The construction of multivariate models that included the patient's age at the diagnosis of ALL and the assigned therapy did not suggest any interaction. . estimated an 8 percent cumulative risk 15 years after diagnosis in a group of 1815 patients, all of whom had received radiation therapy.29 More recently, Pui et al. This represented a 7-fold excess of all cancers and a 22-fold excess of neoplasms of the central nervous system. Supported in part by the Children's Cancer Research Fund of the University of Minnesota and by the Division of Cancer Treatment, National Cancer Institute. The cure of childhood cancers . People who have had cancer can still get the same types of cancers … New York: John Wiley, 1980:14–5. Five, 10, and 15 years after diagnosis, the actuarial estimated cumulative proportions of patients with a second neoplasm were 0.3 percent (95 percent confidence limits, 0.19 percent and 0.48 percent), 1.52 percent (95 percent confidence limits, 1.11 percent and 2.11 percent), and 2.53 percent (95 percent confidence limits, 1.74 percent and 3.38 percent), respectively. Nine brain tumors as a late effect in children "cured" of acute lymphoblastic leukemia from a single protocol study (141) . There were significant differences according to current age and the study in which patients were enrolled, reflecting the difficulty of obtaining information from patients in continued remission for 20 to 30 years. Of the 2169 patients included in this study, 168 (7.7%) developed a secondary neoplasm. Cancer 1987;59:1506–8. Data on patients who died of ALL were censored as of the time of death. . The ratios of observed to expected numbers of cancers in the cohort, calculated on the basis of age-, sex-, and race-specific rates, are shown in Figure 2 for all cancers and various groupings of cancers. Because very few patients not assigned to receive radiation therapy have been followed more than seven years after diagnosis, it is impossible at present to know whether the apparent reduction of risk in the nonirradiated patients will continue or whether there will be more second neoplasms later. Cancer 1983;51:1041–9. THE ability to cure acute lymphoblastic leukemia (ALL) occurring in childhood is regarded as one of the landmark developments of the past 30 years in cancer therapy. Lancet 1982;2:1326–31. Overall, the cohort had accrued 29 179 person-years of follow-up. Cancer 1987;60:2548–52. The median time since the date of the last follow-up was 0.9 years (range, 0.1-15.4 years). However, even with exclusion of basal cell carcinomas, there remains an impressive increase in carcinoma incidence between 25 and 30 years after induction, reflecting cases of more aggressive malignant neoplasms (Figure 3). The overall risk of second neoplasms in the cohort and in specific subgroups was calculated by Kaplan–Meier life-table methods.14 , 15 Ninety-five percent confidence intervals for point estimates on these curves were calculated by the method of Kalbfleisch and Prentice for life-table events of low frequency.16 Cox proportional-hazards analysis was used to analyze the exposures that involved continuous variables and for the categorical analysis of selected subgroups of patient characteristics and treatment assignments. Comparison of Observed with Expected Numbers of Second Neoplasms in the Cohort. Overall, none of the factors analyzed (age ≥10 vs <10 years old; sex; white vs nonwhite race; white blood cell count at diagnosis ≥50 vs <50 × 109/L; anthracyclines; alkylating agents; and cranial/craniospinal irradiation) showed a significant relationship to the cumulative incidence of secondary neoplasms at 20 years of follow-up (data not shown); however, at 30 years, there was a clear trend toward female dominance (4.53% [SE, 1.00%] for men vs 8.51% [SE, 1.62%] for women; P = .06). November 7, 1991N Engl J Med 1991; 325:1330-1336
At the time of the analysis, the cohort had accrued a total of 43,446 person-years of follow-up. Finally, the review of pathological specimens included in this study was not complete. . In retinoblastoma, for example, exposure to alkylating agents and radiation potentiates an already markedly elevated risk of a second neoplasm.32 Associations between childhood central nervous system tumors and hematopoietic neoplasms have also been reported. Among the 41 patients who developed secondary neoplasms after 15 years, 14 had histologically aggressive tumors (Table 2). Cancer 1983;52:1712–9. Parkin DM, Stiller CA, Draper GJ, Bieber CA, Terracini B, Young JL. 32. The total length of therapy ranged from two to five years. et al. Pinkel D. . Nineteen new secondary neoplasms were diagnosed in these groups since publication of the studies, but in each analysis the risk factors retained their original importance. The study results reflect events recorded as of October 26, 2005. Lifetime Risk of Developing Cancer: Approximately 0.1 percent of men and women will be diagnosed with acute lymphocytic leukemia at some point during their lifetime, based on 2015–2017 data. Thirty-nine of the 43 second neoplasms occurred in patients who had received radiation, either at the time of the diagnosis of ALL or at the time of relapse. : National Cancer Institute, 1989. In conclusion, the cumulative incidence of secondary neoplasm after treatment for childhood acute lymphoblastic leukemia does not attain a plateau at 15 to 20 years but continues to increase over 30 years. In this cohort of 9720 patients, 2637 (27.1 