced lung cancer per year would be expected to occur
among 10,000 women who received an average lung dose
of 10 Gy and survived 10 years. Radiotherapy techniques
have since improved, with smaller fields and less exposure
of the lungs, and therefore the risks may be lower in
patients treated more recently.
Grantzau et al21 studied a cohort of patients treated
between 1982 and 2007. A total of 151 women who were
treated for primary breast cancer and developed a second
primary lung cancer were identified; these were matched
to 443 controls who were treated for breast cancer who
did not have a secondary lung cancer. All second primary
lung cancers occurred within irradiated fields. The me-
dian time between initial radiation and the development
of lung cancer was 12 years (range, 1-26 years). The rate
of lung cancer increased linearly by 8.5% per Gy (95%
CI, 3.1-23.3%) in patients who developed a second pri-
mary lung cancer !5 years after breast cancer treatment.
Patients who had ever smoked had an additional excess
risk of lung cancer of 17.3% per Gy (95% CI, 4.5%-
54%) (Table 3).10,11,21,22,35
A study by Morton et al examined the risk of esopha-
geal cancer after radiation for breast cancer.22 A total of
252 cases of esophageal cancer were identified from a
cohort of 289,748 patients with breast cancer who had
survived !5 years and matched with 488 controls
(matched based on breast cancer diagnosis date and sur-
vival interval). Supraclavicular and internal mammary
lymph node treatments were found to be the largest con-
tributors to radiation exposure of the esophagus. The risk
of esophageal cancer increased with increasing radiation
dose. Doses ! 35 Gy were associated with an odds ratio of
8.3 (95% CI, 2.7-28). Alkylating chemotherapy did not
appear to affect risk.22 It is interesting to note that women
who received hormonal agents (mostly tamoxifen) in the
5 years preceding their esophageal cancer diagnosis had a
reduced risk of esophageal cancer.
One interesting question regarding SMN risk after
treatment of primary breast cancer is how the risk trans-
lates to carriers of the BRCA1/2 mutation. These patients
may have more sensitivity to the carcinogenic effect of
radiotherapy due to their impaired DNA repair capacity.
A review by Drooger et al in 201538 examined this risk
based on the current literature. Data were scarce; for
patients who developed breast cancer after age 30 years
and who opted for breast-conserving therapy, there were
no hard data indicating an increased risk of a second pri-
1816
mary breast cancer, either ipsilateral or contralateral. An
analysis of the WECARE study, which examined the risk
of contralateral breast cancer based on dose to the contra-
lateral breast, also did not find different risks based on
germline BRCA1/2 mutations, but the numbers were
small.39 However, low-dose radiation exposure from diag-
nostic procedures has been found to increase the risk of
primary breast cancer in young carriers of the BRCA1/2
mutation (those aged < 30 years), and therefore caution is
necessary in this group when using radiation as part of the
primary treatment of breast cancer (Fig. 2).38 Further
research is needed regarding the long-term effects of thera-
peutic radiation on BRCA carriers.
GYNECOLOGIC MALIGNANCIES
Pelvic radiation is commonly used for gynecologic malig-
nancies, yet there is concern regarding the possible devel-
opment of secondary cancers after pelvic irradiation
(Table 1).14-28 In SEER-based analyses, the cumulative
incidence of developing any second malignancy was
13.2% at 25 years (95% CI, 12.5%-13.8%) after cervical
cancer, 9.1% at 20 years (95% CI, 7.4%-10.9%) after
vaginal cancer, 15.4% at 25 years (95% CI, 14.0%-
16.8%) after vulvar cancer, 17.5% at 25 years (95% CI,
17.1%-17.9%) after uterine cancer, and 9.4% at 25 years
(95% CI, 8.9%-9.9%) after ovarian cancer.29 In a SEER-
based study performed by Wright et al of patients with
cancers of the vulva, cervix, anus, uterus, and rectosig-
moid,23 the risk of leukemia increased by 72% among
those who received radiation (HR, 1.72; 95% CI, 1.37-
2.15). This risk remained elevated 10 to 15 years after the
initial treatment. No association was found between radi-
ation and the development of multiple myeloma (HR,
1.08; 95% CI, 0.81-1.44). However, because radiation
dose and treatment fields are not included in the SEER
database, it is unclear whether there is a particular dose-
response relationship. Prior studies have indicated that
pelvic radiotherapy may increase the risk of future hema-
tologic malignancies.40-44
Lonn et al evaluated the risk of second primary can-
cer in a cohort of 60,949 individuals surviving ! 1 year af-
ter a diagnosis of uterine cancer made between 1973 and
2003 in the SEER database. Incidence rate ratios (IRRs)
were found to be increased among irradiated patients
compared with those who received surgery alone. Com-
bined brachytherapy and external-beam radiotherapy
(EBRT) had an IRR of 1.26 (95% CI, 1.16-1.36),
whereas EBRT alone had an IRR of 1.15 (95% CI, 1.08-
1.22), and brachytherapy alone had an IRR of 1.07 (95%
Cancer June 15, 2016
 Radiation and Secondary Malignancies/Kamran et al

Figure 2. Repair of DNA damage through the BRCA1 and BRCA2 pathway. ATM indicates ataxia telangiectasia mutated; Fancd2,
Fanconi anemia, complementation group D2.

