Seminars in Radiation Oncology
Volume 20, Issue 1 , Pages 67-78, January 2010

Secondary Malignancies Across the Age Spectrum

  • Andrea K. Ng, MD, MPH

      Affiliations

    • Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA
    • Corresponding Author InformationAddress reprint requests to Andrea K. Ng, MD, MPH, Department of Radiation Oncology, 75 Francis St, ASB1-L2, Boston, MA 02115
    • ,
  • Lisa B. Kenney, MD, MPH

      Affiliations

    • Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA
    • ,
  • Ethel S. Gilbert, PhD

      Affiliations

    • Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
    • ,
  • Lois B. Travis, MD, ScD

      Affiliations

    • Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY

Article Outline

Development of a second malignancy is one of the most serious late effects in survivors of both childhood and adult-onset cancers. Patterns of second malignancy risk across the age spectrum can differ in terms of the types of second malignancies observed, magnitude of the risks, the latency period, associated risk factors, and modifying influences. Potential explanations for the varying risk patterns by age include differences in susceptibility of individual tissue/organ to carcinogenesis based on stage of development and level of tissue maturity, microenvironment, attained age, and lifestyle factors. A thorough understanding of these differences is essential when considering treatment modifications in newly diagnosed cancer patients who are aimed at reducing the risk of second malignancy and other late effects without compromising cure. Moreover, an understanding of the variations in second cancer risk according to age at treatment is important in customizing patient follow-up.

 

Improvement in early cancer detection as well as advances in therapy and supportive care have resulted in an increasing number of cancer survivors.1 Second malignancies have emerged as one of the most serious late effects of treatment for both survivors of childhood cancer and adult-onset cancer. A number of potential influences, in addition to radiation and chemotherapy, are known to either contribute to or modify the development of second primary cancers. These include genetic predisposition, environmental exposures, hormonal factors, and immune function.2 Moreover, in considering the site-specific risks of second malignancies, several factors may explain the observed varying patterns of second cancer development based on age at diagnosis and treatment. These include differences in follow-up time and attained age, stage of development of individual organs or tissues at risk, hormonal milieu, and prevalence and chance of cure for the same disease presenting in children vs adults.

In this article, the site-specific risk of second malignancies after selected childhood and adult-onset cancers will be reviewed. In particular, the risk of second malignancy after Hodgkin lymphoma (HL), a highly curable disease that affects both children and adults, will be examined for both age groups. Finally, age-related differences in the risks of second primary cancers of breast, thyroid, and lung will be discussed as specific examples illustrating the differences in patterns of second malignancy development after childhood and adult-onset cancer, respectively.

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Overview of Second Malignancy Risks After Selected Childhood Tumors 

Advances in the treatment of childhood cancer have resulted in excellent prognosis for cure, with a 5-year survival rate at around 75%.1 Despite such improvements, childhood cancer survivors remain at increased risk for life-threatening treatment-associated complications, including major organ toxicity and secondary malignancies.3, 4, 5, 6, 7, 8 Several large cohort studies have shown that secondary malignancies are the leading cause of treatment-related premature mortality in 5-year survivors of childhood cancer.6, 8, 9 Although it is recognized that most childhood cancer survivors will not be diagnosed with a second primary cancer, the 20-year cumulative 3%-4% incidence of secondary malignancies in 5-year survivors is of concern. Furthermore, as childhood cancer survivors are followed to older adulthood, the cumulative incidence of secondary malignancies continues to increase.6

Radiation-associated solid tumors are the most common type of secondary malignancies observed in childhood cancer survivors; however, survivors are also at increased risk for chemotherapy-associated hematologic malignancies.3, 4 Along with treatment exposures, the etiologic factors that contribute to the development of secondary malignancies in childhood cancer survivors include primary cancer diagnosis, age and developmental stage at cancer diagnosis, gender, duration of follow-up, attained age, and hereditary cancer predisposition. Childhood acute lymphoblastic leukemia (ALL), retinoblastoma (RB), and HL are representative pediatric cancer types that have an excellent prognosis for long-term survival, but also have well-characterized risks for secondary malignancies. The most prevalent secondary malignancies associated with these 3 pediatric cancers will be reviewed in this section, illustrating the interplay of various etiologic factors related to the development of subsequent cancers in childhood cancer survivors.

Acute Lymphoblastic Leukemia 

ALL represents approximately 25% of all childhood cancer diagnoses, with a peak age of incidence between 2 and 6 years. Currently, the overall 5-year relative survival is 80%.1 Curative therapy includes multiagent chemotherapy and prophylaxis against central nervous system (CNS) leukemia with intrathecal chemotherapy and/or cranial radiation. Stem cell transplant is reserved for poor prognostic features at diagnosis, or if conventional therapy fails. Although most children with ALL become 5-year survivors, secondary malignancies and other adverse events reduce longer-term survival.

The 15-year cumulative incidence of secondary malignancies for ALL survivors is between 2.5% and 4%;10, 11, 12 however, data from a single institution cohort of over 2000 ALL survivors diagnosed from 1983 to 1995 show an increasing incidence of secondary malignancies with increasing duration of follow-up, with a cumulative incidence of 6% at 30 years.13 The most commonly observed secondary malignancies include CNS tumors, leukemias/lymphomas, and skin cancers. Risk factors associated with secondary malignancies in ALL survivors are younger age at diagnosis (age < 5), female gender, cranial/cranial spinal radiation, and relapse.10, 11, 13 Of note, a lower 10-year cumulative incidence of secondary malignancies, 1.2% (95% CI, 0.8%-1.5%), was reported in a cohort of ALL survivors treated after 1983, when fewer children received cranial radiation as CNS prophylaxis.12

Benign and malignant CNS tumors are reported in ALL survivors treated with cranial radiation. Additional risk factors for secondary CNS tumors are treatment at <5 years of age and presence of CNS leukemia at diagnosis.14, 15 The most common types of secondary CNS malignancies are meningiomas and gliomas; however, primitive neuroectodermal tumors and CNS lymphomas have also been observed.14, 15 Studies report a 10 to 20 fold increased relative risk of secondary brain tumors compared with age-matched general populations.11, 14 The minimal latency period for secondary CNS malignancies varies by tumor type, from 9 years for secondary gliomas to 20 years for meningiomas.14, 15 In a St. Jude's cohort study of 1,251 ALL survivors treated with cranial irradiation, the 20- and 30-year cumulative incidence of CNS tumors was 1.4% and 3.0%, respectively.15 In addition, there is a well-established dose response relationship between cranial radiation dose and incidence of secondary CNS tumors. Further analysis of the same St. Jude cohort showed that the 20-year cumulative incidence of CNS tumors increased in conjunction with radiation dose: 1% at 10-21 Gy; 1.7% at >21-30 Gy; and 3.2% at >30 Gy.15 The contribution of chemotherapy to the risk of CNS malignancies is controversial. Clinical and laboratory studies have suggested an association between radiation-induced brain tumors and an intensive schedule of thiopurine-based chemotherapy;16 however, epidemiologic data from the Childhood Cancer Survivor Study (CCSS) cohort found that chemotherapy did not alter brain tumor risk after adjusting for radiation dose.14

Secondary hematologic malignancies are also observed in childhood ALL survivors.10, 17 Acute leukemia and myelodysplasia are associated with exposure to high cumulative doses of alkylating agents and with topoisomerase II inhibitors, including epipdophyllotoxins and anthracyclines.18 Secondary leukemias associated with high dose alkylating agent exposure usually occur in older children, have a latency of 4-10 years, and are associated with myelodysplasia and deletions in chromosomes 5 and 7.19 In contrast, topoisomerase II-induced secondary leukemias are typically diagnosed in younger children, have a short latency period (median 1-3 years), and are associated with balanced chromosomal translocation 11q23, or less frequently 21q22.16, 17, 19, 20 The cumulative incidence of secondary leukemias is as high as 3.8% at 6 years in ALL survivors treated with topoisomerase II inhibitors.18 A dose–response relationship has been demonstrated for both alkylating agent and topoisomerase II associated leukemias.21 In addition, the administration schedule of epipdophyllotoxins appears to contribute to the risk of secondary leukemias, as prolonged infusions were found to be an independent risk factor.18, 22 The contribution of therapeutic radiation to the development of secondary leukemia is controversial with some studies finding no association between leukemia and exposure to radiation therapy4, 18, 23 and others documenting subsequent leukemia in survivors after exposure to radiation in the absence of chemotherapy.17, 19, 23 Thus, therapeutic radiation likely has a role in secondary leukemogenesis.

