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© 2003 American Society for Clinical Oncology High Risk of Subsequent Neoplasms Continues With Extended Follow-Up of Childhood Hodgkin’s Disease: Report From the Late Effects Study Group
From the City of Hope National Medical Center, Duarte, CA; University of Minnesota, Minneapolis, MN; Royal Manchester Children’s Hospital, Manchester, England; Dana-Farber Cancer Institute, Boston, MA; Istituto Nazionale Tumori, Milan, Italy; Institut Gustave-Roussy, Villejuif, France; Columbus Children’s Hospital, Columbus; Children’s Hospital Medical Center, Cincinnati, OH; Children’s Memorial Hospital, Chicago, IL; Children’s National Medical Center, Washington, DC; Children’s Hospital of Pittsburgh; and Children’s Hospital of Philadelphia, PA. Address reprint requests to Smita Bhatia, MD, MPH, City of Hope National Medical Center, 1500 E Duarte Rd, Duarte, CA 91010-3000; e-mail: sbhatia{at}coh.org.
Purpose: We present an update of a previously reported Late Effects Study Group cohort of 1,380 children with Hodgkin’s disease (HD) diagnosed between 1955 and 1986 in patients aged 16 years or younger. We describe the pattern and incidence of subsequent neoplasms (SNs) occurring with extended follow-up. Patients and Methods: Median age at diagnosis of HD was 11.7 years (range, 0.3 to 16.9 years) and at last follow-up was 27.8 years. Median length of follow-up was 17.0 years. Results: An additional 103 SNs were ascertained (total SNs = 212). The cohort was at an 18.5-fold increased risk of developing SNs compared with the general population (standardized incidence ratio [SIR], 18.5, 95% CI, 15.6 to 21.7). The cumulative incidence of any second malignancy was 10.6% at 20 years, increasing to 26.3% at 30 years; and of solid malignancies was 7.3% at 20 years, increasing to 23.5% at 30 years. Breast cancer was the most common solid malignancy (SIR, 56.7). Other commonly occurring solid malignancies included thyroid cancer (SIR, 36.4), bone tumors (SIR, 37.1), and colorectal (SIR, 36.4), lung (SIR, 27.3), and gastric cancers (SIR, 63.9). Risk factors for solid tumors included young age at HD and radiation-based therapy. Thirty-two patients developed third neoplasms, with the cumulative incidence approaching 21% at 10 years from diagnosis of second malignancy. Conclusion: Additional follow-up of this large cohort of HD survivors documents an increasing occurrence of known radiation-associated solid tumors, (breast and thyroid cancers), as well as emergence of epithelial neoplasms common in adults, (colon and lung cancers) at a younger age than expected in the general population, necessitating ongoing surveillance of this high risk population.
SUBSEQUENT NEOPLASMS (SNs) after Hodgkin’s disease (HD) are being encountered with increasing frequency because of the marked improvement in survival that began to be appreciated approximately 30 years ago.1–4 Several studies of large, well-characterized cohorts have reported cumulative risks of SNs ranging from 7.6% (at 20 years) to 21.9% (at 25 years).5–14 The Late Effect Study Group was established in 1979 and consisted of a multinational cohort of 979 HD patients diagnosed at age 16 years or younger. The patients were observed for a median of 7 years for the development of SNs.14 In 1994 this cohort was expanded to its current size of 1,380 patients diagnosed between 1955 and 1986, with an increase in median follow-up time to 11.4 years.5 The current study extends the median length of follow-up from 11.4 to 17.0 years. This report describes the types of SNs, their incidence, and factors associated with risk of cancer later in life.