Cancer June 15, 2016 1817

Review Article
CI, 1.00-1.16). Leukemia and malignancies of the colon,
rectum, and bladder were most common.26
Onsrud et al reported results with !20 years of
follow-up from the Norwegian Radium Hospital trial; all
patients received vaginal brachytherapy and were then
randomly assigned postoperative EBRT versus no further
treatment between 1968 and 1974.24 Women in the
EBRT arm had a statistically significant increase in the
risk of SMN (HR, 1.42; 95% CI, 1.01-2.00). The median
time to development of an SMN was 15 years. Women
aged < 60 years at the time of diagnosis had an increased
risk of secondary cancer; there was no observed difference
in the risk of SMN in women aged >60 years at the time
of diagnosis. Within the irradiated pelvis, the risk was pre-
dominantly for nonmelanomatous skin cancer (from 0%-
4.4%, most likely due to the lack of skin-sparing radiation
machines used in that era), colon cancer (from 6.8%-
10.3%, compounded by the lack of screening for heredi-
tary nonpolyposis colorectal cancer in that era), and blad-
der cancer (from 0.8%-4.4%).
This finding was challenged by a recent analysis by
Wiltink et al, which included patients from the Post Op-
erative Radiation Therapy in Endometrial Carcinoma
(PORTEC)-145 and PORTEC-246 trials as well as
patients with rectal cancer from the Total Mesorectal
Excision (TME) trial.25,47 In this pooled cohort analysis
of >2,500 patients with a median follow-up of 13 years,
no difference was found in the probability of developing
an SMN between the treatment arms (15-year rates: no
radiation, 26.5% and EBRT, 25.6% [P 5 .94]). Within
the individual trials, no differences were found (POR-
TEC-1: no radiation, 16.9% vs EBRT, 17.3%45; POR-
TEC-2: vaginal brachytherapy, 14.9% vs EBRT,
14.4%46). There was also no difference noted with regard
to the risk of SMN between treatment arms by age ("60
years vs > 60 years). Compared with a matched general
population, the standardized incidence ratio based on all
included patients for all types of SMN was 2.98 (95% CI,
2.82-3.14) (Table 2).10,14,15,25,30 Despite these data dem-
onstrating similar risks for the development of SMNs
between patients who do and those who do not undergo
pelvic irradiation, practitioners should be aware that sur-
vivors of rectal cancer and endometrial cancer have a risk
of developing an SMN that is 3 times higher than that of
the general population.
PEDIATRIC MALIGNANCIES
Treatment for pediatric malignancies has vastly improved,
and overall survival has increased to >80%, thereby also
increasing the risk of developing an SMN. The Child-
1818
hood Cancer Survivor Study (CCSS) found the 30-year
cumulative incidence of SMN among 14,359 5-year sur-
vivors of childhood cancer to be 20.5%, which is 6 times
greater than the risk in the general population.28 Radio-
therapy is often used in the treatment of childhood can-
cers. In the report by the CCSS, radiotherapy was
associated with an RR of developing SMNs of 2.7 (95%
CI, 2.2-3.3) (Table 1).14-28 Even more concerning is the
greater risk noted in patients who have a germline muta-
tion, including mutations that may contribute to pediatric
malignancies, such as TP53 or RB1.48 Patients with these
mutations may be more sensitive to ionizing radiation,
and therefore may need even more prudent follow-up and
surveillance.
The central nervous system (CNS) is a common pri-
mary tumor site among children with pediatric malignan-
cies,35 and radiation to the CNS is often part of
treatment. Children exposed to radiation have an
increased risk of developing a subsequent new CNS pri-
mary tumor, which has been recognized since the 1940s,
when radiation was used for tinea capitis or tonsilli-
tis.27,49,50 The risk of brain tumors was found with the
use of doses as low as 2.5 Gy. A dose-related increase in
cranial tumors was identified in survivors of the atomic
bomb.51 A study using the SEER database reported a 10-
year survival rate of 13.6% for secondary CNS tumors in
survivors of childhood cancer52, and another study
reported that secondary CNS tumors were the second
leading cause of death among survivors of CNS tumors in
childhood, behind primary tumor recurrence.53 In a
review by Bowers et al that examined the recent literature
regarding patients who developed subsequent CNS neo-
plasms after primary treatment for childhood CNS can-
cer, survivors had an incidence of secondary CNS
neoplasms that was 8.1 to 52.3 times higher that that for
the general population, with high-grade glioma and me-
ningioma being the two most common malignancies.