Retinoblastoma 

RB accounts for only 2% of childhood malignancies, with 80% of children diagnosed at <4 years of age. Treatment options include enucleation, external beam radiation therapy, brachytherapy, cryotherapy, photocoagulation, thermotherapy, and chemotherapy. Although the 5-year relative survival rate is 95%, survivors are at risk for multiple secondary malignancies. Approximately 40% of RB cases are hereditary with an identifiable germline deletion in the Rb-1 tumor suppressor gene that confers a genetic predisposition to subsequent neoplasms.24 The specific secondary malignancies for which survivors with hereditary RB are at the highest risk include soft tissue sarcomas, bone sarcomas, and malignant melanoma. Risk for nasal cavity malignancies and brain tumors are also increased.25 In addition, elevated risks of late-onset secondary epithelial cancers, such as lung, female breast, bladder, colon, and corpus uteri are also observed as extended follow-up of large cohorts of RB survivors becomes available.25, 26, 27

Genetic predisposition and treatment exposures are both etiologic factors in the development of secondary malignancies. Extended follow-up of a cohort of over 1500 RB survivors shows that survivors with hereditary RB treated with radiation therapy have a cumulative risk of secondary malignancy as high as 38.2% (95% CI, 32.6%-43.8%) at 50 years of follow-up, and, in comparison, the 50-year cumulative incidence of secondary malignancies for nonirradiated hereditary survivors was 21.0% (95% CI, 9.42%-35.6%).25 Further, the majority of secondary sarcomas observed in hereditary RB survivors are diagnosed in prior radiation fields (60%-70%), and the remaining are diagnosed in anatomic locations beyond the radiation field, such as the lower extremities, where scatter dose would not be an etiologic consideration.25, 27 In contrast, secondary melanomas are more likely to be diagnosed outside the radiation field, and risks for secondary melanoma are similar in both irradiated and nonirradiated survivors, thus supporting the hereditary predisposition for this specific secondary cancer.

In general, survivors of nonhereditary RB are not considered at increased risk of secondary malignancies except for soft tissue sarcomas (SIR = 21.9; 95% CI, 4.5-63.7),27 and female breast cancer (SIR = 2.8; 95% CI, 1.1-5.9).25 It has been suggested that the increased risk of secondary malignancies in survivors with the nonhereditary form of RB is attributable to radiation exposure, or possibly incorrect classification of survivors as having the nonhereditary forms of RB when they actually are carriers of an RB-1 mutation.25, 27

The most frequently observed secondary malignancies in hereditary RB survivors are bone and soft tissue sarcomas. The most common histologic subtypes of sarcomas in order of frequency are leiomyosarcomas, fibrosarcoma, malignant fibrous histiocytoma, rhabdomyosarcoma, and liposarcoma.25 For survivors of hereditary RB who received radiation, the relative risk for soft tissue sarcomas is over 100-fold (SIR = 140; 95% CI, 96-196) compared with the age-matched general population, and the risk of subsequent bone sarcomas is close to 400-fold (SIR = 406; 95% CI, 318-511).25, 28, 29 Similar to other radiation-associated secondary malignancies, there is an established dose–response relationship for secondary bone and soft tissue sarcomas.28, 29 In addition, data support that alkylating agent chemotherapy potentiates the risk of both radiation-associated bone sarcoma and soft tissue sarcomas.25, 30

Attained age is another factor that alters risk for secondary malignancies. Survivors of hereditary RB <5 years old are at risk for “trilateral RB,” which is an intracranial neuroblastic tumor most often of the pineal gland. This secondary malignancy is rarely diagnosed in survivors >5 years old.31 Similarly, most second malignancies diagnosed in RB survivors <30 years are sarcomas, and >30 years of age the increased risk for epithelial cancers, including breast, lung, colon, and bladder emerges.27 In a Dutch registry based study of over 600 RB survivors, with over 40 years of follow-up, after age 40 years secondary epithelial cancers were more common than sarcomas in hereditary RB survivors.27 Other studies have also identified an age difference in incidence of secondary sarcomas, with nonirradiated hereditary RB survivors >25 years old having a much lower proportion of sarcomas (8%-14%), compared with their irradiated counterparts (50%).26, 32

Hodgkin Lymphoma 

Lymphomas represent approximately 15% of childhood cancers. HL diagnosed during childhood and adolescents has a 5-year survival rate of over 90%, and is most often treated with combination chemotherapy and radiation therapy. Survivors have an established risk for subsequent malignancies with a 25-year cumulative incidence of 19%, and no foreseeable plateau in incidence of solid tumors with continued follow-up.33, 34 The most frequently observed solid secondary malignancies are breast cancer, thyroid cancer, and bone/soft tissue sarcomas.6, 12, 33, 34, 35, 36, 37, 38 With extended follow-up of cohorts of young HL survivors, increased risks of common adult carcinomas, including colorectal, lung, and gastric types have emerged, and these cancers are diagnosed at younger ages than observed in the general population.34 Established independent risk factors for secondary solid malignancies are younger age at HL diagnosis (12-16 years), increasing radiation dose, and female gender.33, 34 In the study by Constine et al,33 the relative risks for second malignancy in female vs male childhood HL survivors were 19.9 and 8.4, respectively (P < .0001). The higher risk in female survivors may in part be driven by breast cancer risk, although the difference in second malignancy risk by gender persisted after excluding breast cancer as a second malignancy.

The risk of secondary female breast cancer has been extensively studied in large cohorts of childhood HL survivors. These studies report a 15- to 55 fold increased risk of radiation-associated secondary female breast cancer compared with the age-matched general population.34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44 Risk estimates vary by characteristics of the cohort studied, including mediastinal radiation dose, age at therapy, duration of follow-up, and completeness of follow-up. The cumulative incidence of secondary breast cancer is as high as 12% -35% at 20 years after therapy for HL.34, 35, 36, 37, 38, 39, 40, 41, 42, 43 The typical latency of radiation-associated breast cancer in young survivors of HL is 10-15 years after therapy; however, secondary breast cancer has been reported in women as young as 20 years of age and as soon as 6 years after therapy.39 Female HL survivors at greatest risk for secondary breast cancer are those treated between age 10-30 years with mediastinal radiation doses >25 Gy.43, 45 Similar to other radiation associated secondary malignancies, a dose–response relationship between radiation dose and risk of secondary breast cancer has been established, with higher mediastinal doses associated with greater relative risk.33, 43, 44

Survivors of childhood HL treated with neck and upper thorax radiation are at increased risk for radiation-associated secondary thyroid cancers. Large cohort studies of childhood cancer survivors exposed to neck irradiation report the relative risks of secondary thyroid cancer to be between 10 and 35.34, 35, 46, 47, 48, 49 At 30 years, the cumulative incidence in HL survivors is 4.4%.34 Although the minimum latency period for secondary thyroid carcinoma is 5 years,34, 49, 50 the incidence of thyroid carcinoma remains increased beyond 40 years after irradiation for primary cancer.34, 51, 52 Secondary thyroid cancer is more common in females, and young age at treatment is an independent risk factor.34 The risk of thyroid cancer is related to radiation dose, but unlike most other radiation-induced second cancers, it is greatest at doses 20-29 Gy but declines at doses >30 Gy.48, 53 A case control study of 69 cases showed an increased risk with radiation doses as high as 29 Gy (OR = 9.8; 95% CI, 3.2-34.8), but a decrease in risk at doses >30 Gy.48 This finding supports the “cell–kill” hypothesis, suggesting that higher doses of radiation cause thyroid cell death that reduces the initiation of carcinogenesis observed at lower doses. Finally, chemotherapy does not appear to modify risk of secondary thyroid cancer.48, 49, 50, 51, 52, 53, 54

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Overview of Second Malignancy Risks After Selected Adult-Onset Tumors 

In this section, the focus is on several adult-onset primary malignancies in which considerable data on the risk of second malignancies have accrued. These include HL and testicular cancer, both of which are typified by a relatively young age at diagnosis, high cure rate, and the historical use of large-field radiation therapy. In recent years, a growing amount of data has also emerged on the risk of second malignancies after treatment of several more common cancers, such as breast and prostate, which are also included in this section.

