Affiliations of authors: J. P. Neglia, A. C. Mertens, L. L. Robison, Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis; D. L. Friedman, Department of Pediatrics, University of Washington School of Medicine, and Cancer Prevention Research Program, Fred Hutchinson Cancer Research Center, Seattle; Y. Yasui, Cancer Prevention Research Program, Fred Hutchinson Cancer Research Center; S. Hammond, Department of Pathology, Ohio State University School of Medicine, Columbus; M. Stovall, The University of Texas M. D. Anderson Cancer Center, Houston; S. S. Donaldson, Department of Radiation Oncology, Stanford University Medical Center, Palo Alto, CA; A. T. Meadows, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia.
Correspondence to: Joseph P. Neglia, M.D., M.P.H., MMC #484, 420 Delaware St., S.E., Minneapolis, MN 55455 (e-mail: jneglia{at}tc.umn.edu).
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ABSTRACT |
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INTRODUCTION |
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One possible outcome, the occurrence of a second and subsequent malignant neoplasms (SMNs), has been recognized for many years as late sequelae of therapy (5). Subsets of patients exposed to radiation therapy or to specific chemotherapeutic agents and patients with a known genetic predisposition to malignancy have been shown to be at a higher risk for the occurrence of SMNs (2,4,6). The types of SMNs that occur may vary with the childhood cancer diagnosis, the type of therapy (chemotherapy and/or radiotherapy), and the time from initial treatment. Investigating the occurrence of SMNs in a large, heterogeneous cohort treated over a long interval may clarify and confirm previously reported disease- and therapy-related observations (47) and may define new ones. On the basis of such observations, modifying initial therapeutic approaches, increasing surveillance, or implementing chemopreventive strategies may then be considered.
In this article, we report the occurrences of SMNs within the Childhood Cancer Survivor Study (CCSS) cohort. This large, retrospective cohort, which consists of more than 13 000 5-year survivors of childhood cancers, was constructed to allow for accurate determinations of the incidence of and risk factors for rare events (such as SMNs) in an overall population of childhood cancer survivors. The size of the cohort and the heterogeneous therapeutic exposures make this an ideal setting for these investigations.
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SUBJECTS AND METHODS |
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The Long-Term Follow-up Study is a retrospective cohort constructed from the rosters of all children and adolescents treated for cancer, leukemia, tumor, or other similar illnesses during childhood at each of the 25 collaborating institutions (see the "Appendix" section). Individuals who met the following criteria were included in the CCSS cohort: diagnosis of cancer and initial treatment at one of the collaborating CCSS centers during the period from January 1, 1970, through December 31, 1986; diagnosis of cancer before 21 years of age; and survival for at least 5 years after a childhood cancer diagnosis of leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, neuroblastoma, soft-tissue sarcoma, bone cancer, or a malignant central nervous system (CNS) tumor or kidney tumor. Medical records for each potential participant were reviewed individually to determine eligibility.
The Human Subjects Committee at each participating institution reviewed and approved the CCSS protocol and contact documents. Study cohort members signed written informed consent and medical record release forms.
Cohort members were those patients for whom baseline data were collected from respondents (or parents of patients under age 18 years) with the use of self-administered questionnaires or telephone interviews. Information collected included demographic data, medication usage, diagnosed medical conditions, pregnancy occurrence and outcomes, and health-related behaviors, in addition to information regarding recurrence of the primary cancer or a diagnosis of a new cancer. In situations where the patient had survived 5 years and subsequently died, information was obtained from a family member, usually a parent. Our analysis of SMNs is based on data collected as of January 1, 2000.
Of the 20 245 patients determined to be eligible for the CCSS, data were available for a total of 13 581 cohort members. Of the eligible patients not included in the analysis, 2901 (14.3%) were determined to be lost to further follow-up after rigorous tracing efforts and 3104 (15.3%) refused to participate in the study. The remaining 659 patients were classified as pending, because they have been located only recently and have been asked to consider participating in the study.
