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doi: 10.1097/HP.0000000000000013
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Second Malignant Neoplasms and Cardiovascular Disease Following Radiotherapy

Travis, Lois B.*; Ng, Andrea K.; Allan, James M.; Pui, Ching-Hon§; Kennedy, Ann R.**; Xu, X. George††; Purdy, James A.‡‡; Applegate, Kimberly§§; Yahalom, Joachim***; Constine, Louis S.*; Gilbert, Ethel S.†††; Boice, John D.‡‡‡

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*Rubin Center for Cancer Survivorship and Department of Radiation Oncology, James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY; †Department of Radiation Oncology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; and the Dana-Farber Cancer Institute, Boston, MA; ‡Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK; §Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN; and the University of Tennessee Health Science Center, Memphis, TN; **Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA; ††Nuclear Engineering and Engineering Physics Program, Rensselaer Polytechnic Institute, Troy, NY; ‡‡Department of Radiation Oncology, University of California at Davis, Davis, CA; §§Department of Radiology, Emory University, Atlanta, GA; ***Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY; †††Division ofCancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD; ‡‡‡National Council on Radiation Protection and Measurements, Bethesda, MD, and the Department of Medicine, Vanderbilt University, Nashville, TN.

The authors declare no conflicts of interest.

For correspondence contact: Lois B. Travis, Rubin Center for Cancer Survivorship and Department of Radiation Oncology, James P. Wilmot Cancer Center, University of Rochester Medical Center, 265 Crittenden Blvd, CU 420318, Rochester, NY 14642, or email at Lois_Travis@URMC.Rochester.edu.

Article reprinted with permission from Journal of the National Cancer Institute. Travis LB, Ng AK, Allan JM, Pui CH, Kennedy AR, Xu XG, Purdy JA, Applegate K, Yahalom J, Constine LS, Gilbert ES, Boice JD. Second Malignant Neoplasms and Cardiovascular Disease Following Radiotherapy. JNCI J Natl Cancer Inst (2012) 104 (5): 357-370. doi: 10.1093/jnci/djr533.

Supplemental Digital Content is available in the HTML and PDF versions of this article on the journal’s Web site ( www.health-physics.com).

(Manuscript accepted 13 July 2013)

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Abstract

Second malignant neoplasms (SMNs) and cardiovascular disease (CVD) are among the most serious and life-threatening late adverse effects experienced by the growing number of cancer survivors worldwide and are due in part to radiotherapy. The National Council on Radiation Protection and Measurements (NCRP) convened an expert scientific committee to critically and comprehensively review associations between radiotherapy and SMNs and CVD, taking into account radiobiology; genomics; treatment (i.e., radiotherapy with or without chemotherapy and other therapies); type of radiation; and quantitative considerations (i.e., dose-response relationships). Major conclusions of the NCRP include: (1) the relevance of older technologies for current risk assessment when organ-specific absorbed dose and the appropriate relative biological effectiveness are taken into account and (2) the identification of critical research needs with regard to newer radiation modalities, dose-response relationships, and genetic susceptibility. Recommendation for research priorities and infrastructural requirements include (1) long-term large-scale follow-up of extant cancer survivors and prospectively treated patients to characterize risks of SMNs and CVD in terms of radiation dose and type; (2) biological sample collection to integrate epidemiological studies with molecular and genetic evaluations; (3) investigation of interactions between radiotherapy and other potential confounding factors, such as age, sex, race, tobacco and alcohol use, dietary intake, energy balance, and other cofactors, as well as genetic susceptibility; (4) focusing on adolescent and young adult cancer survivors, given the sparse research in this population; and (5) construction of comprehensive risk prediction models for SMNs and CVD to permit the development of follow-up guidelines and prevention and intervention strategies.
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INTRODUCTION

Advances in cancer therapy, early detection, and supportive care have contributed to steady gains in the 5 y relative survival rate for all cancers combined, which reached 66.0% for patients diagnosed during 1999–2006 (Altekruse et al. 2010). Commensurately, the number of cancer survivors in the United States has tripled since 1971 and is growing by 2% each year. As of 2007, there were ~12 million men and women in the United States (~3.5% of the U.S. population) with a history of cancer (Altekruse et al. 2010). For many patients, these gains in survival have come at the price of serious treatment-associated late adverse effects.

Radiation remains a cornerstone of successful cancer treatment, with 50% of all patients estimated to receive radiotherapy (Ringborg et al. 2003). Second malignant neoplasms (SMNs) and cardiovascular disease (CVD) are two of the most frequent and important life-threatening adverse events associated with radiotherapy. Multiple primary cancers now account for approximately one in six of all incident cancers reported to the US Surveillance, Epidemiology, and End Results Program cancer registry (Altekruse et al. 2010). For patients with Hodgkin lymphoma (Ng et al. 2002a), testicular cancer (van den Belt-Dusebout et al. 2007; Travis et al. 2010), and certain childhood cancers (Friedman et al. 2010), SMNs have emerged as an important cause of death (Travis et al. 2011). Radiotherapy-associated CVD refers to a wide spectrum of disorders and is an important cause of morbidity and mortality, most notably after thoracic radiotherapy for Hodgkin lymphoma and tangential radiotherapy for breast cancer (Yahalom and Portlock 2008; Mulrooney et al. 2009).