Hodgkin Lymphoma 

As in childhood HL, adult HL is associated with a high cure rate, and among patients with favorable-prognosis, early-stage disease, cure can be achieved in >90% of patients.55 However, survivors of HL are at significantly increased risk for mortality from other causes, with second malignancy being the leading cause of death.56, 57 A number of host-related and treatment-related factors contribute to or modify the risk of second malignancy after HL. However, while female gender has been shown to be a risk factor for development of second malignancy among childhood HL survivors,33, 58 the effect of gender in adult HL survivors is more complex.4 Other differences in second malignancy risks between childhood and adult HL survivors will be discussed in a later section in the context of several distinct types of second cancers. These differences are summarized in Table 1.

Table 1. Comparison of Second Malignancy in Survivors of Childhood vs. Adult Hodgkin's Lymphoma⁎
Childhood HLAdult HLComments
Overall risksHigher RR (15-55)Lower RR (3-6)Related to lower background cancer risks with younger age and higher susceptibility of developing organs to radiation-associated carcinogenesis
Female gender as a risk factorYesUnclearIn childhood HL survivors, increased SM in female survivors persist despite excluding breast cancer
Breast cancer after HLRRs increase with increasing age at HL diagnosisRRs decrease with increasing age at HL diagnosisDifference may be due to:
Higher susceptibility to radiation-related carcinogenesis in proliferating and developing breast tissue, compared with prepubertal or mature breast tissue
Differences in breast cancer risk by attained age at follow-up
Risk not affected by exposure to alkylating agentsReduced risk with exposure to alkylating agents in a dose-related mannerDifference may be due to:
Larger reserve of eggs and follicles in girls
Differences in types of alkylating agents and doses between pediatric and adult patients
Lung cancer after HLRepresents a minority of casesRepresents one of the most common SMLung cancer representing a higher proportion of SM in adult HL survivors may be due to:
Shorter time to reach the attained age in which increased lung cancer risks emerge
Higher likelihood of antecedent or concurrent tobacco use in adults
Thyroid cancer after HLRepresents one of the most common SMRepresents a minority of casesThyroid cancer representing a higher proportion of SM in childhood HL survivors may be due to:
Higher susceptibility to radiation-related carcinogenesis of the thyroid in younger patients
Larger number of other cancers at an older attained age

Abbreviations: HL, Hodgkin's lymphoma; RR, relative risk; SM, second malignancy.

⁎Table represents a synthesis of current evidence. With the continued follow-up of both pediatric and adult HL survivors, taken together with the evolution of treatments, these observations may change.

Among various types of second malignancy after HL, solid tumors account for up to 75%-80% of second malignancies.36, 47, 59 Radiotherapy-associated solid tumors usually develop after a latency period of at least 5 to 9 years after treatment, and the increased risks persist for at least 30 years.60 Cancers of the breast, lung, and gastrointestinal sites result in the largest excess absolute risks after HL. In a population-based study of solid tumor risk among 18,862 5-year HL survivors reported to 13 cancer registries, cancers at these 3 sites accounted for almost two-thirds of estimated excess number of cases.60 For breast cancer, many studies have shown that risk is significantly higher among women who received radiation therapy at a young age. Relative risks compared with the general population appear to be particularly low for women treated after age 35. Travis et al45 developed estimates of cumulative absolute risk for use in counseling patients. For example, the cumulative absolute risks for an HL survivor who was treated at age 25 years with a chest radiation dose of ≥40 Gy without alkylating agents were estimated to be 1.4% after 10 years, 11% after 20 years, and 29% after 30 years.

Case-control studies conducted in several of these registries have shown significant dose–response relationships for the development of both breast cancer and lung cancer after radiotherapy for HL.42, 43, 61, 62 For breast cancer after HL, there appears to be a protective effect of early menopause either because of alkylating chemotherapy or radiation dose >5 Gy to the ovaries, suggesting that ovarian hormones play an important role in promoting tumorigenesis once an initiating event has been produced by radiation.42, 43

While alkylating agent chemotherapy for HL is associated with a reduced risk of breast cancer through its effect on ovarian function,42, 43 increased risks of lung cancer risk ensue. In a large international case-control study of lung cancer after HL in which the roles of radiation dose and amount of tobacco use were taken into account,61 a strong lung cancer dose–response relationship was observed for increasing cumulative dose of either mechlorethamine or procarbazine (P trend < 0.001), and with the number of cycles of alkylating agent chemotherapy, a grouping that included not only mechlorethamine or procarbazine, but other agents as well.61 Other studies, albeit not as well controlled for radiation and tobacco use,63 have reported similar results for alkylating agent administration and the risk of subsequent lung cancer.

Tobacco use is an important modifying factor for treatment-related lung cancer after HL. In the international case-control study of lung cancer after HL,61, 62 patients who received either alkylating agent chemotherapy alone or 5 or more Gy of radiation therapy alone to the region of the lung in which cancer developed experienced 4.3-fold and 7.2-fold increased risks of lung cancer, respectively, compared with patients with minimal treatment exposures and who were nonsmokers or light smokers. These relative risks increased to 16.8-fold and 20.2-fold, respectively, among patients who also smoked at least 1 pack of cigarettes per day. For cigarette smokers (at least 1 pack per day) also given alkylating agent chemotherapy and ≥5 Gy of radiation therapy to the area of the lung in which cancer developed, the relative risk of subsequent lung cancer was almost 50-fold. Further analysis indicated that these data were consistent with a multiplicative effect of smoking and treatment.

The risk of second primary cancers for HL patients treated in the modern era will likely be lower than those documented in current reports, in view of the decreased use of alkylating agent chemotherapy, the trend towards the application of smaller radiation fields, and lower doses and the availability of conformal radiation treatment techniques. It is important to institute long-term follow-up of these HL patients to accurately monitor and quantify the associated risks of second cancers and other late effects.

Testicular Cancer 

Second malignancies observed after testicular cancer include contralateral testicular cancer, leukemia, and a number of solid tumors, including malignant mesothelioma, and cancers of the lung, thyroid, esophagus, stomach, pancreas, colon, rectum, kidney, bladder, and connective tissue.64 In a population-based study of 29,515 USA testicular cancer survivors, the 15-year cumulative risk of contralateral testicular cancer was 1.9% and 12.4-fold higher than that expected in the general population.65 The increased risk of contralateral testicular cancer is likely due to underlying predisposition rather than treatment.

Chemotherapeutic agents that have been associated with the development of leukemia after testicular cancer include cisplatin and etoposide.66, 67, 68 Large-field radiation therapy regimens of the past that incorporated mediastinal fields also contribute to excess risks. In a leukemia case-control study of 18,567 1-year survivors of testicular cancer, Travis et al66 found that risk increased significantly with total dose to active bone marrow. As the authors pointed out, this finding reflected the additional use of mediastinal radiotherapy, which is no longer applied. Subdiaphragmatic radiation alone was associated with a nonsignificant 3-fold risk of leukemia.

The largest study of solid tumor risk following testicular cancer was conducted by Travis et al.64 In this international population-based survey, site-specific solid tumor risk among 40,576 testicular cancer survivors who were followed-up for an average of 11.8 years was reported. Men diagnosed with seminomas or nonseminomatous tumors at age 35 years demonstrated cumulative risks of solid cancer of 36% and 31%, respectively by age 75. The excess relative risk of solid tumors, however, decreased with increasing age at testicular cancer diagnosis. The relative risks of developing a solid tumor were significantly increased after both radiation therapy alone and chemotherapy alone (RR, 2.0 and 1.8, respectively). Although the relative risk was somewhat higher among patients who received both chemotherapy and radiation therapy (RR, 2.9), it did not differ significantly from those patients treated with single-modality therapy. Among patients treated with radiotherapy alone, relative risks for sites in typical infradiaphragmatic radiotherapy fields (stomach, pancreas, kidney, bladder) were higher than those for remaining sites (RR = 2.7; 95% CI, 2.4-3.0 vs RR = 1.6; 95% CI, 1.4-1.8). For in-field sites, the significantly increased relative risks persisted for ≥35 years with no evidence of decline over time.