Cancer Treatment Information
Therapeutic exposures were ascertained through review of the medical record of each study participant by trained data abstractors using a standardized protocol. Data were collected on the dates of initiation and cessation of all chemotherapeutic agents, including cumulative doses and routes of administration for 28 specific agents. Data were also collected and coded for all surgical procedures and for radiation therapy. For purposes of this analysis, radiation exposure was considered as a yes/no variable. Four radiation exposure variables were constructed: 1) any radiation; 2) CNS radiation (brain, head, neck, or total-body irradiation [TBI]); 3) breast radiation (chest, spine, abdomen [if abdominal radiation at age 7 years or under], or TBI); and 4) thyroid radiation (chest, spine, neck, or TBI). In the SMN analyses of CNS, breast, and thyroid cancers, we used CNS-, breast-, and thyroid-radiation variables, respectively, as the relevant radiation exposure indicator. In all of the other analyses, the any-radiation exposure variable was used.
Alkylating agent scores were calculated with the use of methods described previously (7). Doses per meter squared of daunorubicin, doxorubicin, and idarubicin (multiplied by 3 to approximate doxorubicin equivalence) were summed to determine cumulative anthracycline exposure, as were doses of etoposide and teniposide for cumulative epipodophyllotoxin exposure. The cumulative dose of carboplatin was divided by 4 and added to the cisplatin dose to assess exposure to platinum compounds (8).
Ascertainment of SMNs
SMNs were ascertained initially through self-report via the baseline questionnaire. Cohort members were asked to report the occurrence of any cancer (either a relapse of the childhood cancer or a new cancer) since the time of the childhood cancer diagnosis, the institution where the second diagnosis was made, and the treating physician. All positive responses were screened by one of the study investigators (J. P. Neglia), and those responses representing likely or possible SMNs were forwarded to the CCSS Pathology Center (Columbus, OH) for verification. A copy of the pathology report was requested from the institution of record. All reports of possible SMNs were reviewed by the CCSS pathologist for inclusion or exclusion in the study. In selected cases where the childhood cancer diagnosis and SMN diagnosis were similar, reports of the childhood cancer diagnosis were also reviewed. If a pathology report could not be obtained, the patient and/or parent response, death certificate, and/or other institutional records were reviewed to determine the presence of an SMN. Premalignant or dysplastic conditions (i.e., cervical dysplasia) were not included in the analysis. Nonmelanoma skin cancers, meningiomas, and other nonmalignant CNS tumors were ascertained and verified but were also excluded from the analysis. Individuals who developed and died of an SMN less than 5 years after the childhood cancer diagnosis were not eligible for this study and thus were not considered in the analysis. Among cohort members, any SMN occurring before entry into the cohort (i.e., 5 years after the childhood cancer diagnosis) was excluded from the analysis.
SMNs were coded by histology with the use of the International Classification Diseases for Oncology (9). Diagnostic groupings of SMNs were constructed as outlined in the International Classification of Childhood Cancer (10).
Statistical Analysis
Standardized incidence ratios (SIRs) of observed-to-expected malignancies were calculated with the use of age- and sex-specific incidence rates (National Cancer Institute's Surveillance, Epidemiology, and End Results [SEER] Program1) (11). For patients who developed multiple malignancies after the primary disease, all of the subsequent malignancies were counted in the numerator of SIRs, in agreement with the SEER Program's incidence calculation. Survivors of childhood cancer were considered to be at risk for an SMN from the time of entry into the cohort (i.e., 5 years after the childhood cancer diagnosis) until the earlier of one of two events: death or completion of the baseline CCSS questionnaire. Males were not included in the analysis of subsequent breast neoplasms because there were no male cohort members with secondary breast cancer.
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. We determined the excess absolute risk by subtracting the expected number of malignancies in the cohort from the observed number, dividing the difference by the person-years of follow-up, and multiplying this value by 1000.
The relative risk (RR) of developing an SMN was estimated for each of the patient characteristics and therapeutic exposures with the use of a Poisson multiple regression model for SIRs (12). A fixed set of explanatory variables was selected a priori and was used to assess their simultaneous impact on the risk of developing SMNs in regression models without any statistical variable selection. These analyses were performed for all SMNs, as well as for each subgroup of SMNs (see Table 5) and by childhood cancer diagnosis (see Table 6
). 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. Cohort members whose medical records were not abstracted because of refusal to participate in the study, loss to follow-up, or delay in submitting the medical record release form were grouped as a separate treatment-exposure category in the regression analyses. All statistical tests were two-sided.