With the increased awareness of the adverse consequences of cancer therapy, it has become critically important to identify measures to mitigate and ameliorate these late adverse effects and to provide cancer survivors with counseling, surveillance, and supportive care. In addition, it is essential to review and balance the risks and benefits of new treatment options as they become available. Providing a research infrastructure for transdisciplinary studies of cancer survivors is also important (NCI 2010). The Childhood Cancer Survivors Study (CCSS) is a critical resource for outcome and intervention research in survivors of pediatric and adolescent cancer (Robison et al. 2009); however, a comparable research base is lacking for survivors of young adult-onset (Travis et al. 2006; Bhatia and Robison 2008) and other cancers. The expanding use of radiotherapy and development of new radiation modalities to treat cancer, coupled with improvements in long-term patient survival, underscores the importance of continuing to provide long-term risk estimates as well as additional research into the molecular underpinnings of treatment-related SMNs and CVD. Moreover, optimal screening and interventional efforts for these late adverse events must be identified (Travis et al. 2010).

To review and address the expanding burden of late adverse effects after treatment with radiation, the National Council on Radiation Protection and Measurements (NCRP) convened a scientific committee of experts in radiation biology, radiation oncology, radiation physics, molecular genetics, medical oncology, pediatric oncology, cardiology, biostatistics, and epidemiology to comprehensively review radiotherapy-associated SMNs and CVD and recommend future research. This article provides a synthesis of the 425-page NCRP report titled Second Primary Cancers and Cardiovascular Disease After Radiotherapy (NCRP 2011).

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RADIOBIOLOGY

The traditional paradigm for the genesis of radiation-induced adverse effects, such as cell killing and carcinogenesis, is that biological responses result from the deposition of energy in or near cellular DNA (Little 2000). Radiation then interacts with DNA, either directly via ionization or indirectly via water-derived free radicals, resulting in genetic and/or epigenetic changes that are passed on to cellular progeny and that can contribute to malignant transformation. However, based on both in vitro and in vivo studies, there is increasing realization that low doses of radiation (e.g., <0.5 Gy) may also contribute to radiation-induced adverse effects such as carcinogenesis and CVD (UNSCEAR 2009). Differences in cellular responses to “low” vs. “high” doses of radiation have also been reported for a number of different biological endpoints, including DNA damage signaling, cell cycle checkpoint activation, DNA repair, gene and protein expression, apoptosis, and cell transformation (Averbeck 2009). However, evidence is emerging that radiation-induced carcinogenesis may be a modifiable process (Kennedy 2009). For example, some agents appear to be capable of either reducing or increasing the incidence of radiation-induced cancer in animal models (Fry and Ley 1984; Burns et al. 2007; Kennedy et al. 2008). Given this prospect, more research is needed to identify clinical interventions to reduce late adverse effects of radiotherapy.

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GENETIC FOUNDATIONS OF LATE EFFECTS OF RADIOTHERAPY

Data from animal models and human studies demonstrate that the genotype of the host influences the risk of radiation-associated late effects. For example, patients who inherit rare pathogenic mutations in genes associated with human cancer susceptibility syndromes are predisposed to radiogenic cancers, including TP53 mutations in Li-Fraumeni syndrome (Nutting et al. 2000; Limacher et al. 2001; Talwalkar et al. 2010), NF1 mutations in neurofibromatosis (Little et al. 1998; Sharif et al. 2006), PTCH1 mutations in Gorlin syndrome (Wallin et al. 2007), WT1 mutations in Wilms tumor (Bassal et al. 2006; Henderson et al. 2007; Breslow et al. 2010), and RB1 mutations in retinoblastoma (Wong et al. 1997; Kleinerman et al. 2005). The increased susceptibility of mice heterozygous for the murine homologs of PTCH1 (Pazzaglia et al. 2004, 2006), TP53 (Backlund et al. 2001), and NF1 (Chao et al. 2005) to radiogenic cancers suggests the importance of these loci in human radiogenic cancers. The well-characterized roles of BRCA1, BRCA2, and ATM in mediating cellular response to ionizing radiation have prompted speculation that germline mutations associated with hereditary cancer may also predispose the mutation carriers to radiogenic cancer, particularly in the contexts of contralateral breast cancer (Bernstein et al. 2010; Graeser et al. 2009) and radiotherapy for Hodgkin lymphoma (Nichols et al. 1999; Offit et al. 2002). However, whether pathogenic mutations in these loci confer increased susceptibility to radiogenic cancer remains controversial. Several studies found no association (Nichols et al. 1999; Offit et al. 2002; Narod et al. 2006), whereas others provided limited evidence suggesting that specific ATM (Bernstein et al. 2010) and BRCA1 (Graeser et al. 2009) alleles may be associated with increased risk of breast cancer, particularly in BRCA1 mutation carriers exposed to radiotherapy before age 40 y (Andrieu et al. 2006; Berrington de Gonzalez et al. 2009; Graeser et al. 2009).

Many human cancer susceptibility genes that encode proteins that mediate cellular responses to ionizing radiation have a high frequency of genetic variants. For example, polymorphisms in TP53 and ATM, with corresponding amino acid changes in the respective proteins, can affect the cellular response to ionizing radiation (Angèle et al. 2003; Gutiérrez-Enríquez et al. 2004; Li et al. 2005; Zhu et al. 2010), making them candidate risk modifiers for radiogenic cancer and other late adverse effects of radiotherapy in a polygenic disease. Targeted gene- and/or pathway-based studies investigating adverse events after low- (Lönn et al. 2007; Sigurdson et al. 2007, 2009a; Bhatti et al. 2008a, 2008b, 2010; Rajaraman et al. 2008; Schonfeld et al. 2010) and high-dose (Chang-Claude et al. 2005, 2009; De Ruyck et al. 2006; Tan et al. 2006; Azria et al. 2008; Burri et al. 2008; Kuptsova et al. 2008; Pugh et al. 2009; Sigurdson et al. 2009b; Werbrouck et al. 2009; Yoshida et al. 2009; Zhang et al. 2010) radiation exposure have identified numerous other variants, loci, and pathways that warrant further investigation; others are readily testable based on known gene-exposure interactions identified by in vitro and ex vivo studies (Zheng et al. 2010). Genome-wide association studies (Knight et al. 2009; Ingle et al. 2010; Best et al. 2011) might identify new gene-exposure interactions; however, this approach will require large well-controlled studies with sufficient statistical power to account for various phenotypic and exposure-related risk factors. Indeed, a genome-wide approach led to the discovery of an allelic variant in PRDM1 (also known as BLIMP1), a gene that predisposes Hodgkin lymphoma survivors to radiogenic cancer (Best et al. 2011). As parallel approaches, whole-genome (Cirulli and Goldstein 2010) or exon-based sequencing technologies could prove equally informative. The ongoing development of radiogenomics consortia (West et al. 2010) with annotated biospecimens is anticipated to provide additional data with regard to genetic variants that may increase the risk for radiogenic cancer.