Recent changes in treatment approaches for testicular cancer will likely alter the profile of second malignancies. Treatment has evolved from large field radiation therapy, to radiation treatment limited to para-aortic fields and lower doses, to an alternative approach of surveillance for patients with early stage disease. However, results of studies on testicular cancer patients treated in earlier eras remain highly valuable, as therapies were effective and resulted in long-term survivors. For these patients, it is important to develop recommendations with regard to appropriate follow-up and screening guidelines.69

Breast Cancer 

Breast cancer is the most common malignancy in women in the USA.70 Contralateral breast cancer accounts for 40% of all second tumors among women with breast cancer, with a 25-year cumulative risk of 6.9%.4 Although these excesses are largely related to preexisting breast cancer risk factors, prior radiation therapy, especially treatment at a young age, may contribute to increased risk.71, 72, 73, 74

In early case-control studies by Boice et al73 and Storm and Jenson75 the overall relative risk of contralateral breast cancer was not significantly increased after radiation therapy (RR = 1.2; 95% CI, 0.94, 1.2).73 However, among women age <45 years at the time of irradiation, the relative risk in the Boice et al study was 1.6 (95% CI, 1.1-2.4). In a recent Dutch study of 7425 1-year survivors of breast cancer, the overall relative risk for contralateral breast cancer for those who received radiation therapy compared with those who did not was not significantly elevated.76 When the dose–response analyses were focused on patients <45 years of age when irradiated, women treated with postlumpectomy radiation (which was associated with higher doses to the contralateral breast) had a significantly 1.5-fold increased risk of contralateral breast cancer compared with patients treated with postmastectomy radiation therapy. A dose–response relationship was observed for any contralateral breast cancer, with a stronger relationship for medially located cancers. The joint effects of tangential breast fields and a strong family history of breast cancer on the risk of contralateral breast cancer was greater than expected when individual risks were summed.

In a report from the Early Breast Cancer Trialists' Collaborative Group,77 a significantly increased risk of contralateral breast cancer was found after radiotherapy, largely during the period 5-14 years after randomization (RR = 1.4; P = .00001). In this study, small excess risks after irradiation were evident even among women aged >50 years at treatment (RR = 1.3; P = .002). In contrast, in a recent multiinstitutional study of 708 women with contralateral breast cancer, Stovall et al78 found no evidence of dose–response in women >40 years of age at treatment. However, women <40 years of age who received >1 Gy of absorbed radiation dose to the specific quadrant of the contralateral breast had a 2.5-fold greater risk for cancer than unexposed women (RR = 2.5; 95% CI 1.5-4.5). For women <40 years of age followed for >5 years, a 3-fold risk was observed, with a significant dose–response.

Tamoxifen has been shown to reduce the risk of contralateral breast tumors by 30%-40%.79 However, a number of large investigations have clearly demonstrated a 2- to 4-fold increased risk of endometrial cancer after tamoxifen therapy.80, 81 Whereas earlier studies indicated that endometrial cancer after tamoxifen therapy might have a more favorable prognosis compared with de novo tumors, more recent data have suggested that tamoxifen-related endometrial cancers may demonstrate more aggressive behavior.82, 83, 84 It should be noted, however that most cases of secondary endometrial cancer are detected at an early stage and are thus able to be surgically resected.84 Consequently, endometrial cancer after tamoxifen therapy does not appear to be associated with poorer endometrial cancer-specific survival.

Other solid tumors that have been linked to radiotherapy for breast cancer include lung cancer, esophageal cancer, and soft tissue sarcoma.4, 71, 85, 86, 87, 88, 89, 90 In several studies,71, 86, 87 women who received radiation had a 1.5- to 3-fold increased risk of developing lung cancer compared with women who did not receive radiation therapy. These excesses appeared to be more clearly related to postmastectomy radiation therapy, in which the target volume often also includes the supraclavicular, axillary, and/or internal mammary nodal region, thus exposing a larger volume of underlying lung tissue to radiation, while the existence of any increased risk after postlumpectomy radiation therapy is less certain.88, 89, 91 The observation that lung cancer after breast cancer therapy is more frequently found in the ipsilateral lung also supports a contributing role of radiation therapy to the elevated risk.88 Several studies showed an even greater increase in lung cancer risk among smokers given breast irradiation.92, 93 In a population-based case control study of lung cancer after breast cancer, 119 cases of lung cancer were matched with 380 controls without lung cancer.94 Compared with nonsmoking women who did not receive postmastectomy radiation therapy, nonsmoking women who received postmastectomy radiation therapy had no higher risk of lung cancer. However, the adjusted odds ratios were 5.9 (95% CI, 2.7-12.8) for ever-smokers who did not receive postmastectomy radiation therapy and 18.9 (95% CI, 7.9-45.4) for ever-smokers who received postmastectomy radiation therapy. Adjusted odds ratios for the joint effects of smoking and postmastectomy radiation therapy were 10.5 (95% CI, 2.9-37.8) for the contralateral lung and 37.6 (95% CI, 10.2-139.0) for the ipsilateral lung.

Elevated risks of esophageal cancer after breast cancer have been reported in several studies.4, 94 Although the roles of treatment, smoking habits, and alcohol use have not been simultaneously addressed, Curtis et al4 and Brown et al85 noted that the pattern of excess risks of esophageal cancer were consistent with a radiation effect. Zablotska et al95 examined the risk of squamous cell esophageal cancer after adjuvant radiation therapy for breast cancer, reporting a significantly increased relative risk only among women who received postmastectomy radiation therapy, but not among those who received postlumpectomy radiation therapy, who presumably received lower doses. In an ongoing National Cancer Institute-international study of breast cancer patients initiated by Travis and colleagues, the relationship between radiation dose to the esophagus and the subsequent risk of both esophageal adenocarcinoma and squamous cell cancer is being quantified; in addition, the possible modifying effects of tobacco use, alcohol, and chemotherapy are being examined.

The 15-year cumulative incidence of sarcoma after breast cancer is low (<0.5%), although the relative risk has been estimated to be as high as 7-fold, given the low background incidence in the general population.71, 96, 97, 98 In an Italian study of breast cancer survivors by Rubino et al,99 all subsequent sarcomas were either localized to previously irradiated fields or to the upper extremity of the arm ipsilateral to the treated breast among women initially given radiotherapy. By estimating the initial radiation dose to the site of sarcoma development, using a dose of ≤14 Gy as reference, women who received 14-44 Gy had a 1.6-fold increased risk of sarcoma whereas those who received ≥45 Gy to the site had a 30.6-fold increased risk (P trend for dose <.001). Angiosarcoma after breast cancer was initially shown to be associated with chronic lymphedema following radical mastectomy.100 Given the increasing use of radiotherapy with breast-conserving surgery, a growing number of reports document the occurrence of cutaneous angiosarcoma of the breast arising in the radiation field.98, 101, 102, 103 Unlike other radiation-associated soft tissue sarcomas, breast angiosarcoma can have a short latency period of just the first 5 years after therapy.

The increased risk of leukemia has been related to antecedent chemotherapy and radiation therapy.73, 104, 105, 106 In a population-based, nested case-control study of women treated for breast cancer between 1973 and 1985, Curtis et al4 showed in a case-control study that, compared with women who did not receive alkylating chemotherapy or radiation therapy, the relative risk of acute myelogenous leukemia after radiation therapy alone, alkylating chemotherapy alone, and both chemotherapy and radiation therapy were 2.4, 10.0, and 17.4, respectively. A significant dose–response relation for subsequent leukemia risk was observed for melphalan, cyclophosphamide, and cumulative radiation dose to the active bone marrow. Recent data demonstrate that the risk of secondary acute leukemia is more strongly related to the dose-intensity of cyclophosphamide than with cumulative dose,107 which may be of particular relevance given the increasing trend toward the use of dose-intensified regimens for breast cancer.

Evolutions in systemic chemotherapy for breast cancer, including targeted therapy, may eventually affect the risk of second malignancies. In addition, recent advances in radiation therapy, including the use of intensity modulated radiation therapy (IMRT), and the growing interest in partial breast irradiation,108 may also influence the risk profile. The degree to which second cancer risk will be affected by these newer radiation therapy approaches and techniques will need to be established through long-term follow-up of large cohorts of breast cancer survivors with sufficient statistical power to detect increased site-specific risks.

