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© 2002 American Society for Clinical Oncology Second Malignant Neoplasms Among Long-Term Survivors of Hodgkin’s Disease: A Population-Based Evaluation Over 25 YearsByFrom the Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD; The University of Iowa, Iowa City, IA; Cancer Care Ontario and The Princess Margaret Hospital, University of Toronto, Ontario, Canada; Department of Oncology, University Hospital, Uppsala, Sweden; Danish Cancer Society, Copenhagen, Denmark; Department of Oncology, Helsinki University Hospital, Helsinki, Finland; the Netherlands Cancer Institute, Amsterdam; The Dr Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; and Department of Radiation Physics, The University of Texas M.D. Anderson Cancer Center, Houston TX. Address reprint requests to Graça M. Dores, MD, MPH, National Cancer Institute, Executive Plaza South, Suite 7039, Bethesda, MD 20892; email: doresg{at}mail.nih.gov
PURPOSE: To quantify the relative and absolute excess risks (AER) of site-specific second cancers, in particular solid tumors, among long-term survivors of Hodgkin’s disease (HD) and to assess risks according to age at HD diagnosis, attained age, and time since initial treatment. PATIENTS AND METHODS: Data from 32,591 HD patients (1,111 25-year survivors) reported to 16 population-based cancer registries in North America and Europe (1935 to 1994) were analyzed. RESULTS: Two thousand one hundred fifty-three second cancers (observed-to-expected ratio [O/E] = 2.3; 95% confidence interval [CI] = 2.2 to 2.4), including 1,726 solid tumors (O/E = 2.0; 95% CI, 1.9 to 2.0) were reported. Cancers of the lung (observed [Obs] = 377; O/E = 2.9), digestive tract (Obs = 376; O/E = 1.7), and female breast (Obs = 234; O/E = 2.0) accounted for the largest number of subsequent malignancies. Twenty-five years after HD diagnosis, the actuarial risk of developing a solid tumor was 21.9%. The relative risk of solid neoplasms decreased with increasing age at HD diagnosis, however, patients aged 51 to 60 years at HD diagnosis sustained the highest cancer burden (AER = 79.2/10,000 patients/year). After a progressive rise in relative risk and AER of all solid tumors over time, there was an apparent downturn in risk at 25 years. Temporal trends and treatment group distribution for cancers of the esophagus, stomach, rectum, female breast, bladder, thyroid, and bone/connective tissue were suggestive of a radiogenic effect. CONCLUSION: Significantly increased risks of second cancers were observed in all HD age groups. Although significantly elevated risks of stomach, female breast, and uterine cervix cancers persisted for 25 years, an apparent decrease in relative risk and AER of solid tumors at other sites is suggested.
THE REMARKABLE GAINS in survival attributable to successful treatments for Hodgkin’s disease (HD) over the past three decades have been accompanied by a significantly increased risk of second neoplasms.1 Second cancers now comprise the leading cause of death among 15-year survivors of this lymphoma.2 Few population-based studies, however, quantify site-specific excesses among large numbers of long-term survivors,3,4 address second cancer risk by age at HD diagnosis,3 provide estimates of absolute excess risk (AER),3 or consider attained age.3 The AER provides the optimal measure of disease burden in a population because relative risks are affected by underlying cancer incidence rates, which increase with increasing age. Accordingly, we evaluated the absolute and relative site-specific risks of second cancers among 32,591 HD patients, including 2,861 20-year survivors, taking into account time since treatment, age at treatment, and attained age. In particular, we sought to determine whether the increased risks of second cancers reported within 15 to 20 years after treatment for HD4-10 persist into the third decade of follow-up.