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RESULTS |
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In total, the SIR of observed-to-expected SMNs was 6.38 (95% CI = 5.69 to 7.13) (Table 3). Excesses of SMNs were observed among all major diagnostic groups. The largest excesses of SMNs were observed for breast cancers (60 observed, 3.71 expected; SIR = 16.18; 95% CI = 12.35 to 20.83), bone cancers (28 observed, 1.46 expected; SIR = 19.14; 95% CI = 12.72 to 27.67), and thyroid cancers (43 observed, 3.79 expected; SIR = 11.34; 95% CI = 8.20 to 15.27). Excesses were not statistically significant for secondary lymphoma (SIR = 1.51; 95% CI = 0.80 to 2.58).
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The SIRs for SMNs were examined in 5-year intervals, beginning 5 years after the childhood cancer diagnosis and continuing through 30 years of follow-up. The risk of developing an SMN was increased over all intervals examined. The risk of developing leukemia was highest from 5 to 9 years of follow-up (SIR = 11.53; 95% CI = 7.35 to 18.07) and decreased thereafter (SIR = 4.48 [95% CI = 0.63 to 31.78] at 2030 years of follow-up). The risk of developing solid cancers, including breast or thyroid cancer, was significantly elevated during the entire follow-up period (SIRs for breast cancer = 10.11 [95% CI = 3.26 to 31.34] at 59 years of follow-up and 10.07 [95% CI = 5.42 to 18.71] at 2030 years of follow-up; SIRs for thyroid cancer = 11.26 [95% CI = 6.24 to 20.33] at 59 years of follow-up and 8.56 [95% CI = 3.21 to 22.80] at 2030 years of follow-up).
We next compared the risk indices for each of the major childhood cancer diagnostic groups (Table 4). Excesses of SMNs were observed among all diagnostic groups. The excess of SMNs was highest among patients diagnosed with Hodgkin's disease in childhood (SIR = 9.70; 95% CI = 8.05 to 11.59) and lowest among patients diagnosed with non-Hodgkin's lymphoma in childhood (SIR = 3.21; 95% CI = 1.76 to 5.39).
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Multivariate models, which adjusted for radiotherapy exposure, were constructed to determine independent risk factors for the occurrence of SMNs (Table 5). SMNs of any type were independently associated with female sex (P<.001), childhood cancer diagnosis at a young age (P for trend <.001), childhood cancer diagnosis of Hodgkin's disease or soft-tissue sarcoma (P<.001 and P = .01, respectively), and increasing exposure to anthracyclines and/or epipodophyllotoxins (P for trends = .02 and .02, respectively). Treatment era (more recent treatment time) was not an independent risk factor for overall SMNs or for any specific SMN.
When we analyzed for specific SMNs, increasing epipodophyllotoxin exposure was an independent risk factor for leukemia (P for trend = .01) but not for any other cancer (Table 5). Breast cancers were associated with a childhood cancer diagnosis of kidney tumors (RR = 12.38 [95% CI = 1.95 to 78.71] compared with a childhood cancer of leukemia) and marginally associated with a childhood cancer of Hodgkin's disease (RR = 4.89; 95% CI = 0.95 to 25.24). Breast cancers were not associated with any of the age strata or chemotherapy exposures. A childhood diagnosis of leukemia (compared with all solid tumors) was independently associated with the occurrence of a malignant CNS tumor, as was younger age at original diagnosis (P for trend = .005). Bone cancers were independently associated with childhood cancer diagnosis of either a sarcoma (RR = 13.21; 95% CI = 3.19 to 54.77) or a bone tumor (RR = 10.93; 95% CI = 2.16 to 55.39). Bone cancers were also associated with increasing exposure to alkylating agents (P for trend = .07). Both sarcomas and thyroid cancers were independently associated with childhood cancer diagnoses at a younger age (P for trend <.001 and P for trend = .003, respectively). Complete results from the multivariate analysis by exposure and demographic variables are shown in Table 5
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We also conducted a multivariate analysis to determine independent risk factors for SMNs by childhood cancer diagnosis (Table 6). Among cohort members with a childhood cancer diagnosis of leukemia, younger age at the time of childhood leukemia and increasing exposure to epipodophyllotoxins were associated with SMNs (P for trend <.001 and P for trend = .001, respectively). Younger age at the time of a childhood cancer diagnosis of soft-tissue sarcoma was also associated with increased risk for SMNs (P for trend <.001). Female cohort members were at greater risk of developing an SMN if their childhood cancer diagnoses were either Hodgkin's disease (RR = 2.55; 95% CI = 1.65 to 3.92) or non-Hodgkin's lymphoma (RR = 5.99; 95% CI = 1.83 to 19.58).