The low frequencies of overtly pathogenic alleles, such as TP53 and ATM, suggest that they make a relatively small contribution at the population level. In addition, the heterogeneous patient responses to the acute and chronic effects of radiotherapy imply that these toxicities have complex genetic etiologies, rather than representing a monogenic trait. Furthermore, the fact that a single susceptibility locus with high-penetrance allelic variants for radiogenic cancer has not yet, to our knowledge, been identified further underscores the hypothesis that susceptibility to radiogenic cancer constitutes a polygenic trait, where cumulative risk is determined by co-inheritance of multiple low- and/or intermediate-penetrance “risk” alleles at several different loci, including, for example, PRDM1 (Best et al. 2011). Understanding how multiple variants interact with each other and with radiation and phenotypic risk modifiers should be considered when developing risk prediction models to inform intervention strategies. Indeed, the inclusion of genetic data has substantially improved the accuracy of risk prediction models for SMNs or recurrence after head and neck cancer (Wu et al. 2009). Risk models that integrate genotypic, phenotypic, and treatment data and other variables should also be developed for Hodgkin lymphoma (Longo 2005; Travis et al. 2005a) and other malignancies (Travis et al. 2010) where SMNs, CVD, and other late effects are important causes of morbidity and mortality.

An understanding of genetic and molecular factors that predispose individuals to the development of radiotherapy-induced cancers will also provide a foundation for the study of other late effects of radiation that have, in part, a known genetic basis, including CVD (Hindorff et al. 2009; NHGRI 2010). Although some genetic risk factors will undoubtedly be effect specific, the observation that some human diseases have overlapping transcriptional signatures in pathways such as lipid metabolism and carcinogenesis suggests that some pathways might apply to seemingly unrelated radiation-induced late effects, including cancer and CVD (Hirsch et al. 2010). Other pathways directly responsible for mediating cellular response to ionizing radiation are also likely to involve nonspecific risk factors. For example, radiation-induced reactive oxygen species can initiate an inflammatory response that leads to genomic instability and fibrosis, which have been implicated in the etiologies of cancer and CVD, respectively. In addition, Wethal et al. (2010) showed that long-term survivors of testicular cancer with elevated serum levels of C-reactive protein, which is produced in response to inflammatory stimuli, had a two- to threefold increased risk of developing either SMN [hazard ratio (HR) = 2.21; P < 0.05] or CVD (HR = 2.79; P < 0.05).

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RADIOTHERAPY MODALITIES, TECHNOLOGIES, AND DOSIMETRY

Technical innovations have changed the practice of radiotherapy (Purdy 2007). Modern anatomical imaging technologies provide three-dimensional anatomical models of the patient that are often complemented with functional imaging studies such as positron emission tomography or magnetic resonance spectroscopy. Advanced imaging results in a more accurate determination of the tumor volumes and spatial relationships with the surrounding tissue and organs. Three-dimensional treatment planning systems, which take full advantage of these imaging advances, have facilitated the implementation of three-dimensional conformal radiation therapy as a standard of practice (Purdy 2007).

The development of medical linear accelerators equipped with computer-controlled multileaf collimator systems along with advanced computer-based treatment planning systems allow precise shaping of radiation dose distributions for each patient. Intensity-modulated radiation therapy (IMRT) can achieve even greater dose conformity through a computer-aided optimization process that creates a fluence of photons per radiation beam that is customized to the patient (IMRTCWG 2001). The use of conformal radiation therapy has further evolved from IMRT to image-guided IMRT, also called image-guided radiation therapy. For very small tumor volumes adjacent to sensitive critical structures, cobalt-60 and linear accelerator-based stereotactic radiosurgery have been increasingly used in recent years, and new image-guided stereotactic body radiation therapy systems have been developed (Leksell 1951, 1968; Lutz et al. 1988; Brown et al. 2005).

These advances have renewed interest in the use of protons for external beam radiotherapy (Delaney and Kooy 2008). This technology allows conformal therapy to take advantage of the improved depth dose characteristics of the proton beam, which peak at the end of the range of the charged particle (Delaney and Kooy 2008). In proton therapy, there are two techniques for beam production: passive scattering and beam scanning (Delaney and Kooy 2008), with the latter method resulting in a lower amount of secondary neutrons.

The use of real-time imaging techniques to ensure the accuracy of new treatment modalities is increasing (Bortfeld et al. 2005). Although the radiation dose from a single imaging technique is small compared with a therapeutic dose, repeated and daily image-guidance procedures can lead to cumulative exposures to normal tissues and possibly a slight increase in the risk of SMN (Hall 2006). The transition from two-dimensional radiation therapy to three-dimensional conformal radiation therapy and/or IMRT has also resulted in changes in dose distribution compared with techniques used in prior SMN studies (Hodgson et al. 2007).