Prostate Cancer 

Prostate cancer is the most common malignancy among men in the USA,70 with increasing amounts of data available on the risk of second malignancies. Curtis et al4 evaluated the risk of subsequent primary malignancies among over 308,000 patients reported to the population-based surveillance, epidemiology and end results (SEER) Program (1973-2000). Prostate cancer survivors experienced increased risks for malignant melanoma and subsequent cancers of the small intestine, soft tissue, bladder, thyroid, and thymus. It was concluded that treatment with radiotherapy appeared to be associated with increased risks for selected solid cancers that occurred within the abdominal and pelvic fields, especially bladder cancer.

Other series have compared the risk of second malignancies among prostate cancer patients initially given radiation therapy with the risk among those who did not receive radiation therapy. Associations have been reported between radiation therapy and subsequently increased risks of cancers of the bladder and rectum.4, 109 Notably, Curtis et al4 did not observe increased risks of rectal cancer (O/E = 0.98) among over 90,000 prostate cancer survivors initially treated with radiotherapy in their report. Similarly, Kendal et al110 found no excess rectal cancers after prostate irradiation.

Chrouser et al111 showed that excess bladder cancers were limited to patients who received adjuvant radiation therapy after a radical prostatectomy, which may reflect the larger volume of bladder tissue exposed to radiation in the postoperative setting. In a survey of prostate cancer patients reported to the British Columbia Tumor Registry, an increased relative risk of bladder cancer was observed only in the nonirradiated cohort (RR = 1.3; P < .01), but not among irradiated patients.112

In studies that report significant cancer excesses after radiotherapy for prostate cancer, the overall risk appears to be low. In an early investigation of men with prostate cancer reported to the SEER program conducted by Brenner et al,113 the risk of developing a second malignancy was estimated at 1 in 290. In the last few years, IMRT has been increasingly utilized to treat prostate cancer to permit more conformal dose distribution and dose escalation.114 Depending on treatment energy, IMRT is associated with a 3- to 5-fold higher number of monitor units (1 monitor unit gives an absorbed dose of, 1 cGy at a depth of maximum dose for a field size of 10 × 10 cm2 for a source-to-axis distance of 100 cm) compared with conventional treatment. Applying risk coefficients from the National Council of Radiation Protection and Measurements for specific anatomic sites to this configuration, the risks of second malignancies using IMRT techniques have been estimated to be 2-3 times higher than that after conventional radiation therapy.115 This is due to exposure of larger volumes of normal tissue to low doses of radiation with IMRT compared with conventional conformal techniques. These preliminary estimates remain to be confirmed in epidemiologic studies that include large numbers of patients given IMRT who have been followed for sufficient periods to permit detection of any increased radiotherapy-associated risks.

In the interim, conflicting observations with regard to the contribution of radiotherapy to various second malignancies after prostate cancer may reflect a number of factors, including the practice of most registries to gather data only on initial course of therapy, the incomplete registration of initial treatment, misclassification of therapy, and the absence of data on subsequent treatment. Moreover, selection bias may be present in decisions to administer surgery or radiation therapy to treat prostate cancer, and the limited data available in most population-based registries do not allow for the identification of confounding factors. Patients with significant comorbid illnesses and/or a history of heavy tobacco use may not be treated with surgery and may be more likely to be given radiation therapy. Further, radiation therapy and treatment-related sequelae, such as cystitis, hematuria, proctitis, and rectal bleeding may lead to additional cystoscopies or colonoscopies that can then result in an apparently increased incidence of urological and colorectal cancers.

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Second Malignancy Risk Across the Age Spectrum 

The patterns of second primary malignancies in survivors of pediatric cancer and adult-onset cancer differ in the observed types of second tumors, magnitude of risks, latency periods, and the influence of modifying factors. Possible explanations for these variations include the genetic underpinnings and etiology of the first cancer diagnosis in different age groups, and variations in treatment approaches for children compared with adults (eg, different chemotherapeutic regimens and doses, radiation fields, doses, and techniques). In addition, the susceptibility of specific organs or tissues to radiocarcinogenesis likely varies depending on developmental stage and the microenvironment. The differences may also be influenced by the strong dependence of baseline risks on attained age, the period needed to reach an attained age for certain malignancies, and the contributions and modifying effects of exposures to environmental factors (eg, tobacco or alcohol). Moreover, treatment outcomes for similar diagnoses differ in children and adults, for example, ALL has a better prognosis in children than in adults.116 Highlighted below are examples of several types of second malignancies where differences in incidence according to age at first primary cancer diagnosis have been consistently reported.

Breast Cancer as a Second Malignancy 

The radiosensitivity of the breast at age <40 years has been well-established.117 Most of the data has been reported in survivors of childhood cancer,34, 39, 118 young adult HL (most of these studies also included a small proportion of pediatric patients),42, 43 and of breast cancer.73, 75, 76, 77, 78 For radiation-related breast cancer in survivors of adult cancer, a decreasing risk with increasing age at radiation therapy has generally been noted, with little risk for patients exposed at >40 years old.36, 60, 73 In pediatric cancer survivors, the risk of breast cancer appears less affected by age at treatment possibly because of the more limited age range. In a report by Bhatia et al34 from the Late Effects Study Group on second malignancy risk after childhood HL, age at diagnosis was not significantly associated with subsequent breast cancer risk. Travis et al42 focused on women given radiotherapy for HL before age 30, where no trend with age was detected, although the range was relatively narrow at 13-30 years (median 22 years). Similarly, Inskip et al118 found that in female 5-year survivors of childhood cancer, the radiation sensitivity of the breast in girls ages 10-20 was confirmed. However, a strong effect of age at exposure was not demonstrated within this narrow range. The age at initial cancer diagnosis was <13 years in only 15/107 cases. Kenney et al39 published one of the most comprehensive studies on breast cancer risk in childhood cancer survivors. Based on data from the CCSS, among 6068 eligible female childhood cancer survivors, 95 women (68% of whom were survivors of pediatric HL) had 111 confirmed cases of breast cancer. After adjustment for chest irradiation, age at treatment was not significantly associated with risk of breast cancer. Girls who were treated between ages 5-9 did not experience a significantly increased risk of subsequent breast cancer, while the risk became significantly increased after age 10. These findings suggest that in contrast to prepubertal breast tissues, proliferating and developing breast tissues may be more sensitive to the tumorigenic effect of radiation. However, breast cancer has been linked with radiation exposure at very young ages (<5) in other settings.117 Another possible explanation may be due to the relatively narrow age range, and that the length of follow-up time may not be long enough for younger survivors to reach an attained age when the breast cancer risk rises.

As noted above, the studies by Travis et al42 and van Leeuwen et al43 have shown the importance of hormonal stimulation in the development of radiation-associated breast cancer in women treated during young adulthood. A protective effect of alkyating agents or radiation dose to the ovary at >5 Gy was not found in the study by Inskip et al,118 who pointed out that ovaries in adolescent girls have a larger reserve of eggs and follicles relative to older women and are less likely to experience loss of function for a given dose of alkylating agent or radiation. Similarly, Kenney et al39 did not observe a protective effect of alkylating chemotherapy, even at the highest dose level. Finally, in the CCSS study, almost one quarter of the breast cancer cases were diagnosed in women who had not been exposed to previous chest radiation. Thus, in selected younger patients, familial cancer syndromes may play a critical role in breast cancer risk, a finding that may influence breast cancer screening recommendations.