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DISCUSSION |
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SMNs are infrequent but extremely serious events following therapy for primary cancers. In the CCSS cohort, we found all childhood cancer diagnostic groups to have an increased risk for SMNs. Survivors of childhood cancers who were female, who were originally diagnosed at a younger age, or who were originally diagnosed with Hodgkin's disease were at greatest risk for SMNs. Survivors treated previously with anthracyclines or epipodophyllotoxins were also at increased risk.
Despite the overall increased risk for SMNs among the cohort, the distribution of SMNs was heterogeneous when the cohort members were grouped according to their original childhood cancer diagnoses. For example, survivors of Hodgkin's disease, who comprised 13.4% of the cohort, contributed 37.3% of all SMNs, with an SIR of 9.7. Survivors of leukemia, who comprised 33.6% of the cohort, contributed only 21.5% of all SMNs, with an SIR of 5.7. In addition, survivors of bone cancers or soft-tissue sarcomas, who comprised 17.1% of the cohort, contributed 20.1% of all SMNs.
In the CCSS cohort, the most common SMN was breast cancer, which had one of the largest excess SIRs (SIR = 16.18). In previous studies (6,1318), breast cancer was reported in excess of that expected in female survivors of Hodgkin's disease. In our study, female survivors of Hodgkin's disease were at increased risk for breast cancer, although the RR reached only marginal statistical significance compared with that for leukemia survivors. Survivors of Wilms' tumors were also at increased risk for breast cancer; however, with a low number of cases, there was less stability in the risk estimate.
Studies (6,13) have shown that girls between the ages of 10 and 16 years at the time of radiation therapy for Hodgkin's disease are at greatest risk of breast cancers, presumably because the radiation therapy is delivered at a time when breast tissue is proliferating. These observations have resulted in sex- and age-based recommendations regarding radiation therapy for Hodgkin's disease. However, our analysis calls these recommendations into question. Using the multiple Poisson regression of SIRs and adjusting for age at childhood cancer diagnosis, years of patient follow-up, and sex-specific change in the risk for breast cancer with attained age, we found that older age at childhood cancer diagnosis was not a statistically significant risk factor for breast cancer. Although the difference between the risks for each age group was not statistically significant among cohort members, the risk of breast cancer was actually higher in those diagnosed at ages 59 years (RR = 1.77; 95% CI = 0.54 to 5.79) than in those diagnosed at ages 1014 years (RR = 1.45; 95% CI = 0.78 to 2.71) and in those diagnosed at ages 15 years and older.
The difference in the analytic methods that we used may explain the conflicting findings between our results and the results of other investigations (6,13). Most previous studies of SMNs (6,13,15) have used Cox regression models, adjusting for the age at original diagnosis and the duration of patient follow-up but not for the "normal" changes in site- and sex-specific cancer risk that occur with aging in the general population. Without proper adjustment for these changes, the breast cancer analysis would be expected to show that female survivors of Hodgkin's disease who were older at their childhood cancer diagnosis are at higher risk for breast cancer because the overall breast cancer risk is higher in older females. Although such analyses are methodologically correct, the results should not be interpreted as evidence for a stronger effect of cancer therapy on breast SMN risk in the older patient group. To assess whether the original cancer therapy has a differential influence on breast SMN risk by age at original diagnosis, the model must adjust for the fact that older females are at higher risk for breast cancer in the general population. In our SIR regression model, this adjustment is incorporated into the expected numbers of breast cancer, i.e., the denominator of SIRs. Because Hodgkin's disease is more commonly a disease of adolescents than of younger children, more survivors of adolescent Hodgkin's disease are nearing the age group where breast cancer is seen with greater frequency in the general population. Children treated for Hodgkin's disease or for Wilms' tumor at younger ages have not yet reached an age when breast cancer incidence begins to rise in the general population, but our analysis shows that they are still at increased risk. In fact, children treated at younger ages were at higher RR for breast cancer than children treated at older ages, when compared with the age- and sex-matched general population. Therefore, all female survivors of Hodgkin's disease should be considered to be at increased risk for breast cancer, and it is only with continued follow-up that the true lifetime risk will become evident for all age groups.
We are now conducting a detailed analysis of risk factors for breast cancer following Hodgkin's disease in this cohort. This will include a rigorous dosimetry analysis and a further analysis of the combined effect of age at childhood cancer diagnosis and attained age at breast cancer diagnosis. If radiation therapy is found to be a statistically significant treatment-related risk factor for breast cancer in female survivors of Hodgkin's disease, reduction in dose or elimination of radiotherapy for Hodgkin's disease should not be limited to those older than 9 years at diagnosis. Similar considerations should be given to the analysis of any other secondary event that would occur at low frequency in younger adults.