Fifteen Late Effect Study Group member institutions participated in this study. The cohort consisted of children ages 16 years or younger at diagnosis of HD, who received their primary treatment between 1955 and 1986. At each institution, eligible patients had been treated per institutional or cooperative group protocols for which informed consents were obtained, and this report represents a follow-up of these patients. A roster of all patients with HD was prepared, and data were abstracted from clinical records. These data included sex, date of birth, date of diagnosis, stage and sites of disease, whether or not splenectomy was performed, and treatment of initial tumor and recurrences. Radiation therapy doses, fields, and equipment used were noted, as were chemotherapeutic agents, doses, and duration of chemotherapy. Date of last contact was abstracted from the clinical records for all patients. Presence or absence of SNs and current activity of HD were recorded. For patients in whom SNs developed, the date of diagnosis, histology and site of tumor, and whether or not the tumor arose in the radiation therapy field was recorded. If the patient died, the date and cause of death were also reported. Pathologic findings were confirmed at the treating institution. The time at risk for SNs was computed from the date of diagnosis of HD to the date of diagnosis of SN, date of death or the date of last contact, whichever came first. For the purpose of analysis, patients were placed into one of three mutually exclusive treatment groups: radiation therapy alone, chemotherapy alone, and radiation and chemotherapy (as part of the primary treatment or as salvage therapy for recurrence). An alkylating agent dose score was calculated for each patient as follows: a single alkylating agent of 6 months’ duration was assigned a score of 1; two alkylating agents for 6 months received a score of 2, etc. The score was thus an approximate measure of the total amount of alkylating agent received.14
To estimate the risk of subsequent malignancies, the number of person-years at risk under observation was compiled for the cohort. Annual age- and sex-specific incidence rates of cancer, observed in the entire registry of the Surveillance, Epidemiology, and End Results (SEER) Program of the National Institutes of Health,15 were used as reference rates in the calculation of the expected number of cases (indirect standardization16). Specifically, the expected number for each survivor i was given by Ei = For patients who developed multiple malignancies after the primary disease, all subsequent malignancies were counted in the numerator of SIRs, in agreement with the SEER Program’s incidence calculation. Survivors of HD were considered to be at risk for an SN from the time of entry into the cohort (from diagnosis of HD) until the earlier of one of the two events: death or date of last contact. All neoplasms not reportable to the SEER database (such as nonmelanomatous skin cancers, meningioma, and carcinoma-in-situ) were excluded from the calculation of SIRs. Excess absolute risk was calculated as an additional indicator of the impact of the cancer diagnosis and therapy on members of the cohort in contrast with the general population. Excess absolute risk, expressed per 1,000 person-years, was determined by subtracting the expected number of subsequent malignancies in the cohort from the observed number, dividing the difference by person-years of follow-up, and multiplying this number by 1,000. Cumulative incidence of second malignancies over time was calculated using competing risks methods.17 Cumulative incidence calculations were conducted both including and excluding basal cell carcinomas. Benign tumors were excluded from both sets of cumulative incidence calculations. The adjusted relative risk of developing a second malignancy was estimated with the use of Poisson multiple regression model for SIRs.18 A fixed set of explanatory variables was selected a priori and was used to assess their simultaneous impact on the rate of developing a second malignancy without any statistical variable selection. Variables included in the regression model were age at diagnosis, sex, clinical stage, treatment groups, splenectomy, alkylating agent score, and recurrence of HD. Age at diagnosis of HD was taken as a categoric variable (0 to 5 v 6 to 9 v 10 to 16 years). Clinical stages I and II and clinical stages III and IV were grouped because of similarities between the stage groups, in clinical presentation and treatment. Recurrence was included as a time-dependent covariate in the regression model. These analyses were performed for all second malignancies, as well as for each subgroup of second malignancies. The regression analysis did not include third or subsequent cancers and terminated person-time at risk at the time of diagnosis of a second malignancy because therapy information for second malignancies was incomplete. All statistical tests were two-sided.
The characteristics of the cohort are shown in Table 1  . By extending the median follow-up by 5.6 years, the number of SNs (benign and malignant) increased from 109 to 212, developing in 173 patients. Multiple SNs were observed in 32 patients. Thus, 141 patients developed one SN, 26 patients developed two, five patients developed three, and one patient developed four SNs. The second neoplasms (n = 173) included 104 solid malignancies, 27 secondary leukemias, six cases of non-Hodgkin’s lymphoma (NHL), and 36 benign tumors. The third neoplasms (n = 32) included 27 solid malignancies, one secondary leukemia, one case of NHL, and three benign tumors. The fourth neoplasms (n = 5) included four solid malignancies and one benign tumor. The fifth malignancy (n = 1) was a solid malignancy. The histologic details of the multiple neoplasms are shown in Table 2.