Patients with a first primary diagnosis of HD (1935 to 1994) who survived 1 or more years were identified from population-based cancer registries in Ontario, Sweden, Denmark, Finland, Connecticut, and nine areas of the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program. In the Netherlands, patients were identified from affiliated tumor registries of the Netherlands Cancer Institute in Amsterdam and The Dr Daniel den Hoed Cancer Center. Features of each cancer registry have been described elsewhere.11 To ensure complete reporting from population-based registries, a subgroup of patients (21%) described in previous reports3,12 are included, with follow-up for 927 Dutch patients extended to 1995.12 Participating cancer registries routinely collect data on patient demographics, tumor characteristics, and vital status. Except in Ontario and Sweden, general information regarding initial treatment received for HD is available in terms of broad categories, such as radiotherapy and/or chemotherapy. Data on subsequent therapy are not collected. Before 1960, small doses of radiation, if any, were used to treat early-stage HD,13,14 although 25 to 30 Gy were administered to involved nodal and proximal areas at some medical centers.15 In the 1960s, doses of 40 to 44 Gy to involved fields were often given,16 whereas from the mid-1970s through 1994, smaller doses (30 to 40 Gy) were commonly used when given without cytotoxic drugs;13,16 when combined with chemotherapy, an average of 30 Gy was administered.13 Children and adolescents may have received smaller doses, as previously described.3 Radiation doses received by various organs during mantle and inverted Y radiotherapy (35 Gy) for adult HD are provided in the Appendix. Treatment with single chemotherapeutic agents (mechlorethamine and triethylenemelamine) was introduced into clinical practice after 1947, usually for the treatment of advanced HD.15 After the late 1960s, combination therapy with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) was increasingly administered,17 and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) was added to treatment options in the mid-1970s.18 Cancer registry incidence files were searched for second malignant, invasive neoplasms that developed at least 1 year after diagnosis of HD, with confirmation based on routine procedures at each site.11 The risk of second cancers was estimated by compiling person-years (PY) of observation according to age, sex, and calendar-year periods from 1 year after the date of HD diagnosis to the date of death, date of last follow-up evaluation, date of diagnosis of second cancer, or the end of the study, whichever occurred first. Study end date varied between registries: December 31, 1995 (the SEER Program, Finland, and the Netherlands), December 31, 1993 (Denmark, Sweden, and Ontario), and December 31, 1992 (Connecticut 1935 to 1972). Cancer incidence rates specific for each region, 5-year age groups, sex, and 5-year calendar-year intervals were multiplied by the accumulated PY at risk to estimate the number of cancer cases expected. The observed and expected numbers of second cancers from each registry were then summed, with the relative risk expressed as the ratio of observed-to-expected (O/E) cases. The AER was determined by subtracting the expected number from the observed number of second cancers and then dividing the difference by the number of PY at risk. The number of excess second cancers was expressed per 10,000 HD patients per year. Risks of second cancers were stratified by sex, age group at HD diagnosis, attained age, time since HD diagnosis, and initial treatment (radiotherapy, chemotherapy, or chemotherapy and radiotherapy). Statistical tests and 95% confidence intervals (CI) were based on the assumption that the observed number of second cancers was distributed as a Poisson variable. Tests for heterogeneity and linear trend were conducted using the methods of Breslow et al.19 Cumulative probabilities of developing solid tumors over time were calculated using life-table methods.20
The average age at diagnosis of HD for the 32,591 study patients (57.4% male) was 37 years (Table 1). Six thousand one hundred ninety-five, 2,861, and 1,111 patients were followed for 15, 20, and 25 years, respectively. Second malignancies developed in 2,153 patients (O/E = 2.3; 95% CI, 2.2 to 2.4; AER = 47.2) (Table 2). Second cancer risk was significantly elevated in each registry (O/E = 1.9 to 2.3), with the largest excesses (O/E = 4.8) observed in patients from the Netherlands.
Significantly elevated two-fold risks were observed for all solid tumors taken together (observed [Obs] = 1,726; O/E = 2.0; 95% CI, 1.9 to 2.0), with respiratory sites contributing the largest number of cancers (Obs = 416; O/E = 2.8). Significant two- to six-fold excesses were evident for cancers of lip, tongue, salivary gland, gum and mouth, pharynx, esophagus, stomach, lung, female breast, uterine cervix, thyroid, bone, and connective tissue, and risks of a smaller magnitude were observed for malignant melanoma and cancers of the colon, liver and gallbladder, pancreas, kidney, bladder, and brain and CNS. No cancer occurred significantly below expectation. The relative risk and AER of all solid tumors taken together were similar in men and women. When sex-specific cancers were excluded, relative risks remained comparable (O/E = 2.1 and 2.2, respectively), however, AER were larger in men (AER = 32.2) than women (AER = 20.1), due to a substantially greater number of lung cancers (Obs = 284, AER = 12.7). Breast cancer accounted for the largest AER of neoplasms among women (AER = 10.5). Significantly elevated risks for malignant melanoma and cancers of tongue, liver/gallbladder, and brain/CNS seemed confined to men, whereas significant seven-fold excesses of bone tumors seemed restricted to women.