Bone cancers and soft-tissue sarcomas have also been reported in excess after treatment of childhood cancer with radiation therapy and perhaps alkylating agents (5,7,19,20). Survivors of Ewing's sarcoma appear to be at risk for osteosarcoma, independent of treatment (21). In the CCSS cohort, childhood cancer diagnoses of bone cancer or soft-tissue sarcoma were risk factors for secondary bone cancers and soft-tissue sarcomas, independent of primary treatment, although the RR for soft-tissue sarcomas among bone cancer survivors reached only marginal statistical significance compared with that for leukemia survivors. Cohort members treated for Hodgkin's disease or kidney tumors were also at increased risk for soft-tissue sarcoma. Analysis of the patients in our cohort indicates that treatment for the childhood cancer with alkylating agents increased the risk for bone cancers and that treatment with anthracyclines increased the risk for soft-tissue sarcomas. Although it is possible that there is some interaction between radiation therapy and doxorubicin, a known radiation sensitizer (22), small subgroup numbers preclude a statistically sound analysis of interaction.
In the CCSS cohort, there were 43 thyroid cancers, making thyroid cancer the second most frequent SMN. The thyroid gland is highly radiosensitive, and thyroid cancers have been reported in previously irradiated fields (23). We found that childhood cancer survivors who were treated for leukemia or CNS tumors at a younger age were at highest risk for thyroid tumors, an effect that has been noted previously (23). Using the Poisson regression model of SIRs, we did not detect an increased risk for thyroid tumors in females. Although the majority of the thyroid cancers did occur in females, the same sex distribution of thyroid cancer is seen in the general population.
CNS tumors, both benign and malignant, have been reported (2426) to occur with increased frequency among patients treated with cranial irradiation for acute lymphoblastic leukemia. The patients at greatest risk are those treated when less than 6 years of age, the time of greatest brain tissue growth (2426). Our data support these findings. Of the 36 CNS SMNs, 23 followed therapy for leukemia. Younger age at initial therapy was an independent risk factor for CNS SMNs. Cohort members treated previously for childhood leukemia represented 33.7% of the cohort, but they contributed 64% of the subsequent CNS cancers. Of note, those patients who were treated with higher doses of radiation for a childhood CNS cancer had a lower RR for a second CNS cancer. Treatment with chemotherapy agents, including alkylating agents, did not increase the risk for CNS cancers. Recent data (27) have suggested that children with leukemia who are also deficient in the metabolism of the thiopurines may be at increased risk for CNS cancers. Although it is unknown if the patients in the cohort were deficient in thiopurine metabolism, our high incidence of CNS tumors following leukemia could be interpreted as supportive of this association. Further study of this group will be performed to confirm these findings.
Therapy-related acute leukemia following treatment of a primary malignancy has been associated with the use of several groups of chemotherapeutic agents, including alkylating agents (5,6,16), topoisomerase II inhibitors (2830), anthracyclines (20), and platinum compounds (8). However, of the 314 SMNs in our cohort, only 24 (7.6%) were cases of second leukemia, a smaller percentage than reported in other studies (6,13,21,31). Moreover, we found that alkylating agents, anthracyclines, or platinum exposure did not increase the risk of secondary leukemia. There was, however, an independent, dose-dependent epipodophyllotoxin effect on the risk of secondary leukemia that was statistically significant in a test for trend. The cumulative dose of epipodophyllotoxins was not found to increase risk for secondary leukemia in a National Cancer Institute review of 13 clinical trials that included treatment with epipodophyllotoxins (29), although the schedule of administration may have been an important factor in risk for secondary leukemia (28). The doseresponse relationship in our study suggests that a higher cumulative dose of epipodophyllotoxins may indeed increase the risk for therapy-related leukemia. However, we did not evaluate the schedule of epipodophyllotoxin administration, which may have confounded the results of the dose response. Given the short latent period for epipodophyllotoxin-related leukemia, there may have been patients who developed a therapy-related leukemia within the first 5 years after their childhood cancer diagnosis. However, because this is a study of 5-year survivors of childhood cancer, no events that occurred in the first 5 years following initial childhood cancer diagnosis were ascertained.