Five-year survival rates ranged from 0% to 19.5% for
patients with high-grade gliomas, and overall survival
rates ranged from 6% to 15%. Neglia et al analyzed CNS
SMNs using data from the CCSS,30 and found a statisti-
cally significant relationship between radiation dose and
risk of CNS neoplasms, including glioma and meningi-
oma. The excess RR was 0.33 per Gy for glioma, 1.06 per
Gy for meningioma, and 0.69 per Gy for all CNS neo-
plasms compared with controls matched by age at the
time of the initial cancer diagnosis and sex (Table
2).10,14,15,25,30
Thyroid cancer is a common SMN in survivors of
childhood cancer. Using data from 12,547 5-year
Cancer June 15, 2016

survivors of childhood cancer in the CCSS, Bhatti et al an-
alyzed the radiation dose received.54 The risk of thyroid
cancer increased linearly with radiation doses up to 20 Gy
(RR at 20 Gy, 14.6). However, for doses > 20 Gy, a
downturn was observed, similar to that found in the study
by Berrington de Gonzalez et al.4 This suggests that thy-
roid tissue is exceptionally sensitive to high-dose
radiation.
Because of the increased incidence and concern for
SMNs in survivors of childhood cancer, many radiation
oncologists are turning to newer technologies in an
attempt to reduce this risk, most notably proton beam
therapy. In a study by Brodin et al, risks were modeled for
pediatric patients with medulloblastoma who were treated
with either 3-dimensional conformal radiotherapy, inver-
sely optimized rapid arc therapy, or intensity-modulated
proton therapy.35 Estimates of SMN were higher for the
rapid arc plans, and the intensity-modulated proton ther-
apy plans fared better than the photon techniques, even
when taking secondary neutron irradiation into account
(Table 3).10,11,21,22,35
GASTROINTESTINAL AND
GENITOURINARY MALIGNANCIES
Pelvic irradiation for patients with locally advanced gas-
trointestinal (GI) and genitourinary (GU) malignancies,
particularly rectal cancer, is considered the standard of
care. However, data regarding SNM after radiation are
conflicting.25 Testicular cancer is a disease of young men
and often deemed curable, with a 10-year survival rate of
95%; therefore, late manifestations of treatment, particu-
larly SMN, are of growing concern. For patients treated
with radiation for GI/GU cancers, SMN sites include can-
cers of the stomach, colon, rectum, pancreas, lung, pleura,
prostate, kidney, bladder, connective tissue, and thyroid.
Patients with prostate cancer have multiple options for
treatment, including radiation. Within radiotherapy, dif-
ferent modalities may be used, including brachytherapy,
EBRT, or a combination of both, with unclear conclu-
sions regarding the risk of SNM for those treated with the
various radiotherapy techniques.
CONCLUSIONS
SMN can be a serious long-term consequence of the treat-
ment of primary malignancies. Data exist regarding the
risks of SMN after radiotherapy, but modern techniques
may render much of the evidence no longer applicable.
Other factors, including age at the time of primary treat-
ment, environmental factors, and genetic predisposition,
alter the risk of SMNs, although to the best of our knowl-
Cancer June 15, 2016
Radiation and Secondary Malignancies/Kamran et al
edge the question of how these factors modify risk has not
been clearly elucidated. In addition, other potential fail-
ings of the existing data include the frequent use of the
general population as controls without the recognition
that these individuals generally are not exposed to the
same risk factors for developing cancer as cancer survi-
vors are (eg, genetic predisposition), as well as the lack
of radiation-specific cohorts and other general biases in-
herent to retrospective or survey-based analyses. Further
confounding the risk of SMN development is the need
for close follow-up in cancer survivors that incorporates
low-dose, whole-body diagnostic radiation exposure
over a long period of time, potentially contributing to
SMN risk. This risk factor needs to be explored further.
Nevertheless, practitioners should recognize SMN risks
and practice judicious surveillance of cancer survivors;
the use of nonionizing radiation imaging techniques or
biomarkers when available should be considered in can-
cer survivors. Ongoing and future studies that incorpo-
rate modern radiotherapy techniques and control for
the impact of posttreatment surveillance scans, age, hor-
monal status, chemotherapy use, and genetic predisposi-
tion are important to assess the incidence and biology
of radiation-induced SMNs and to further predict who
may be at increased risk in the present era.
FUNDING SUPPORT
No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES
Akila N. Viswanathan is supported by National Institutes of Health
grant R21 167800.
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