percent) had died at the time of analysis, 6644 (68.4 percent) were still alive and were being followed at the treating institution or another institution belonging to the Children's Cancer Study Group, and 439 (4.5 percent) were reported by the primary institution as being lost to follow-up. To determine whether there was an excess risk of cancer among members of the cohort, the number of cancers expected to occur from the diagnosis of ALL to the time of censoring or of an event was determined by applying age-, sex-, and race-specific incidence rates from the Surveillance, Epidemiology, and End Results (SEER) data of the National Cancer Institute to the person-years accumulated by this cohort in the corresponding categories.19 Any excess of observed cancers over expected cases was tested for statistical significance under the assumptions of a Poisson model.20. We observed that the percentage with contact in the last 2 years differed according to age and study, reflecting the difficulty of maintaining contact with aging survivors, which introduces a potential bias. Currently, the Study Group includes 31 institutions. reported a 4.7 percent risk of acute nonlymphocytic leukemia (ANLL) six years after therapy in a group of 733 patients.7. Selected multivariate models were also constructed.17 The product-limit curve for second neoplasms after exposure to radiation was calculated, with radiation exposure considered as a time-dependent covariate.18 Cox modeling of radiation exposure was not considered appropriate, given the assumptions of the model. The estimated cumulative risk for radiation exposure is shown in Figure 4 (with the patients irradiated at the time of relapse being transferred to the exposed group as of the time of radiation). The SIR was calculated by comparing the observed incidence of secondary neoplasm in patients with the expected age- and sex-specific rates of cancers in the general population using data from SEER (Table 3). Peer-reviewed journal featuring in-depth articles to accelerate the transformation of health care delivery. The cumulative incidence of each tumor type at 30 years was 2.19% (SE, 0.32%) for myeloid malignancy, 0.17% (SE, 0.10%) for lymphoma, 3.00% (SE, 0.59%) for brain tumor, 4.91% (SE, 1.04%) for carcinoma, and 0.57% (SE, 0.37%) for sarcoma. However, as demonstrated by SIR analysis, the risk of solid tumor development was still 2.4-fold higher than in the age- and sex-matched general population after 2 decades of follow-up. Cox analysis of age (a continuous variable) showed a nonsignificant trend toward an increased risk with younger age. One patient had t(9;22) at the time of diagnosis and developed i(9q) 6 years later. Adult acute lymphoblastic leukemia (ALL; also called acute lymphocytic leukemia) is a cancer of the blood and bone marrow. Malone M, Lumley H, Erdohazi M. . Pathological material was reviewed by the Pathology Center in the case of 15 of the 24 central nervous system tumors, 5 of the 10 leukemias and lymphomas, and 4 of the 9 miscellaneous neoplasms. We therefore reviewed the medical records of patients with acute lymphoblastic leukemia treated at St Jude Children's Research Hospital, Memphis, Tenn, over 3 decades to estimate the long-term cumulative incidence of secondary neoplasm occurring in first complete remission, to compare the observed number of secondary neoplasms developing in patients with acute lymphoblastic leukemia with the expected number of cancer cases in the general US population, and to identify risk factors associated with secondary neoplasm development in first complete remission. It was also possible to assess the effect of cranial/craniospinal irradiation on the cumulative incidence of secondary neoplasms in relation to the US general population by stratifying patients according to receipt or no receipt of cranial/craniospinal irradiation (Table 3). 9. Cancer in relatives of children with central-nervoussystem neoplasms . However, there was nearly complete concordance between the pathological diagnosis assigned at the patient's institution and the diagnosis assigned by the reviewing pathologist for all patients studied by both. Among the 2169 patients who achieved complete remission without additional therapy, 879 had relapse as a first event and 1290 patients remained in complete remission. These cases were treated as a competing event, similar to relapse of acute lymphoblastic leukemia, in this analysis. et al. Dr Pui is an American Cancer Society professor. Gray RJ. Second malignant neoplasms (SMNs) after diagnosis of childhood acute lymphoblastic leukemia (ALL) are rare events. The statistical analysis of failure time data. CONCLUSIONS: The cumulative incidence of secondary neoplasms increases steadily over 30 years after treatment of acute lymphoblastic leukemia. For the purposes of this analysis, one meningioma was excluded from the observed cases, because it would not have been considered a SEER-reportable cancer. Compared with the results from the Children's Cancer Group (CCG)10 or Berlin-Frankfurt-Münster (BFM) study group,11 in which meningioma and basal cell carcinoma accounted for less than 4% of all secondary neoplasms, the proportion of such tumors is considerably higher (approximately 15%) in our patient population. Among the 1290 patients who remained in complete remission, 123 (9.5%) developed a secondary neoplasm as their first event, 1099 (85.2%) remained alive without events, and 68 (5.3%) died in complete