Thyroid Cancer as a Second Malignancy 

In a CCSS study of 13,581 childhood cancer survivors followed for at least 5 years (median follow-up 15.4 years),3 thyroid cancer was the second most common subsequent malignant neoplasm after breast cancer. Thyroid cancer (43 cases) represented 15% of all solid tumors, with a significantly elevated 11-fold risk compared with the matched normal population. Thyroid cancer as a second malignancy in survivors of adult-onset cancer has been reported predominantly after adult HL. In the Hodgson et al60 study on solid tumor risk after HL, 40 cases of thyroid cancer were diagnosed among 1490 solid tumors, with a strong decline in the relative risk with increasing age at HL diagnosis. Although the risk of thyroid cancer was significantly elevated at RR = 3.1 (95% CI, 1.8-5.2) for patients diagnosed at age 30, cancers of this site were far less common than breast, lung, head, and neck, and genitourinary cancers, and represented only 2.7% of all reported cases of solid tumors. There were an estimated 29 excess number of cases of thyroid cancer in this cohort, compared with 175 and 226 excess cases of breast and lung cancer, respectively. These differences between survivors of adult and childhood cancer likely reflect the well-documented radiosensitivity of the thyroid in younger patients.34, 48 Unlike radiation-related breast cancer, lung cancer and sarcoma, for thyroid cancer there appears to be a reduction in the radiation dose–response at doses >30 Gy, consistent with a cell-killing effect.48

Lung Cancer as a Second Malignancy 

An increased risk of lung cancer as a second malignancy is seen after a number of adult-onset primary malignancies, including HL, non-Hodgkin's lymphoma, head and neck cancers, cervical cancer, and breast cancer. In fact, lung cancer is one of the most common second malignancies in survivors of adult HL.60 Although analytical studies have linked excess second primary lung cancers to antecedent chest irradiation and alkylating chemotherapy in patients with HL,61, 62 and to radiation in women with breast cancer,87 it is clear that smoking plays a major role. In a review of 2 million cancer survivors reported to the NCI SEER Program, Curtis et al4 concluded that tobacco or alcohol-related cancer sites accounted for about 35% of the total excess risk of subsequent cancers. Although lung cancer represents a sizable proportion of second malignancies after selected adult-onset tumors, it is less commonly observed in pediatric cancer survivors. In an early report from the CCSS, at a median follow-up time of 15.4 years, second primary lung cancers had not yet been observed.3 In a later publication from the same group that included additional information from a follow-up questionnaire, 4 cases of lung cancer were reported, 3 of which were in survivors of HL.54 This suggests that most pediatric cancer survivors have not reached the attained age at which lung cancer rates increase. Moreover, any effects of tobacco use have not yet become manifest, and a longer follow-up time will be needed to document any increased risks. In the interim, it is critical to continue to both undertake measures to both prevent smoking onset and to encourage smoking cessation in survivors of both adult-onset and childhood cancers.119

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Conclusions 

Efforts to characterize differences in the long-term, site-specific patterns of excess second malignancies between survivors of childhood cancer and adult-onset cancer may eventually permit insights into mechanisms of carcinogenesis, including the roles of contributing etiologic factors and interactions between influences (including gene–environment and gene–gene interactions). Moreover, an improved understanding of the impact of age at treatment and attained age on second cancer risks should facilitate customization of screening and prevention strategies as well as the identification of high-risk patients for intensified efforts. Although differences exist in the risk of second malignancies across the age spectrum, lessons learned from 1 age group may potentially be applicable to other age groups as treatments evolve, follow-up time increases, and our understanding of secondary carcinogenesis improves.