The risks of all solid tumors and cancers at selected sites are listed in Table 3 according to primary treatment and time since diagnosis of HD. Significantly elevated relative risks of solid tumors were observed 1 to 9 years (O/E = 1.6; AER = 20), 10 to 14 years (O/E = 2.4; AER = 50), 15 to 19 years (O/E = 2.5; AER = 63), 20 to 24 years (O/E = 3.0; AER = 110), and
Significant excesses of lung cancer occurred throughout the first 25 years after HD diagnosis then decreased to expectation. The histologic distribution (38% squamous cell, 24% adenocarcinoma, 16% small-cell, 20% unspecified, and 2% other) of lung cancers for which morphology was recorded (Obs = 318) was similar to the pattern of first primary lung cancers reported to the SEER Program.22 Women treated with radiotherapy for HD experienced a 2.5-fold increased risk of breast cancer (Obs = 122; 95% CI, 2.0 to 2.9), compared with no excess risk after chemotherapy alone (O/E = 1.1; 95% CI, 0.6 to 1.8; Obs = 15), albeit based on small numbers. Breast cancer risk was significantly elevated in the intervals of 10 to 14, 15 to 19, 20 to 24, and  25 years (P trend < .001) after HD, with somewhat larger risks in women treated with radiotherapy. Risk for cancers of all digestive tract sites taken together was significantly elevated after therapy with radiation alone (O/E = 1.8; 95% CI, 1.5 to 2.2; Obs = 128) or combined-modality therapy (O/E = 2.8; 95% CI, 1.9 to 4.0; Obs = 30) but not chemotherapy alone (O/E = 1.2; 95% CI, 0.9 to 1.7; Obs = 37). In contrast to colon cancer, significantly increased risks of rectal cancer occurred only among long-term HD survivors given radiotherapy. A significant two-fold risk of bladder cancer was observed 10 to 14 and 15 to 19 years after HD, with four- to six-fold excesses after radiotherapy in the 15- to 19- and 20- to 24-year intervals. Fifteen-fold risks for bone/connective tissue cancers occurred 10 to 14 and 15 to 19 years after radiotherapy. Discernible temporal trends were not apparent for excess cancers of brain, kidney, or pancreas or malignant melanoma (data not shown).
The relative risk and AER of all second cancers and those at selected sites are presented in Table 4 by age at diagnosis of HD. The relative risk of all second cancers taken together decreased with increasing age at HD diagnosis (P < .001), whereas the AER tended to increase (P < .001); the apparent decline in both parameters observed in the
The site-specific burden of cancer varied according to age at HD diagnosis. For patients treated before age 21 and 21 to 30 years, the AER of breast cancer superseded that of all other second cancers. For individuals diagnosed with HD at 31 to 40, 41 to 50, or 51 to 60 years, the largest AER was due to lung cancer, and for those treated after age 60, non-Hodgkin’s lymphoma (AER = 12.8) and lung cancer (AER = 12.3) accounted for the largest excesses. The relative risk and AER of all solid tumors and those at selected sites are listed in Table 5 according to age at HD diagnosis and age at second cancer occurrence. Within each age category, the AER and relative risk of all solid tumors taken together decreased with increasing attained age. In women less than 21 years at HD diagnosis, the AER of breast cancer decreased moderately with advancing age, although the relative risk diminished sharply. Despite a decrease in the relative risk of breast cancer with increasing age in patients treated between ages 21 and 40, the AER exhibited only a subtle decline. For women treated for HD after age 40, relative risk and AER of breast cancer decreased to expectation by age 60. The largest AER of cancers of lung and digestive tract were observed in patients older than 40 years of age at HD diagnosis.
The actuarial risk of developing any solid tumor 25 years after HD was 21.9% overall; among males, the risk was 19.3% (95% CI, 17.5% to 21.1%) and among females 24.8% (95% CI, 22.4% to 27.2%) (Fig 1). At 25 years, the actuarial risk of lung cancer was significantly higher in males (6.2%; 95% CI, 5.0% to 7.4%) than females (3.2%; 95% CI, 2.2% to 4.2%), whereas the risk of digestive tract cancers was similar in both sexes. The actuarial risk of female breast cancer 25 years after HD was 9.3% (95% CI, 7.5% to 11.1%).