Advances in radiotherapy have also resulted in increased doses to normal tissue but an overall reduction in the volume of normal structures receiving high doses. However, especially with IMRT, a considerably larger volume of normal tissue within the irradiated field receives low doses. Because these doses outside the target field are much smaller than the tumor doses, they are generally not recorded in radiotherapy documentation nor are additional doses due to image-guided radiation therapy reported in medical records. This unwanted radiation leakage and scatter dose can be decreased through several designs, as reviewed elsewhere (Purdy 2008). It will be important for clinical trial quality assurance centers that monitor radiotherapy protocols to capture radiation doses to multiple organs outside radiation fields for those patients enrolled in advanced technology clinical trials to enable eventual correlation with late effects (Purdy 2008).

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SMNS FOLLOWING RADIOTHERAPY FOR ADULT-ONSET CANCER

A sizable amount of SMN data has accrued for several adult-onset cancers in which radiotherapy has played pivotal roles, including Hodgkin lymphoma, non-Hodgkin lymphoma, and cancers of cervix, testis, breast, and prostate (NCRP 2011). The methods for estimating risk of SMNs from epidemiological data are described in Supplemental Digital Content 1 ( http://links.lww.com/HP/A17).

Hodgkin lymphoma survivors have elevated relative risks (RRs) for most SMNs (except bladder and prostate cancers), particularly breast and lung (Hodgson et al. 2007). Radiotherapy at a young age, especially before the age of 35 y, is associated with increased breast cancer risk (Travis et al. 2003; van Leeuwen et al. 2003; Ng et al. 2002b; De Bruin et al. 2009a), whereas treatment-related premature menopause is associated with decreased risk (Travis et al. 2003; van Leeuwen et al. 2003; Basu et al. 2008; De Bruin et al. 2009a). Both radiotherapy and alkylating chemotherapy have been associated with increased risks of lung cancer (Swerdlow et al. 2001; Travis et al. 2002). The risk of SMNs for pediatric Hodgkin lymphoma survivors appears to persist following low therapeutic doses of radiation and chemotherapy (O’Brien et al. 2010). Several case-control studies, some with detailed organ-specific dose reconstructions (Travis et al. 2002, 2003; van Leeuwen et al. 2003; Stovall et al. 2008; van den Belt-Dusebout et al. 2009), have reported statistically significant trends of increasing risks of breast (Travis et al. 2003; van Leeuwen et al. 2003; Stovall et al. 2008; Mauch et al. 2005), lung (van Leeuwen et al. 1995; Travis et al. 2002), and stomach (van den Belt-Dusebout et al. 2009) cancers with increasing radiation dose among several populations of survivors of adult-onset cancer.

Survivors of non-Hodgkin lymphoma are at increased risk for SMNs (Travis et al. 1991, 1992, 1993a, 1993b, 1994, 1995, 1996; Dores et al. 2006; Mudie et al. 2006; Tward et al. 2006; Landgren et al. 2007; Sacchi et al. 2008), and some of the increased risks are associated with radiotherapy. Radiotherapy for non-Hodgkin lymphoma has been linked to increased risks of acute leukemia (Greene et al. 1983; Travis et al. 1994), bladder cancer (Travis et al. 1995; Dores et al. 2006; Mudie et al. 2006), kidney cancer (Travis et al. 1995), and mesothelioma (Tward et al. 2006; Hodgson et al. 2007; Teta et al. 2007). The use of total body irradiation as part of transplantation approaches is associated with increased risks of acute leukemia and myelodysplastic syndrome (Pedersen-Bjergaard et al. 2000; Hosing et al. 2002; Metayer et al. 2003; Brown et al. 2005) and solid tumors (Brown et al. 2005; Friedman et al. 2008; Rizzo et al. 2009), including breast cancer (Friedman et al. 2008).

Among testicular cancer survivors, past treatment with large-field radiotherapy is statistically significantly associated with the risk of leukemia; past treatment with infradiaphragmatic radiation is associated with a threefold increased non-statistically significant risk of leukemia (Travis et al. 2000). Statistically significant increased risks of cancers of the lung, thyroid, esophagus, stomach, pancreas, colon, rectum, kidney, bladder, and connective tissue have also been observed among long-term survivors of testicular cancer (Travis et al. 2005b). These SMNs typically represent nontarget sites that were included in radiation fields (Travis et al. 2005b). Concerns about radiation-related SMNs have prompted the adoption of observation-alone strategies following stage I seminoma (Chung et al. 2010).

Cancers associated with breast cancer radiotherapy include those of the contralateral breast (Boice et al. 1992; Hemminki et al. 2007; Kirova et al. 2007; Hooning et al. 2008; Stovall et al. 2008), lung (Kirova et al. 2007; Deutsch et al. 2003; Zablotska and Neugut 2003; Kaufman et al. 2008), and esophagus (Zablotska et al. 2005), as well as sarcoma (Kirova et al. 2005). The risk of contralateral breast cancer after radiotherapy for breast cancer appears to be limited to women who are younger than age 40–45 y at receipt of radiotherapy (Boice et al. 1992; Hooning et al. 2008; Stovall et al. 2008) and is dose related (Stovall et al. 2008). Risks for cancers of the lung and esophagus are higher after postmastectomy radiotherapy than after post lumpectomy radiotherapy (Zablotska and Neugut 2003; Zablotska et al. 2005; Kaufman et al. 2008), likely reflecting the differing volumes of normal tissue in the treatment fields. Although the risk of sarcoma after breast cancer radiotherapy is increased compared with the risk of sarcoma in the general population, radiation-induced sarcoma remains a rare event (absolute risk <0.5% at 15 y after radiotherapy) (Kirova et al. 2005).