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References 

  1. Ries L, Melbert D, Krapcho M. SEER Cancer Statistics Review, 1975-2004. Bethesda, MD: National Cancer Institute; 2007;
  2. Travis L, Rabkin C, Brown L. Cancer survivorship—genetic susceptibility and second primary cancers: Research strategies and recommendations. J Natl Cancer Inst. 2006;98:15–25
  3. Neglia JP, Friedman DL, Yasui Y. Second malignant neoplasms in five-year survivors of childhood cancer: Childhood cancer survivor study. J Natl Cancer Inst. 2001;93:618–629
  4. Curtis R, Freedman D, Ron E. New Malignancies Among Cancer Survivors: SEER Cancer Registries, 1973-2000. NIH publication 05-5302 Bethesda: National Cancer Institute; 2006;
  5. Jenkinson HC, Hawkins MM, Stiller CA. Long-term population-based risks of second malignant neoplasms after childhood cancer in Britain. Br J Cancer. 2004;91:1905–1910
  6. Meadows AT, Friedman DL, Neglia JP. Second neoplasms in survivors of childhood cancer: Findings from the Childhood Cancer Survivor Study cohort. J Clin Oncol. 2009;27:2356–2362
  7. Mertens AC, Yasui Y, Neglia JP. Late mortality experience in five-year survivors of childhood and adolescent cancer: The Childhood Cancer Survivor Study. J Clin Oncol. 2001;19:3163–3172
  8. Moller TR, Garwicz S, Barlow L. Decreasing late mortality among five-year survivors of cancer in childhood and adolescence: A population-based study in the Nordic countries. J Clin Oncol. 2001;19:3173–3181
  9. Cardous-Ubbink MC, Heinen RC, Langeveld NE. Long-term cause-specific mortality among five-year survivors of childhood cancer. Pediatr Blood Cancer. 2004;42:563–573
  10. Neglia JP, Meadows AT, Robison LL. Second neoplasms after acute lymphoblastic leukemia in childhood. N Engl J Med. 1991;325:1330–1336
  11. Loning L, Zimmermann M, Reiter A. Secondary neoplasms subsequent to Berlin-Frankfurt-Münster therapy of acute lymphoblastic leukemia in childhood: Significantly lower risk without cranial radiotherapy. Blood. 2000;95:2770–2775
  12. Bhatia S, Sather HN, Pabustan OB. Low incidence of second neoplasms among children diagnosed with acute lymphoblastic leukemia after 1983. Blood. 2002;99:4257–4264
  13. Hijiya N, Hudson MM, Lensing S. Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia. JAMA. 2007;297:1207–1215
  14. Neglia JP, Robison LL, Stovall M. New primary neoplasms of the central nervous system in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2006;98:1528–1537
  15. Walter AW, Hancock ML, Pui CH. Secondary brain tumors in children treated for acute lymphoblastic leukemia at St Jude Children's Research Hospital. J Clin Oncol. 1998;16:3761–3767
  16. Relling MV, Rubnitz JE, Rivera GK. High incidence of secondary brain tumours after radiotherapy and antimetabolites. Lancet. 1999;354:34–39
  17. Hawkins MM, Wilson LM, Stovall MA. Epipodophyllotoxins, alkylating agents, and radiation and risk of secondary leukaemia after childhood cancer. BMJ. 1992;304:951–958
  18. Pui CH, Ribeiro RC, Hancock ML. Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Engl J Med. 1991;325:1682–1687
  19. Smith SM, Le Beau MM, Huo D. Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: The University of Chicago series. Blood. 2003;102:43–52
  20. Pui CH, Relling MV, Rivera GK. Epipodophyllotoxin-related acute myeloid leukemia: A study of 35 cases. Leukemia. 1995;9:1990–1996
  21. van Leeuwen FE, Chorus AM, van den Belt-Dusebout AW. Leukemia risk following Hodgkin's disease: Relation to cumulative dose of alkylating agents, treatment with teniposide combinations, number of episodes of chemotherapy, and bone marrow damage. J Clin Oncol. 1994;12:1063–1073
  22. Le Deley MC, Vassal G, Taibi A. High cumulative rate of secondary leukemia after continuous etoposide treatment for solid tumors in children and young adults. Pediatr Blood Cancer. 2005;45:25–31
  23. Haddy N, Le Deley MC, Samand A. Role of radiotherapy and chemotherapy in the risk of secondary leukaemia after a solid tumour in childhood. Eur J Cancer. 2006;42:2757–2764
  24. Cavenee WK, Murphree AL, Shull MM. Prediction of familial predisposition to retinoblastoma. N Engl J Med. 1986;314:1201–1207
  25. Kleinerman RA, Tucker MA, Tarone RE. Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: An extended follow-up. J Clin Oncol. 2005;23:2272–2279
  26. Fletcher O, Easton D, Anderson K. Lifetime risks of common cancers among retinoblastoma survivors. J Natl Cancer Inst. 2004;96:357–363
  27. Marees T, Moll AC, Imhof SM. Risk of second malignancies in survivors of retinoblastoma: More than 40 years of follow-up. J Natl Cancer Inst. 2008;100:1771–1779
  28. Hawkins MM, Wilson LM, Burton HS. Radiotherapy, alkylating agents, and risk of bone cancer after childhood cancer. J Natl Cancer Inst. 1996;88:270–278
  29. Wong FL, Boice JD, Abramson DH. Cancer incidence after retinoblastoma: Radiation dose and sarcoma risk. JAMA. 1997;278:1262–1267
  30. Tucker MA, D'Angio GJ, Boice JD. Bone sarcomas linked to radiotherapy and chemotherapy in children. N Engl J Med. 1987;317:588–593
  31. Kivela T. Trilateral retinoblastoma: A meta-analysis of hereditary retinoblastoma associated with primary ectopic intracranial retinoblastoma. J Clin Oncol. 1999;17:1829–1837
  32. Kleinerman RA, Tucker MA, Abramson DH. Risk of soft tissue sarcomas by individual subtype in survivors of hereditary retinoblastoma. J Natl Cancer Inst. 2007;99:24–31
  33. Constine LS, Tarbell N, Hudson MM. Subsequent malignancies in children treated for Hodgkin's disease: Associations with gender and radiation dose. Int J Radiat Oncol Biol Phys. 2008;72:24–33
  34. Bhatia S, Yasui Y, Robison LL. High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin's disease: Report from the Late Effects Study Group. J Clin Oncol. 2003;21:4386–4394
  35. Sankila R, Garwicz S, Olsen JH. Risk of subsequent malignant neoplasms among 1,641 Hodgkin's disease patients diagnosed in childhood and adolescence: A population-based cohort study in the five Nordic countries (Association of the Nordic Cancer Registries and the Nordic Society of Pediatric Hematology and Oncology). J Clin Oncol. 1996;14:1442–1446
  36. Ng AK, Bernardo MV, Weller E. Second malignancy after Hodgkin disease treated with radiation therapy with or without chemotherapy: Long-term risks and risk factors. Blood. 2002;100:1989–1996
  37. Swerdlow AJ, Barber JA, Hudson GV. Risk of second malignancy after Hodgkin's disease in a collaborative British cohort: The relation to age at treatment. J Clin Oncol. 2000;18:498-450
  38. Green DM, Hyland A, Barcos MP, et al. Second malignant neoplasms after treatment for Hodgkin's disease in childhood or adolescence. J Clin Oncol. 2000;18:1492–1499
  39. Kenney LB, Yasui Y, Inskip PD. Breast cancer after childhood cancer: a report from the Childhood Cancer Survivor Study. Ann Intern Med. 2004;141:590–597
  40. Curtis RE, Metayer C, Rizzo JD. Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: An international case-control study. Blood. 2005;105:3802–3811
  41. Mauch P, Ng A, Aleman B. Report from the Rockefeller Foundation Sponsored International Workshop on reducing mortality and improving quality of life in long-term survivors of Hodgkin's disease. Eur J Haematol Suppl. 2005;66:68–76
  42. Travis LB, Hill DA, Dores GM. Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA. 2003;290:465–475
  43. van Leeuwen FE, Klokman WJ, Stovall M. Roles of radiation dose, chemotherapy, and hormonal factors in breast cancer following Hodgkin's disease. J Natl Cancer Inst. 2003;95:971–980
  44. Guibout C, Adjadj E, Rubino C. Malignant breast tumors after radiotherapy for a first cancer during childhood. J Clin Oncol. 2005;23:197–204
  45. Travis LB, Hill D, Dores GM. Cumulative absolute breast cancer risk for young women treated for Hodgkin lymphoma. J Natl Cancer Inst. 2005;97:1428–1437
  46. Sklar C, Whitton J, Mertens A. Abnormalities of the thyroid in survivors of Hodgkin's disease: Data from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab. 2000;85:3227–3232
  47. van Leeuwen FE, Klokman WJ, Veer MB. Long-term risk of second malignancy in survivors of Hodgkin's disease treated during adolescence or young adulthood. J Clin Oncol. 2000;18:487–497
  48. Sigurdson AJ, Ronckers CM, Mertens AC. Primary thyroid cancer after a first tumour in childhood (the Childhood Cancer Survivor Study): A nested case-control study. Lancet. 2005;365:2014–2023
  49. Acharya S, Sarafoglou K, LaQuaglia M. Thyroid neoplasms after therapeutic radiation for malignancies during childhood or adolescence. Cancer. 2003;97:2397–2403
  50. Black P, Straaten A, Gutjahr P. Secondary thyroid carcinoma after treatment for childhood cancer. Med Pediatr Oncol. 1998;31:91–95
  51. Tucker MA, Jones PH, Boice JD. Therapeutic radiation at a young age is linked to secondary thyroid cancer (The Late Effects Study Group). Cancer Res. 1991;51:2885–2888
  52. Schneider AB, Ron E, Lubin J. Dose-response relationships for radiation-induced thyroid cancer and thyroid nodules: Evidence for the prolonged effects of radiation on the thyroid. J Clin Endocrinol Metab. 1993;77:362–369
  53. Ronckers CM, Sigurdson AJ, Stovall M. Thyroid cancer in childhood cancer survivors: A detailed evaluation of radiation dose response and its modifiers. Radiat Res. 2006;166:618–628
  54. Bassal M, Mertens AC, Taylor L. Risk of selected subsequent carcinomas in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. J Clin Oncol. 2006;24:476–483
  55. Ferme C, Eghbali H, Meerwaldt JH. Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease. N Engl J Med. 2007;357:1916–1927
  56. Ng AK, Bernardo MP, Weller E. Long-term survival and competing causes of death in patients with early-stage Hodgkin's disease treated at age 50 or younger. J Clin Oncol. 2002;20:2101–2108
  57. Aleman BM, van den Belt-Dusebout AW, Klokman WJ. Long-term cause-specific mortality of patients treated for Hodgkin's disease. J Clin Oncol. 2003;21:3431–3439
  58. Tarbell NJ, Gelber RD, Weinstein HJ. Sex differences in risk of second malignant tumours after Hodgkin's disease in childhood. Lancet. 1993;341:1428–1432
  59. Dores GM, Metayer C, Curtis RE. Second malignant neoplasms among long-term survivors of Hodgkin's disease: A population-based evaluation over 25 years. J Clin Oncol. 2002;20:3484–3494