In Fig 2, the cumulative incidence of all solid tumors is depicted according to calendar period of HD diagnosis: 1935 to 1964, 1965 to 1979, and 1980 to 1994. For patients diagnosed with HD between 1965 and 1979, the actuarial risk of developing a solid tumor 25 years after treatment was 23.8% (95% CI, 21.8% to 25.8%) compared with 16.9% (95% CI, 14.4% to 19.4%) among those diagnosed in the earliest calendar year period. After 14 years of follow-up, the cumulative incidence of all solid tumors in patients treated between 1965 to 1979 did not differ significantly from those treated between 1980 to 1994. Additional follow-up is required to assess the magnitude of the long-term risk of second cancers among patients treated between 1980 to 1994.
Our results are based on the largest population-based study of HD patients to date, including over 2,800 20-year survivors, which enabled us to assess cancer risk over three decades. The sizable number of patients and second cancers also enabled us to quantify relative risk and AER in terms of both age at HD diagnosis and attained age. Data describing second cancer risk 20 or more years after treatment for HD are sparse,3,4,6,10,12,23,24 with each published study based on five to 40 solid tumors in this time interval. Few studies have estimated second cancer risk in 25-year survivors of HD.12 Some investigators have described a persistent increase in relative risk of solid tumors over 20 years,6,10,23,24 whereas others have noted a decrease in relative risk, but continued increase in AER.3,12 We report an overall downturn in relative risk and AER of all solid tumors at 25 years. Despite this declining overall trend, it is apparent that 25-year survivors of HD remain at increased risk for cancers of breast, esophagus, stomach, and uterine cervix. The site-specific risk of solid tumors according to age at HD diagnosis has been addressed in several surveys.3,5,6,9,12,24,25 Studies of atomic bomb survivors have shown that the young may be especially susceptible to the carcinogenic effects of radiation.26 However, a major finding in our study is the consistently increased relative risk and AER of solid tumors in each age category of HD diagnosis. Thus, despite the high relative risks of second cancers reported among children and adolescents with HD,3,10,23 we found that patients diagnosed with HD at older ages sustain the greatest second cancer burden. The two studies of HD patients3,12 that have attempted to separate the effects of age at treatment and attained age on second cancer risk, based on 157 and 106 solid tumors, respectively, are included in the current report. Based on 1,726 solid tumors, we show that the AER and relative risk of solid tumors seem to decline with advancing attained age. The decline in relative risk with increasing attained age might be expected, given the increase in baseline risk with advancing age in the general population, but the attenuation in AER indicates that the tumor burden is diminishing. Temporal trends and treatment group distribution for site-specific cancer excesses followed two general patterns. For several solid tumor sites (ie, esophagus, stomach, colon, rectum, female breast, and bladder), risks did not increase until 10 years after HD diagnosis and remained elevated for at least a decade, suggestive of the late effects of radiotherapy and consistent with the known radiogenicity of some, but not all, of these sites.27-30 For other solid tumors (ie, lung, melanoma, thyroid, and bone/connective tissue), excess risks were apparent in most latency periods after HD diagnosis, favoring a role for other influences, including chemotherapy, or heightened surveillance, possibly in addition to radiation. Several surveys have linked cancers of lung, thyroid, and bone to prior radiation exposure.29,31-36 A new finding in our study is that a significantly increased risk of breast cancer persists for more than 25 years after HD diagnosis. Elevated risks of female breast cancer have been well documented in several populations exposed to therapeutic radiation at a young age (reviewed37). For young women treated with mantle-field radiation for HD, premature ovarian failure related to pelvic irradiation and/or MOPP chemotherapy might be expected to attenuate radiation-related breast cancer excesses; whether this effect might be tempered by hormone replacement therapy25 is unclear. The risk of lung cancer according to age at adult HD has been described in few population-based studies. Our observation that the largest AER of lung cancer occurs among patients diagnosed with HD at age 41 to 50 and 51 to 60 might reflect longer exposure times to tobacco. The shortened interval for the development of lung cancer after therapy for HD is consistent with other reports.38,39 A recent study by Travis et al40 described significantly increased risks of lung cancer beginning 1 to 4 years after initial treatment with alkylating agents and 5 to 9 years after radiotherapy. Tobacco use seemed to multiply treatment-related lung cancer risk.40 In contrast to prior surveys of adult HD patients,4,6,24 we found a significantly elevated risk of esophageal cancer. Our observation complements the significant 31- to 169-fold increased risks of esophageal cancer previously noted in pediatric and young adult HD populations.3,12,41 During mantle radiotherapy for HD, the esophagus can receive doses of 35 Gy (Appendix) and