Kleinerman et al. (1982) reported that radiotherapy for cervical cancer was associated with statistically significantly increased risks of cancers of bladder, kidneys, rectum, corpus uteri, and ovaries; these findings were confirmed in subsequent surveys (Boice et al. 1987, 1988; Kleinerman et al. 1995). In the most recent update (Chaturvedi et al. 2007), the risks for several solid pelvic tumors remained statistically significantly elevated for more than 40 y after radiotherapy.

Some (Brenner et al. 2000; Pickles and Phillips 2002; Moon et al. 2006; Abdel-Wahab et al. 2009), but not all (Movsas et al. 1998; Chrouser et al. 2005; Kendal et al. 2006), studies have reported increased risks of colorectal cancer, bladder cancer, soft tissue sarcoma, and lung cancer among men treated with radiation for prostate cancer. The absolute risk of developing any SMN appeared modest (1 in 290 patients) (Brenner et al. 2000), and some excess SMNs were detected incidentally during colonoscopies or cystoscopies.

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SMNS FOLLOWING RADIOTHERAPY FOR CHILDHOOD CANCER

The risk of SMNs among childhood cancer survivors is associated with radiotherapy, chemotherapy, and genetic predisposition. In a recent CCSS update (Friedman et al. 2010), the cumulative incidence of all subsequent neoplasms at 30 y after diagnosis was 20.5% [95% confidence interval (CI) = 19.1–21.8%] among 5 y survivors of childhood cancer treated from 1970 through 1986 and was higher for patients who received radiation therapy than for those who did not (~25 vs. 10%); radiation therapy exposure was associated with a statistically significantly increased risk of a subsequent neoplasm (RR = 2.7, 95% CI = 2.2–3.3). Overall, cumulative incidence of SMNs at 30 y of follow-up was 7.9%, and, again, was higher among patients who received radiotherapy than among those who did not receive radiotherapy (~10 vs. 5%). Radiotherapy was associated with increased risks of secondary central nervous system tumors, bone and soft tissue sarcomas, thyroid cancer, and non-melanoma skin cancer. A more recent CCSS report showed that, overall, patients who developed a second neoplasm had a cumulative incidence of developing yet another primary cancer by 20 y after the SMN of 46.9%; the cumulative incidence of an additional primary cancer after an SMN was 41.3% among patients who received radiotherapy for the first cancer compared with 25.7% for those not treated with radiation; however, treatment for the SMN was not considered in these estimates (Armstrong et al. 2011). A study of 5 y survivors of childhood solid tumors in Great Britain and France showed an association between integral radiation dose and risk of death from SMNs, with secondary carcinoma as the leading cause of death, followed by sarcoma and then hematological malignancies (Tukenova et al. 2011). Survivors of hereditary retinoblastoma have the highest risk of SMNs, with a cumulative incidence at 50 y after diagnosis of 36% (95% CI = 31–41%) compared with 5.7% (95% CI = 2.4–11%) for survivors of nonhereditary retinoblastoma (Kleinerman et al. 2005).

Among survivors of nonfamilial or hereditary malignancies, survivors of Hodgkin lymphoma appear to have the highest overall risk for SMNs. In a recent CCSS report of 2,742 Hodgkin lymphoma survivors, of whom 94% received radiation (Castellino et al. 2011), the 30 y cumulative incidence of any SMN was 10.9% (95% CI = 8.3–13.4%) in males and 26.1% (95% CI = 22.4–29.8%) in females; the difference in cumulative incidence was due to invasive breast cancer (cumulative incidence = 18.3%; 95% CI = 16.0–20.6%). The highest absolute excess risks (excess cancers per 10,000 person-y of follow-up) were observed for the following solid cancers: bone = 22.3 (95% CI = 10.0–49.6), thyroid = 17.6 (95% CI = 13.0–24.0), and breast = 17.0 (95% CI = 14.0–21.7).

The median time from Hodgkin lymphoma diagnosis to diagnosis of invasive breast cancer was 21.0 y (range = 6.7–33.5 y), with no apparent plateau.

The lower risk of SMN in survivors of childhood leukemia compared with survivors of childhood solid tumors is due to the less frequent use of radiotherapy in the former group (Löning et al. 2000; Leung et al. 2001; Neglia et al. 2001; Bhatia et al. 2002; Pui et al. 2003; Hijiya et al. 2007; Friedman et al. 2010; Tukenova et al. 2011). The most frequent second neoplasms following radiotherapy for acute lymphoblastic leukemia are brain tumors, acute myeloid leukemia, and carcinomas of skin, thyroid, and parotid gland (Löning et al. 2000; Neglia et al. 2001; Bhatia et al. 2002; Pui et al. 2003; Hijiya et al. 2007). The majority of late-onset radiation-associated second neoplasms in survivors of acute lymphoblastic leukemia are low-grade (i.e., meningiomas and basal cell carcinomas) (Goshen et al. 2007; Hijiya et al. 2007).