Overall, 136 solid malignancies, 28 leukemias, seven NHL cases, and 40 benign tumors were identified in this cohort. The benign tumors included thyroid adenomas (n = 30), osteochondromas (n = 4), breast fibroadenoma (n = 3), and miscellaneous tumors (n = 3). Benign tumors were excluded from all subsequent analyses. Breast cancer was the most common solid malignancy (n = 42). Other solid malignancies included basal cell carcinoma (n = 24), thyroid cancer (n = 19), bone tumors (n = 8), colorectal cancer (n = 8), lung cancer (n = 4), gastric cancer (n = 3), and other miscellaneous malignancies (n = 29). The clinical characteristics of patients who developed solid malignancies are presented in Table 3 .
Figure 1 shows the estimated cumulative incidence of all second malignancies, solid tumors, and leukemia for the 2000 analysis. The estimated cumulative incidence of any second malignancy in the 2000 analysis was 10.6% (95% CI, 8.6% to 12.7%) at 20 years after diagnosis of HD, and rose to 26.3% (95% CI, 20.8% to 31.8%) at 30 years. After excluding basal cell carcinoma from the analyses, estimated cumulative incidence of any second malignancy was 9.3% (95% CI, 7.4% to 11.2%) at 20 years and 23.7% (95% CI, 18.1% to 29.2%) at 30 years. Most of this risk was due to solid tumors, with a steep increase in cumulative incidence from 7.3% (95% CI, 5.5% to 9.1%) at 20 years to 23.5% (95% CI, 18.2% to 28.9%) at 30 years. After exclusion of basal cell carcinomas from the analyses, the cumulative incidence of solid tumors was 5.9% (95% CI, 4.3% to 7.5%) at 20 years and 20.1% (95% CI, 14.9% to 25.3%) at 30 years. In contrast, the risk of leukemia reached a plateau at 2.1% (95% CI, 1.3% to 2.9%) after 14 years.
Third neoplasms were observed in 32 patients after a median of 4.5 years (range, 0.0 to 26.0 years) from diagnosis of second neoplasms. The cumulative incidence of third malignancies approached 21.1% at 10 years from diagnosis of second malignancies.
Observed and expected numbers of subsequent malignancies are shown in Table 4
The SIRs for the subsequent malignancies were examined in 5-year intervals of follow-up from diagnosis of HD (Table 5 ). The risk of developing any subsequent malignancy, as well as the risk of developing a solid tumor, was elevated throughout all intervals examined. The risk of developing leukemia was highest in the first 5 years of follow-up and declined during the next 10 years. No cases of leukemia were observed beyond this time.
Multiple regression models were constructed to determine independent risk factors for the occurrence of second malignancies (Table 6 ). Second malignancies of any type were associated with recurrent disease (P = .059) and combined-modality therapy (P = .047). Increased risk of leukemia was associated with advanced HD (P = .019) and use of chemotherapy-based regimens (P = .003). Solid tumors were independently associated with younger age (0 to 5 years) at diagnosis of HD (P = .02) and use of radiation-therapy–based regimens (P = .014).
Breast Cancer Forty-two cases of breast cancer were diagnosed in 30 patients (29 women and one man). Twelve patients either presented with bilateral breast cancer (n = 3) or subsequently developed contralateral disease (n = 9). These tumors were either infiltrating ductal (65%) or lobular carcinomas (35%). Two patients were diagnosed with ductal carcinoma-in-situ and were excluded from calculations of SIRs. The median age at diagnosis of HD was 14.2 years (range, 6.6 to 15.6 years) and at the time of development of breast cancer was 32 years (range, 16.3 to 42.7 years). The median time to development of breast cancer from diagnosis of HD was 18.1 years (range, 4.3 to 28.3 years). Fourteen (47%) of the 30 patients had received radiation alone, whereas 16 (53%) had received combined-modality therapy. All tumors developed within or at the margin of the radiation field. The median dose of mantle radiation received by this cohort of patients with breast cancer was 35 Gy (range, 26 to 46 Gy).