  60. Hodgson DC, Gilbert ES, Dores GM. Long-term solid cancer risk among 5-year survivors of Hodgkin's lymphoma. J Clin Oncol. 2007;25:1489–1497
  61. Travis LB, Gospodarowicz M, Curtis RE. Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease. J Natl Cancer Inst. 2002;94:182–192
  62. Gilbert ES, Stovall M, Gospodarowicz M. Lung cancer after treatment for Hodgkin's disease: Focus on radiation effects. Radiat Res. 2003;159:161–173
  63. Swerdlow AJ, Schoemaker MJ, Allerton R. Lung cancer after Hodgkin's disease: A nested case-control study of the relation to treatment. J Clin Oncol. 2001;19:1610–1618
  64. Travis LB, Fossa SD, Schonfeld SJ. Second cancers among 40,576 testicular cancer patients: Focus on long-term survivors. J Natl Cancer Inst. 2005;97:1354–1365
  65. Fossa SD, Chen J, Schonfeld SJ. Risk of contralateral testicular cancer: A population-based study of 29,515 U.S. men. J Natl Cancer Inst. 2005;97:1056–1066
  66. Travis LB, Andersson M, Gospodarowicz M. Treatment-associated leukemia following testicular cancer. J Natl Cancer Inst. 2000;92:1165–1171
  67. Pedersen-Bjergaard J, Daugaard G, Hansen SW. Increased risk of myelodysplasia and leukaemia after etoposide, cisplatin, and bleomycin for germ-cell tumours. Lancet. 1991;338:359–363
  68. Kollmannsberger C, Hartmann JT, Kanz L. Therapy-related malignancies following treatment of germ cell cancer. Int J Cancer. 1999;83:860–863
  69. Vaughn DJ, Gignac GA, Meadows AT. Long-term medical care of testicular cancer survivors. Ann Intern Med. 2002;136:463–470
  70. Hayat MJ, Howlader N, Reichman ME. Cancer statistics, trends, and multiple primary cancer analyses from the Surveillance, Epidemiology, and End Results (SEER) Program. Oncologist. 2007;12:20–37
  71. Kirova YM, Gambotti L, De Rycke Y. Risk of second malignancies after adjuvant radiotherapy for breast cancer: A large-scale, single-institution review. Int J Radiat Oncol Biol Phys. 2007;68:359–363
  72. Gao X, Fisher SG, Emami B. Risk of second primary cancer in the contralateral breast in women treated for early-stage breast cancer: A population-based study. Int J Radiat Oncol Biol Phys. 2003;56:1038–1045
  73. Boice JD, Harvey EB, Blettner M. Cancer in the contralateral breast after radiotherapy for breast cancer. N Engl J Med. 1992;326:781–785
  74. Hill-Kayser CE, Harris EE, Hwang WT. Twenty-year incidence and patterns of contralateral breast cancer after breast conservation treatment with radiation. Int J Radiat Oncol Biol Phys. 2006;66:1313–1319
  75. Storm HH, Jensen OM. Risk of contralateral breast cancer in Denmark 1943-80. Br J Cancer. 1986;54:483–492
  76. Hooning MJ, Aleman BM, Hauptmann M. Roles of radiotherapy and chemotherapy in the development of contralateral breast cancer. J Clin Oncol. 2008;26:5561–5568
  77. Clarke M, Collins R, Darby S. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet. 2005;366:2087–2106
  78. Stovall M, Smith SA, Langholz BM. Dose to the contralateral breast from radiotherapy and risk of second primary breast cancer in the WECARE study. Int J Radiat Oncol Biol Phys. 2008;72:1021–1030
  79. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet. 2005;365:1687–1717
  80. Fisher B, Costantino JP, Redmond CK. Endometrial cancer in tamoxifen-treated breast cancer patients: Findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst. 1994;86:527–537
  81. Fisher B, Costantino JP, Wickerham DL. Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90:1371–1388
  82. Magriples U, Naftolin F, Schwartz PE. High-grade endometrial carcinoma in tamoxifen-treated breast cancer patients. J Clin Oncol. 1993;11:485–490
  83. Bergman L, Beelen ML, Gallee MP. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer (Comprehensive Cancer Centres' ALERT Group. Assessment of Liver and Endometrial cancer Risk following Tamoxifen). Lancet. 2000;356:881–887
  84. Saadat M, Truong PT, Kader HA. Outcomes in patients with primary breast cancer and a subsequent diagnosis of endometrial cancer: Comparison of cohorts treated with and without tamoxifen. Cancer. 2007;110:31–37
  85. Brown LM, Chen BE, Pfeiffer RM. Risk of second non-hematological malignancies among 376,825 breast cancer survivors. Breast Cancer Res Treat. 2007;106:439–451
  86. Roychoudhuri R, Evans H, Robinson D. Radiation-induced malignancies following radiotherapy for breast cancer. Br J Cancer. 2004;91:868–872
  87. Neugut AI, Robinson E, Lee WC. Lung cancer after radiation therapy for breast cancer. Cancer. 1993;71:3054–3057
  88. Zablotska LB, Neugut AI. Lung carcinoma after radiation therapy in women treated with lumpectomy or mastectomy for primary breast carcinoma. Cancer. 2003;97:1404–1411
  89. Deutsch M, Land SR, Begovic M. The incidence of lung carcinoma after surgery for breast carcinoma with and without postoperative radiotherapy (Results of National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials B-04 and B-06). Cancer. 2003;98:1362–1368
  90. Kirova YM, De Rycke Y, Gambotti L. Second malignancies after breast cancer: The impact of different treatment modalities. Br J Cancer. 2008;98:870–874
  91. Travis LB, Curtis RE, Inskip PD. Re: Lung cancer risk and radiation dose among women treated for breast cancer. J Natl Cancer Inst. 1995;87:60–61
  92. Neugut AI, Murray T, Santos J. Increased risk of lung cancer after breast cancer radiation therapy in cigarette smokers. Cancer. 1994;73:1615–1620
  93. Ford MB, Sigurdson AJ, Petrulis ES. Effects of smoking and radiotherapy on lung carcinoma in breast carcinoma survivors. Cancer. 2003;98:1457–1464
  94. Kaufman EL, Jacobson JS, Hershman DL. Effect of breast cancer radiotherapy and cigarette smoking on risk of second primary lung cancer. J Clin Oncol. 2008;26:392–398
  95. Zablotska LB, Chak A, Das A. Increased risk of squamous cell esophageal cancer after adjuvant radiation therapy for primary breast cancer. Am J Epidemiol. 2005;161:330–337
  96. Huang J, Mackillop WJ. Increased risk of soft tissue sarcoma after radiotherapy in women with breast carcinoma. Cancer. 2001;92:172–180
  97. Karlsson P, Holmberg E, Samuelsson A. Soft tissue sarcoma after treatment for breast cancer—a Swedish population-based study. Eur J Cancer. 1998;34:2068–2075
  98. Kirova YM, Vilcoq JR, Asselain B. Radiation-induced sarcomas after radiotherapy for breast carcinoma: A large-scale single-institution review. Cancer. 2005;104:856–863
  99. Rubino C, de Vathaire F, Shamsaldin A. Radiation dose, chemotherapy, hormonal treatment and risk of second cancer after breast cancer treatment. Br J Cancer. 2003;89:840–846
  100. Jessner M, Zak FG, Rein CR. Angiosarcoma in postmastectomy lymphedema (Stewart-Treves syndrome). AMA Arch Derm Syphilol. 1952;65:123–129
  101. Esler-Brauer L, Jaggernauth W, Zeitouni NC. Angiosarcoma developing after conservative treatment for breast carcinoma: Case report with review of the current literature. Dermatol Surg. 2007;33:749–755
  102. Virtanen A, Pukkala E, Auvinen A. Angiosarcoma after radiotherapy: A cohort study of 332,163 Finnish cancer patients. Br J Cancer. 2007;97:115–117
  103. Simonart T, Heenen M. Radiation-induced angiosarcomas. Dermatology. 2004;209:175–176
  104. Curtis RE, Boice JD, Stovall M. Risk of leukemia after chemotherapy and radiation treatment for breast cancer. N Engl J Med. 1992;326:1745–1751
  105. Praga C, Bergh J, Bliss J. Risk of acute myeloid leukemia and myelodysplastic syndrome in trials of adjuvant epirubicin for early breast cancer: Correlation with doses of epirubicin and cyclophosphamide. J Clin Oncol. 2005;23:4179–4191
  106. Campone M, Roche H, Kerbrat P. Secondary leukemia after epirubicin-based adjuvant chemotherapy in operable breast cancer patients: 16 years experience of the French Adjuvant Study Group. Ann Oncol. 2005;16:1343–1351
  107. Smith RE, Bryant J, DeCillis A. Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: The National Surgical Adjuvant Breast and Bowel Project Experience. J Clin Oncol. 2003;21:1195–1204
  108. Chen PY, Vicini FA. Partial breast irradiation: patient selection, guidelines for treatment, and current results. Front Radiat Ther Oncol. 2007;40:253–271
  109. Moon K, Stukenborg GJ, Keim J. Cancer incidence after localized therapy for prostate cancer. Cancer. 2006;107:991–998
  110. Kendal WS, Eapen L, Macrae R. Prostatic irradiation is not associated with any measurable increase in the risk of subsequent rectal cancer. Int J Radiat Oncol Biol Phys. 2006;65:661–668
  111. Chrouser K, Leibovich B, Bergstralh E. Bladder cancer risk following primary and adjuvant external beam radiation for prostate cancer. J Urol. 2005;174:107–110discussion 110-101
  112. Pickles T, Phillips N. The risk of second malignancy in men with prostate cancer treated with or without radiation in British Columbia, 1984-2000. Radiother Oncol. 2002;65:145–151
  113. Brenner DJ, Curtis RE, Hall EJ. Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery. Cancer. 2000;88:398–406
  114. Guckenberger M, Flentje M. Intensity-modulated radiotherapy (IMRT) of localized prostate cancer: A review and future perspectives. Strahlenther Onkol. 2007;183:57–62
  115. Kry SF, Salehpour M, Followill DS. The calculated risk of fatal secondary malignancies from intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys. 2005;62:1195–1203
  116. Pulte D, Gondos A, Brenner H. Improvement in survival in younger patients with acute lymphoblastic leukemia from the 1980s to the early 21st century. Blood. 2009;113:1408–1411
  117. Preston DL, Mattsson A, Holmberg E. Radiation effects on breast cancer risk: A pooled analysis of eight cohorts. Radiat Res. 2002;158:220–235
  118. Inskip P, Robison L, Stovall M. Radiation dose and breast cancer risk in the childhood cancer survivor study. J Clin Oncol. 2009;27:3901–3907
  119. Emmons KM, Puleo E, Mertens A. Long-term smoking cessation outcomes among childhood cancer survivors in the Partnership for Health Study. J Clin Oncol. 2009;27:52–60

PII: S1053-4296(09)00067-8

doi:10.1016/j.semradonc.2009.09.002

Seminars in Radiation Oncology
Volume 20, Issue 1 , Pages 67-78, January 2010

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