The risk of a radiation-associated brain tumor in survivors of childhood cancer is positively associated with young age at time of radiation (<6 y), higher radiation dose (>30 Gy), and concomitant treatment with antimetabolites (especially in patients with thiopurine methyltransferase deficiency) or growth hormone (Walter et al. 1998; Relling et al. 1999; Ergun-Longmire et al. 2006; Neglia et al. 2006). In the Berlin-Frankfurt-Münster trials, which involved multimodal intensive therapy that includes chemotherapy and radiation (Löning et al. 2000; Schrappe et al. 2000), the 15 y cumulative risk of SMNs was 1.7% (95% CI = 0.1–3.4 %) among patients treated with 12 Gy cranial irradiation, which was lower, albeit not statistically significantly, compared with a 15 y cumulative risk of 3.2% (95% CI = 1.1–5.3 %) for those receiving at least 18 Gy. The markedly reduced use of prophylactic cranial irradiation in contemporary clinical trials for pediatric leukemia is anticipated to reduce the occurrence of SMNs. Indeed, the 10 y cumulative risk of SMNs ranged from only 0.1% [standard error (SE) = 0.1%] to 3.3% (SE = 1.2%) in patients treated for leukemia in the 1990s (Pui et al. 2011) and was particularly low (i.e., 0.1 and 0.3%) in the two studies that did not use cranial irradiation (Pui et al. 2009; Kamps et al. 2010).

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SMNS WITH RADIATION DOSE-RESPONSE RELATIONSHIPS

Table 1 summarizes epidemiological studies of SMNs following radiotherapy that included the estimated dose of radiation to the organ of interest. Most of these studies had a nested case-control design, and the relative risk parameter served as the primary risk measure.

Table 1
Table 1
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Radiotherapy is associated with secondary leukemia (Boice et al. 1987; Curtis et al. 1992, 1994), and several studies have reported an attenuation of the risk of secondary leukemia at very high radiation doses. For example, in an international study of nearly 150,000 women treated for cervical cancer, the risk of leukemia increased with increasing dose to active bone marrow up to ~4 Gy (RR ~2.5) and then declined to ~1.5 at a dose of 17 Gy (Boice et al. 1987). In these studies (Boice et al. 1987; Curtis et al. 1992), secondary chronic lymphocytic leukemia was not associated with radiotherapy (Boice et al. 1987; Curtis et al. 1992).

Case-control studies of female breast cancer following treatment for Hodgkin lymphoma before age 30 y (Travis et al. 2003) and in childhood cancer survivors (Inskip et al. 2009) provide evidence of a radiation dose-response relationship. In both studies, the risk of breast cancer increased with increasing radiation dose to the breast, reaching an odds ratio of 8 or more at doses of 40 Gy or more with no evidence of a downturn in the risk of breast cancer at the highest doses (Fig. 1a). A radiation dose to the ovary exceeding 5 Gy reduced the slope of the radiation dose-response relationship for breast cancer in women given chest radiotherapy, and alkylating agents also reduced the risk of breast cancer in Hodgkin lymphoma survivors. Several studies (Travis et al. 2003; van Leeuwen et al. 2003; Basu et al. 2008; De Bruin et al. 2009a) have shown that this latter effect is due to treatment-related premature menopause. Dose-response relationships have been identified at lower doses (mainly doses <5 Gy) for contralateral breast cancer but only among patients diagnosed with a first breast cancer before the age of 45 y (Hooning et al. 2008; Stovall et al. 2008; Boice et al. 1992).

Fig. 1
Fig. 1
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An international study of lung cancer in survivors of Hodgkin lymphoma demonstrated a statistically significant radiation dose-response relationship (Travis et al. 2002; Gilbert et al. 2003). This radiation dose-response was well described by a linear relationship with a modeled risk of sevenfold at 40 Gy; thus, lung cancer risk increased with increasing radiation dose (i.e., a downturn in risk at the highest doses was not apparent). This finding implies that the lower radiation doses administered to treat Hodgkin lymphoma today will likely be associated with lower risks of lung cancer. Elevated risk was apparent 5–9 y after radiation treatment and persisted for at least 20 y. The combined effect of radiation dose and therapy with alkylating agents was additive, whereas the combined effect of radiation and smoking was more than additive (P < 0.001) and consistent with a multiplicative relationship.

There are few data on the relationship between radiation dose incidentally received by active bone marrow in the course of cancer treatment and subsequent leukemia risk. Kaldor et al. (1990) found that among 11 Hodgkin lymphoma survivors who developed leukemia, the risk of leukemia in those who had received >20 Gy to the bone marrow was seven times larger than in those who had received smaller doses.

Information regarding radiation dose-response relationships and subsequent tumors of the central nervous system is sparse. Neglia et al. (2006) found statistically significant radiation dose-response relationships for both gliomas and meningiomas in childhood cancer survivors, and the relative risks at a given dose were higher for meningiomas than for gliomas (Fig. 1b). In a case-control study of childhood cancer survivors (Sigurdson et al. 2005), the risk of thyroid cancer increased with increasing dose to ~29 Gy (RR ~10) and then decreased for doses of 30 Gy or higher (Fig. 1c).

Increased risks of bone cancer and soft tissue sarcomas have been reported in many patient populations that received therapeutic doses exceeding 10 Gy (Tucker et al. 1987; Boice et al. 1988; Wong et al. 1997). Especially, high relative risks of these SMNs have been observed among childhood cancer survivors, and a genetic interaction has been demonstrated in retinoblastoma survivors (Wong et al. 1997). A large international case-control study of cervical cancer that provided dose-response curves for 16 SMNs in addition to leukemia found statistically significant dose-response relationships at very high doses (≥30 Gy) for cancers of the rectum and bladder and all female genital cancers (Boice et al. 1988).