This cohort was at a 56.7-fold increased risk of developing breast cancer, compared with the general population (Table 4
Thyroid Cancer Thyroid cancer developed in 19 patients after a median of 15.3 years from diagnosis of HD. The cumulative incidence of developing thyroid cancer approached 4.4% at 30 years from HD diagnosis. Histologically, the thyroid cancers were either papillary (63%) or follicular carcinomas (37%). This cohort was at a 36.4-fold increased risk of developing a thyroid cancer. Ninety-five percent of the malignancies developed within the radiation field. Multiple regression analysis (Table 6  ) revealed a younger age (0 to 5 years) at diagnosis of HD to be associated with an increased risk for the development of thyroid cancer (P = .048).
Other Solid Malignancies
Sensitivity Analysis
Among the 1,380 patients treated for childhood HD between 1955 and 1986, the estimated cumulative incidence of SN was 26.3% at 30 years after diagnosis of HD. This report provides evidence that children treated for HD before 1986 have an 18.5-fold increased risk of developing an SN. Twenty-four patients developed SNs within 5 years from diagnosis of HD. Data on early tumors are intriguing, because they do not fit typical perspectives on radiation carcinogenesis, and early events have often been excluded in other secondary cancer analyses, either due to study design (by including only 5-year survivors) or because of classification of these early events as possible synchronous primaries. In the present study, 18 of the 24 early events were either secondary leukemia or NHL, typically known to have short latencies.5 The early events of interest, therefore, are the six solid tumors that include one each of breast, thyroid, bone, parotid, and ovarian cancers, and one case of neuroblastoma. Breast cancer continues to be the most common solid tumor among women who have received radiation to the mantle region, and the risk remains elevated for a considerable length of time.5,7–10,19–28 Since 1994, we have identified 20 additional cases of breast cancer, representing a 90% increase. Forty percent of the patients with breast cancer developed contralateral disease. The women in our cohort had a 55.5-fold excess risk of breast cancer, compared with the general population. None of the patients who developed breast cancer had received < 26 Gy of radiation to the mantle region. This is a reassuring observation, because the current combined-modality therapeutic protocols routinely recommend radiation doses < 26 Gy to the mantle region. Nonetheless, patients with low-dose radiation exposure need to be followed carefully long-term for a possible delayed risk with lower dose exposure. Elevated risks of breast cancer have been reported to be concentrated in pediatric patients treated at age 10 years or older.6–9,19,24,29–34 For women treated after the age of 30 years, no excess breast cancers have been reported.19 In the 1994 analysis of our cohort, we reported an association between the risk of breast cancer after HD and age at radiation exposure, with 10- to 16-year olds being at a higher risk than those younger than 10 years.5 The putative rationale for this association was based on breast tissue proliferation and radiosensitivity at the time of puberty.32,33 Although 39 of the 42 instances of breast cancer in the 2000 analysis developed among patients diagnosed with HD between 10 and 16 years, using the multiple Poisson regression of SIRs and adjusting for years of patient follow-up and sex-specific change in the risk for breast cancer with attained age, we and others10 have found that age at diagnosis of HD was not a statistically significant risk factor. Rather, use of different analytic methods is the basis for these conflicting findings, given that most of the previous studies (including our 1994 analysis)5 had used Cox regression models, adjusting for the age at original diagnosis and duration of patient follow-up, but not for so-called normal changes in site- and sex-specific cancer risk that occur with aging in the general population. Thyroid cancer is the second most common solid tumor reported among survivors of childhood HD.10 With the 2000 update of our cohort, an additional nine patients with thyroid cancer were observed, and our cohort was at a 36-fold increased risk of thyroid cancer. Ninety-five percent of the malignancies developed within the radiation field, and the risk was increased among those young than 5 years at the time of exposure to radiation therapy. These findings are similar to those in previous reports.35–38 Few studies have described the risk of solid tumors other than breast and thyroid cancer among childhood HD survivors.5,7–10 Adult series report an increased risk of lung cancer after HD.39,40 Smoking has been linked with lung cancer among adult HD survivors, higher risks being reported with increasing doses of radiation, suggesting a positive interaction on a multiplicative scale.41 Overall, our cohort was at a 27.3-fold increased risk of developing lung cancer, and all patients with lung cancer received radiation therapy to the mantle region. Similar to other radiation-associated tumors, the median time to diagnosis of lung cancer was 25.7 years. Unfortunately, details