remission. Br J Cancer 1987;56:339–47. Three patients (1 each with acute myeloid leukemia, transitional cell carcinoma, and hepatocellular carcinoma) died of secondary neoplasms, and a patient with meningioma died after developing hepatocellular carcinoma as a third neoplasm. Cancer 1986;57:1979–85. The cumulative incidences of secondary neoplasm for different subgroups were compared using the test of Gray,25 which allows for comparisons of cause-specific failure distributions when competing risks are present. Risk of a Second Neoplasm According to the Patient's Age at the Diagnosis of ALL. This analysis was performed with and without the inclusion of low-grade tumors (basal cell carcinoma and meningioma) and according to specific classes of tumors. People who received certain chemotherapy drugs. abstract. Non-menaloma skin cancer … Secondary Neoplasms Observed in First Complete Remission and After Relapse of Acute Lymphoblastic Leukemia Of the 2169 patients included in this study, 168 (7.7%) developed a … Cancer. Hodgkin's disease in a child with acute lymphoblastic leukemia . . reported nine brain tumors among 896 children treated in one study by the Children's Cancer Study Group30; additional tumors of the central nervous system developed subsequently in several other children in that study and are included in this series. Critical revision of the manuscript for important intellectual content: Hijiya, Hudson, Lensing, Zacher, Onciu, Behm, Razzouk, Ribeiro, Rubnitz, Sandlund, Rivera, Evans, Relling, Pui. Chemotherapy (including anthracyclines and alkylating agents) and cranial/craniospinal irradiation were coded for each patient on the basis of protocol-specified doses and schedules, using an intention-to-treat rationale. Since the major emphasis of this study was on the development of secondary neoplasms in patients who had at least 15 years of follow-up, we first report the results of a risk factor analysis for the 845 patients who were treated in the early era of therapy (Total Therapy studies I to IX), with survivors accruing 17.1 to 41.3 years of follow-up (median, 30.1 years). (N Engl J Med 1991;325:1330–6.). Nonparametric estimation from incomplete observations . Effective forms of treatment for acute lymphoblastic leukemia (ALL) in childhood now result in survival rates above 70 percent at five years, but the treatments are potentially carcinogenic. To determine the occurrence of second neoplasms within this cohort, the principal investigators were each sent a listing of all eligible patients with ALL who had been registered in an ALL clinical trial by their institutions and affiliates. Biometrics 1974;30:89–99. Silverman LB, Gelber RD, Dalton VK. Secondary acute lymphoblastic leukemia (s-ALL) is rare and poorly defined and data regarding outcomes post-transplant are lacking. 29. The median age of acute lymphoblastic leukemia diagnosis was 4.0 years (range, 2 months to 18 years). Low incidence of second neoplasms among children diagnosed with acute lymphoblastic leukemia after 1983. 15. Coccia PF. Breslow NE, Day NE. Drafting of the manuscript: Hijiya, Hudson, Lensing. 19. The distribution of second cancers according to age at the diagnosis of ALL is shown in Figure 5. Peto R, Peto J. . ALL occurs in the United States at an annual rate of 32 cases per 1 million children under the age of 15, or more than 2000 new cases each year.3 Population-based data indicate that patients with ALL diagnosed between 1980 and 1985 have a five-year survival rate of 70.7 percent.4 Thus, there are approximately 1500 patients annually who become long-term survivors of childhood ALL. Flow sheets and all other data on the patients' treatment that were available at the Operations Office were reviewed, and if needed information was lacking, requests were directed to the institution where the diagnosis had been made. 25. Pratt et al. Third, given that the 5-year event-free survival rate before Total Therapy Study X was only 40%, there are few long-term survivors to assess (and, therefore, fewer secondary neoplasms and small risk-factor subgroup sizes at later years of follow-up), thus limiting the investigation of risk factors in the early era. Kaplan EL, Meier P. . J Clin Oncol 1986;4:744–52. J R Stat Soc [A] 1972;135:185–206. . Adult survivors of childhood leukemia have increased risks of secondary cancers, cardiovascular disease, and other chronic illnesses, largely secondary to therapies for childhood cancer. Stay connected to what's important in medical research and clinical practice, Subscribe to the most trusted and influential source ofmedical knowledge. Hammond GD. Nonetheless, the incidence of secondary neoplasms in patients who received cranial/craniospinal irradiation in the early era has not attained a plateau after 3 decades, and lifelong monitoring is necessary in this cohort. . 16. There were 2 patients with acute lymphoblastic leukemia that was considered secondary acute lymphoblastic leukemia because of the shift in cytogenetic findings thought to represent a new clone. This study did not confirm the recent report of an excess of ANLL after childhood ALL.7 Secondary myeloid leukemia developed in only 2 of 9720 patients during this period of observation. Second malignant neoplasms in five-year survivors of childhood cancer: childhood cancer survivor study. Unfortunately, being treated for cancer doesn’t mean you can’t get another cancer. . 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