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CVD IN PATIENTS WHO RECEIVED RADIATION THERAPY

Radiation, chemotherapy, and biological agents, independently and in combination, increase the risk of CVD in cancer survivors. For survivors of some cancers, radiotherapy-related CVD is the leading noncancer cause of mortality (Applefeld et al. 1981; Kaldor et al. 1990; Ling et al. 1999; Swerdlow et al. 2000; van Leeuwen et al. 2003; Reulen et al. 2010). Radiation-related CVD includes pericardial disease, coronary artery disease, valvular dysfunction, conduction abnormalities, and cerebrovascular disease. However, the risk of pericarditis is rare with modern techniques of irradiation and dose fractionation. When at least 60% of the heart is irradiated at doses of 40 Gy or less, the risk for mild pericarditis is <5%, and severe pericarditis is rare (Stewart et al. 1995).

Coronary artery disease results from injury and replacement of damaged cells by myofibroblasts and the deposition of platelets, followed by a cascade of events that result in atherosclerosis (Mauch et al. 2005). Myocardial infarction is one of the most common types of CVD in long-term Hodgkin lymphoma survivors. High-dose (i.e., >30–35 Gy) mediastinal radiation, particularly in younger Hodgkin lymphoma patients, increases the risk of coronary artery disease (Hancock et al. 1993a; Aleman et al. 2007). The resulting high rate of complications and/or death most frequently occurs in Hodgkin lymphoma patients who have diastolic dysfunction (Heidenreich et al. 2005). Among 2232 consecutive Hodgkin lymphoma patients treated from 1960 through 1991, irradiated children and adolescents had a markedly increased risk of death due to heart disease (RR = 28–37), and all of these deaths were in patients who received doses of 42–45 Gy (Hancock et al. 1993b). When this analysis was extended to include all Hodgkin lymphoma patients, the overall relative risk of death from acute myocardial infarction was 3.2 (Hancock et al. 1993b). The increased risks of death from myocardial infarction were statistically significant within 5 y after radiotherapy, the average time from completion of radiotherapy to myocardial infarction was 10.3 y, and the risk of death from myocardial infarction remained elevated throughout the follow-up period (>20 y).

Many studies of breast cancer survivors have reported a statistically significant increase in coronary artery disease and/or nonfatal myocardial infarction associated with left-sided radiotherapy compared with right-sided radiotherapy or no radiotherapy (Højris et al. 1999; Vallis et al. 2002; Hill-Kayser et al. 2006; Borger et al. 2007; Correa et al. 2007; Hooning et al. 2007; Paszat et al. 2007). Breast cancer patients treated with internal mammary node radiotherapy may also be at increased risk for coronary artery disease (Harris et al. 2006; Correa et al. 2007; Hooning et al. 2008).

Radiotherapy is associated with an increased risk of valvular dysfunction (Carlson et al. 1991; Tamura et al. 2007). Hull et al. (2003) reported that valvular dysfunction developed in 25 of 415 Hodgkin lymphoma survivors at a median of 22 y after radiotherapy. In a large Dutch study of breast cancer survivors (Hooning et al. 2007), the hazard ratio of valvular dysfunction for internal mammary node radiotherapy vs. no radiotherapy was 3.17 (95% CI = 1.90–5.29). The 2009 CCSS survey (Mulrooney et al. 2009) showed that the cumulative incidence of self-reported valvular disease increased with increasing cardiac radiation dose.

Radiation may cause fibrosis of cardiac conduction pathways, which can lead to life-threatening arrhythmias or other conduction defects. Serious post-radiation abnormalities include atrioventricular nodal bradycardia, all levels of heart block including complete heart block, and sick sinus syndrome (Orzan et al. 1993). The frequency of one type of cardiac conduction damage (i.e., QTc > 0.44 s) in 134 childhood cancer survivors was 12.5% after chest radiotherapy alone and 18.9% after radiotherapy and anthracyclines (Orzan et al. 1993). Persistent fixed-rate tachycardia and loss of circadian variability in the heart rate have also been documented following chest radiotherapy that resulted in cardiac exposure. In one study (Adams et al. 2004), 74.5% of long-term survivors of Hodgkin lymphoma treated with chest radiotherapy had a cardiac conduction defect or arrhythmia, 31% had sustained tachycardia, and 57% had a monotonous heart rate. Autonomic nervous system dysfunction could lead to the decreased perception of angina observed by some patients.

Myocardial infarction due to radiotherapy can also lead to congestive heart failure. When myocardial dysfunction develops after standard-dose mediastinal irradiation, it is typically mild or subclinical (Glanzmann et al. 1998) and involves diastolic and systolic left ventricular dysfunction (Cameron et al. 1998). Restrictive cardiomyopathy is more common in cancer survivors treated with radiotherapy who have not received an anthracycline (Tolba and Deliargyris 1999). Subtle left ventricular dysfunction has been detected by echocardiography and radionuclide angiography in Hodgkin lymphoma patients evaluated a few years after mediastinal irradiation (Marks et al. 2005). Two retrospective studies (Harris et al. 2006; Hooning et al. 2007) of congestive heart failure among irradiated breast cancer patients yielded conflicting results. A multi-institutional study with a median follow-up of 18 y found an increased risk of congestive heart failure with radiotherapy compared with no radiotherapy (Hooning et al 2007), whereas another investigation (Harris et al. 2006) found no increased incidence of congestive heart failure associated with radiotherapy laterality or internal mammary node radiotherapy.