of smoking history were not available for our cohort. Increased risk of second primary bone tumors is reported in patients with hereditary retinoblastoma, Ewing’s sarcoma, and other malignant bone tumors and is associated with increasing doses of radiation therapy and exposure to alkylating agents.42–44 Our cohort was at a 37.1-fold increased risk of developing bone tumors. The median age at diagnosis of HD was younger for patients who developed bone tumors compared with those who did not. All patients with bone tumors had received radiation therapy, and the bone tumors developed after a median interval of 11.8 years. Epithelial neoplasms, such as gastric and colorectal cancers, are beginning to be reported.7,10,45,46 The update of our cohort demonstrates that the risk of colorectal and gastric cancer is significantly elevated, with these malignancies occurring at much younger ages when compared to the general population. Longer follow-up of this large, multinational cohort has resulted in the emergence of solid malignancies with long latencies that are typically observed among adults, although occurring at a much younger age in this cohort. This study has also revealed the emergence of multiple radiation-associated neoplasms among certain individuals. However, as with other large cohorts, there is patient attrition with extended follow-up. In order to compensate for the impact of loss to follow-up on the magnitude of risk, we have conducted sensitivity analyses, based on the assumption that patients lost to follow-up are alive and have not had the adverse event of interest. This extremely conservative assumption allows one to put a lower limit on the magnitude of risk, thus permitting an estimate of the true risk somewhere between the reported value and that derived by these sensitivity analyses. Although the magnitude of risk is slightly blunted compared with the reported estimate, it continues to be significantly elevated. Thus, with this extended follow-up, we have found that after a relatively short latent period, the cumulative incidence of leukemia rose sharply but appeared to reach a plateau after 14 years from diagnosis, consistent with data from other studies.47 In contrast, the cumulative incidence of solid tumors continued to increase beyond 15 years and approached 23.5% at 30 years from diagnosis. High risk of solid tumors raises issues regarding screening of high-risk populations to decrease the morbidity associated with these malignancies. Recommendations made by the Children’s Oncology Group for monitoring patients at increased risk of breast cancer include the following: clinical breast examinations yearly until the age of 25 years, then every 6 months; and annual mammograms beginning at age 25 years or 8 years following radiation (whichever comes last). We recommend that clinicians teach patients how to perform breast self-exams and encourage them to perform these every month, reporting changes in the exams promptly to the clinicians. For patients at high risk for colorectal malignancies, we recommend the monitoring begin 10 years following radiation or at age 25 years (whichever occurs last). The clinicians can choose from one of three options: annual fecal occult blood testing on three consecutive specimens plus sigmoidoscopy every 5 years; double contrast barium enema every 5 years; or colonoscopy every 10 years. These recommendations are based on those offered by the American Cancer Society for individuals considered to be at the highest risk of developing these malignancies in the general population, modified to take into consideration the age of exposure and the latency of the specific malignancies. Emergence of these and other adult-onset cancers raises the issues of continued follow-up of these cohorts, identification of high-risk groups, and development of appropriate surveillance guidelines targeted to the high-risk groups. At the same time, efforts should continue to develop treatments for HD that are curative but with less carcinogenic potential.
Late Effects Study Group member institutions and investigators: Dana-Farber Cancer Institute, Boston L Diller, F Li, Columbus Children’s Hospital, Columbus FB Ruymann, Children’s Hospital of Philadelphia AT Meadows (Chairperson), Children’s Memorial Hospital, Chicago E Morgan, Institut Gustave-Roussy, Villejuif, France O Oberlin, Istituto Nazionale Tumori, Milan, Italy F Fossati-Bellani, Royal Manchester Children’s Hospital, Manchester, England J Birch, P Morris-Jones, Emma Kinderziekenhuis, Amsterdam P.A. Voute, Cor van dev Bos, University of Minnesota, Minneapolis L Robison, M Nesbit, Children’s Hospital of Los Angeles M Nelson, K Ruccione, D Tishler, Hospital for Sick Children, Toronto M Greenberg, Children’s Hospital Medical Center, Cincinnati C DeLaat, Children’s National Medical Center, Washington DC G Reaman, Children’s Hospital of Pittsburgh J Tersak, AK Ritchey, and Roswell Park D Green.
The authors indicated no potential conflicts of interest.
Presented in part at the 43rd Annual Meeting of the American Society of Hematology, Orlando, FL, December 7–11, 2001.
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ABSTRACT
INTRODUCTION
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