significant excesses of esophageal cancer have been reported after radiation therapy for breast cancer.42 Chemotherapy has been linked with the development of Barrett’s esophagus in humans43-45 and with esophageal cancer in laboratory animals.46,47 During radiotherapy for HD, the stomach can receive doses of 4.2 to 13.0 Gy (Appendix). Sustained elevations in stomach cancer risk have been described in other irradiated cohorts receiving 0.23 Gy to 26.2 Gy to the stomach,27-30,48 but analytic studies of HD patients have not been conducted to date. Combined-modality therapy for HD has been associated with significantly larger risks of stomach cancer compared with treatment with either radiation or chemotherapy alone.5,24 Orally-administered nitroso compounds induce stomach cancers in laboratory animals,47,49-51 but to our knowledge, specific chemotherapy agents have not been implicated in human stomach cancer. Several surveys report an excess of colon can-cers3-7,12,24,41,52 after HD, but in only one series was risk evaluated according to age at HD and time since diagnosis.5 We observed significantly elevated colon cancer risks in most age groups, with a progressive increase in AER with advancing age. Our data are not consistent with a radiogenic effect for colon cancer, and generally fewer than 50% of these second tumors in other surveys of HD patients have occurred within radiation fields.7,9,24,52 Radiation doses to the colon of 0.1 to 24.9 Gy during treatment for benign and malignant diseases27-29,48,53 have not been followed by increased risks of cancers at this site, although data from the atomic bomb survivors (mean colon dose, 0.23 Gy)26 are suggestive of a radiogenic etiology. High doses of radiation (30 to 60 Gy) have been linked with rectal cancer 20 years after treatment for cervical cancer,27 but increased risks have not been detected in patients exposed to lower doses.29,30,48 Our study is among the first to report a significant excess of bladder cancer after HD.4-7 The bladder may receive doses of 30 Gy during inverted Y radiotherapy for HD (Appendix), and increasing doses of radiation have been strongly linked to increasing risk of bladder cancer in other series.30 Cyclophosphamide, a known bladder carcinogen,54 may also have been included in some chemotherapy regimens for HD. Bone cancer risk has been related to radiation dose and cumulative amount of alkylating agents in children treated for cancer,33,34,55 but few data exist for adult HD patients.5 We found excess bone/soft tissue sarcomas in all age groups. In our series, a radiogenic effect for bone/connective tissue cancers in adult HD patients is supported by the temporal pattern and distribution between treatment groups. Treatment regimens for HD have undergone appreciable modification over the past 35 years, and evaluation of second cancer risk among long-term survivors often reflects the effects of earlier, more aggressive protocols. Quantification of long-term risks, however, is essential to continue to maximize HD cure rates while minimizing toxic effects. Population-based studies are associated with less selection bias than hospital or clinic-based series; however, our results also must be interpreted in the context of weaknesses inherent to registry data. Migration of patients outside of the registry catchment areas would result in underreporting of second cancers, and thus our findings may represent conservative estimates of risk. This is less of an issue in Nordic countries, where cancer data is collected nationwide. Interpretation of our results must also consider that only initial treatment information was available and that, given the multiple comparisons undertaken in this study, some statistically significant associations could be due to chance alone. The apparent downturn in second cancer risk in patients older than 60 years of age at HD diagnosis should be viewed circumspectly given the relatively short follow-up period for this group. Similarly, the number of patients in the latency period beyond 25 years is comparatively smaller than those included in other time intervals; thus, our finding that long-term relative risk and AER of second cancers may decrease must be interpreted with caution. We estimated an actuarial probability of 21.9% for the development of a solid tumor at 25 years; however, early censoring because of deaths from other causes (ie, HD) may tend to exaggerate the 25-year estimate, especially when a number of second malignancies occur in later follow-up periods when fewer patients are at risk.56 Using alternative methods that adjust for competing causes of death,57 we calculate the cumulative incidence of solid tumors to be 11.7%. Additional studies with further follow-up will help to more precisely define second cancer risk, particularly when taking treatment era into account. Future investigations should incorporate comprehensive treatment data for HD to assess the contribution of therapy, environmental influences, gene-environment interactions, and other factors in second cancer risk.
Supported in part by the Division of Cancer Prevention, National Cancer Institute, Bethesda, MD. We thank Heather Clancy for computer support and data management, Rebecca Albert for technical assistance, and Dr Charles Land for helpful comments and review of the manuscript.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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