Few analytic data describe the relationship between radiation dose to the heart and adverse outcomes. The 2009 CCSS survey is thus noteworthy for the detailed dose-response evaluations conducted following radiotherapy and anthracycline treatments and the risks (albeit self-reported) of congestive heart failure, myocardial infarction, pericardial disease, and valvular abnormalities (Fig. 2). Compared with siblings, childhood cancer survivors were statistically significantly more likely to report congestive heart failure (HR = 5.9, 95% CI = 3.4–9.6), myocardial infarction (HR = 5.0, 95% CI = 2.3–0.4), pericardial disease (HR = 6.3, 95% CI = 3.3–11.9), and valvular abnormalities (HR = 4.8, 95% CI = 3.0–7.6). Cardiac radiation exposure of at least 15 Gy increased the risk of congestive heart failure, myocardial infarction, pericardial disease, and valvular abnormalities by two- to sixfold compared with nonirradiated survivors. There was no evidence for increased risks of any of these conditions following exposure to <5 Gy, and the slight elevations in these risks were not statistically significant at exposures between 5 and 15 Gy. The hazard ratios for the four cardiac conditions ranged from 3.6 to 5.5 for cardiac doses >35 Gy. The cumulative incidence of adverse cardiac outcomes in childhood cancer survivors continued to increase up to 30 y after diagnosis and ranged from ~2% to slightly >4% overall, but to much higher levels for those who received the highest cardiac radiation doses (Fig. 2) and the highest cumulative dose of anthracyclines. Recent data from the German-Austrian DAL-HD (German Association for Childhood Leukemia Research and Treatment and Hodgkin’s disease) studies show a dose-response relationship for cardiac diseases in children treated for Hodgkin lymphoma with combined anthracycline-based chemotherapy (cumulative doxorubicin dose was uniformly 160 mg m−2) and radiation (Schellong et al. 2010). The 25 y cumulative incidence of cardiac disease was 3% with no radiotherapy, 5% after 20 Gy, 6% after 25 Gy, 10% after 30 Gy, and 21% after 36 Gy (Schellong et al. 2010).

Fig. 2
Fig. 2
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Patients treated for head and neck cancer with radiation doses of 40–70 Gy, and particularly with doses >60 Gy, have an elevated risk for stroke and occlusive carotid artery disease (Smith et al. 2008; De Bruin et al. 2009b; Scott et al. 2009). In one study (De Bruin et al. 2009b), the median time from radiotherapy to stroke diagnosis was 10.9 y (range = 1.3–21 y). Another study (Scott et al. 2009) reported 66 cerebrovascular events among 2,567 head and neck cancer patients who were treated with 30–66 Gy radiotherapy compared with only 12 events among 4,119 nonirradiated patients (odds ratio = 9.0; P < 0.001).

In a 2009 study of 2,201 5 y survivors of Hodgkin lymphoma (De Bruin et al. 2009b), 96 patients developed cerebrovascular disease (55 had a stroke, 31 had a transient ischemic attack, and 10 had both) at a median age of 52 y. The standardized incidence ratio was 2.2 for stroke and 3.1 for transient ischemic attack. Radiation to the neck and mediastinum was an independent risk factor for ischemic cerebrovascular disease (HR = 2.5, 95% CI = 1.1–5.6 compared with no radiotherapy).

The incidence of stroke in the CCSS cohort was almost 10-fold higher than in the sibling comparison group (Bowers et al. 2006). Leukemia survivors were six times more likely to suffer a stroke compared with the siblings, and brain tumor survivors were 29 times more likely. Of the brain tumor cohort, 69 (4.9%) of 1,411 patients who had a history of radiotherapy reported a stroke, and the cumulative incidence of stroke at 25 y after radiation therapy was 6.9% (95% CI = 4.5–9.3%). Cancer survivors who were exposed to cranial radiotherapy at a dose of 30 Gy or higher had an increased risk for stroke, with the highest risk among those treated with a dose of 50 Gy or higher (Bowers et al. 2006). Adult survivors of childhood Hodgkin lymphoma who were treated with thoracic radiotherapy (median dose = 40 Gy), which included mediastinal and neck radiotherapy, had a 5.6-fold increased risk of stroke compared with the siblings.

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CONCLUSIONS AND RESEARCH RECOMMENDATIONS

The conclusions and recommendations of the NCRP (2011) are summarized in Box 1 and reproduced in their entirety in the Supplemental Digital Content 2 ( http://links.lww.com/HP/A18). The reader is referred to NCRP Report No. 170 (NCRP 2011) for in-depth discussion of each of the conclusions and recommendations. In summary, although modern therapies prolong the lives of cancer patients, this success carries an increased risk of late adverse health effects, including SMNs and CVD. Awareness, evaluation, counseling, and amelioration strategies are recommended (NCRP 2011).

Box 1
Box 1
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Acknowledgements

Funding: Supported in part by grant CA21765 from the National Institutes of Health, the American Lebanese Syrian Associated Charities (Ching-Hon Pui), and the University of Rochester Medical Center (Lois B. Travis).

Notes: We wish to thank Laura Atwell (NCRP) and Charles Church (National Center for Physical Acoustics, University of Mississippi) for their support of NCRP Scientific Committee 1–17, as well as Tom Tenforde (President, NCRP) and David Schauer (Executive Director, NCRP). We are also indebted to Laura Brumbaugh (URMC) for expert editorial assistance. The NCRP Committee was responsible for preparing the comprehensive report (upon which this paper is based) with NCRP’s financial support from the National Cancer Institute under Grant Number R24 CA074206. The funding agency had no role in design, analysis, or interpretation of the reviewed data; in the decision to submit the paper for publication; or the writing of the paper. The content of this paper is the sole responsibility of the co-authors and does not necessarily reflect the views of the funding agency (NCI). NCRP Report No. 170 (2011) is available at http://www.ncrponline.org.

Before publication, NCRP reports undergo comprehensive review by an outside panel of experts, who provide substantive and critical comments that are then addressed by the scientific committee. The revised report is then reviewed by all members of the NCRP before final revision, publication, and endorsement by the NCRP.

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Keywords:

cancer; health effects; medical radiation; National Council on Radiation Protection and Measurements

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