Genetic conditions associated with an increased risk of multiple primary cancers include hereditary retinoblastoma, LiFraumeni syndrome, neurofibromatosis, familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, and multiple endocrine neoplasia (32). Several patterns noticed in our cohort suggest familial cancer syndromes. For example, the association that we noted between SMNs of bone and soft-tissue sarcoma following a childhood cancer diagnosis of sarcoma could represent a genetic cancer syndrome such as the LiFraumeni syndrome, where bone and soft-tissue sarcomas are noted in multiple family members younger than 45 years (33,34). The observation that CNS tumors occur following a childhood diagnosis of leukemia or CNS tumor may support a previously described familial syndrome that includes hematopoietic cancers, and CNS tumors may also comprise part of a familial cancer syndrome (3537). Family history of cancer and molecular epidemiology studies are under way in our cohort to clarify some of these associations. Such studies may also identify previously unrecognized family cancer syndromes in which multiple primary cancers occur in a single individual. Interactions between genetic predisposition, the environmental factors, disease characteristics, and treatment are complicated and will require additional studies that are possible only with the ongoing follow-up of a large cohort, such as the CCSS cohort.
There are several limitations to our study. For example, because of our eligibility criteria, a direct comparison of our SMN occurrence frequencies to those of other reports (5,6,1316,18,20,21,31) is not possible because entry into the CCSS cohort required survival 5 years from the childhood cancer diagnosis. Thus, our eligibility criteria excluded individuals who developed an SMN and died before 5 years and excluded SMNs in cohort members that occurred before the 5-year entry date. Our cohort also excluded children with retinoblastoma, who are well known to be at an increased risk of SMNs (38). Accordingly, our analysis somewhat underestimates the overall risk of SMNs from the time of the childhood cancer diagnosis. In addition, it is possible that some cancers occurred among eligible members but were missed because the participant or the respondent for the questionnaire was unaware of the secondary cancer diagnosis. To minimize this possibility, all responses suggesting either an SMN or a recurrence of the childhood cancer diagnosis were reviewed and investigated at the CCSS Pathology Center.
Another limitation to our study is that we classified radiation exposure as a dichotomous variable indicating exposure to the tumor site. To specifically categorize each SMN in relation to and within the radiation field and to adjust for dose was beyond the scope of the current analysis. We, therefore, elected not to report increased risk for SMN by radiation therapy. For those SMNs in which radiation therapy presumably plays a clinically significant role (i.e., secondary breast and CNS tumors), we are undertaking nested casecontrol studies that include rigorous dosimetry evaluations of tissue-specific dose estimates to determine risk conferred by radiation therapy.
Although survivors of childhood cancers are at increased risk of SMNs relative to the population at large, the frequency of such cancers is low compared with the frequency of cancer cures. Indeed, the absolute risk of SMNs was small, with an estimated 1.88 additional cancers occurring within the cohort for each 1000 person-years of follow-up. Even among long-term survivors of Hodgkin's disease, the subgroup at highest risk for SMNs, the absolute excess of SMNs was five per 1000 person-years of follow-up. Thus, the great success in the last three decades in treating children with cancer should not be overshadowed by the incidence of SMNs. Furthermore, patients and health-care providers need to be aware of those at the highest risk of SMNs so that surveillance is focused toward potential primary and secondary prevention, based on risk factors. Preventive strategies could include modification of therapies for childhood cancer when possible without compromising survival, early mammograms for women who have received radiotherapy to the breasts as children, and possibly chemoprevention for high-risk groups. Further investigations, using nested casecontrol studies, are required to better define the pathogenesis of SMNs and to facilitate the implementation of such strategies.
Given the large size and extended follow-up of the CCSS cohort, this article represents, to our knowledge, the most precise estimates to date of the risk and occurrences of SMNs in survivors of childhood cancers. Continued follow-up of this unique cohort will provide important insights into the long-term consequences of therapy and subsequent risks of SMNs.
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NOTES |
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See "Appendix" section for participating investigators and institutions of the Childhood Cancer Survivor Study.
J. P. Neglia and D. L. Friedman contributed equally to the preparation of this article.
Supported by Public Health Service grant CA55727 from the NCI, National Institutes of Health, Department of Health and Human Services; and by the Children's Cancer Research Fund, Minneapolis, MN.
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Manuscript received August 22, 2000; revised February 13, 2001; accepted February 16, 2001.
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