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© 1999 American Society for Clinical Oncology Cancer and Cardiac Mortality Among 15-Year Survivors of Cancer Diagnosed During Childhood or AdolescenceFrom the Departments of Cancer Prevention, Epidemiology and Biostatistics, Education, Nursing, Pediatrics, and Psychology, Roswell Park Cancer Institute, and Department of Pediatrics and Social and Preventive Medicine, School of Medicine and Biomedical Sciences, and Department of Natural Sciences, Roswell Park Graduate Division, University at Buffalo, State University of New York, Buffalo, NY. Address reprint requests to Daniel M. Green, MD, Department of Pediatrics, Roswell Park Cancer Institute, Elm and Carlton Sts, Buffalo, NY 14263; email green{at}sc3101.med.buffalo.edu
PURPOSE: To evaluate the impact of cardiac disease and second malignant neoplasms on late mortality rate and to identify risk factors for late mortality among 15-year survivors of cancer diagnosed during childhood or adolescence. PATIENTS AND METHODS: Gender-specific all-cause and cause-specific (cardiac disease, cancer) standardized mortality ratios were calculated. Kaplan-Meier survival estimates and Cox regression analyses were performed to determine the relationship of several demographic and treatment variables to survival. RESULTS: Patients who survived for 15 years after diagnosis had excess subsequent all-cause, cancer (second malignant neoplasms only), and cardiac mortality rates. No decrease in the late mortality rate by treatment era (1960 to 1970, 1971 to 1984) was identified. Risk factors for males included disease recurrence during the first 15 years after diagnosis, treatment with doxorubicin, and the diagnosis of Hodgkin's disease. Those for females included treatment with radiation therapy, treatment with an alkylating agent, and disease recurrence during the first 15 years after diagnosis. Cox regression analysis demonstrated that only an initial duration of remission of less than 15 years (P < .01) and treatment with doxorubicin (P = .08) were significantly associated with shorter survival time for males. No variable was significantly associated with shorter survival time for females in Cox regression analysis. CONCLUSION: Fifteen-year survivors of childhood cancer have excess mortality. More effective treatments must be developed to reduce this excess risk. Fifteen-year relapse-free survivors did not have excess mortality. This group will require continued observation to determine whether excess mortality will become apparent as more events occur.
ADVANCES IN TREATMENT have increased the survival rate of children and adolescents with cancer dramatically.1 Li et al reported that, although the survival rate of 5-year survivors of diverse types of childhood cancer2 or Wilms' tumor3 treated before the era of megavoltage irradiation and combination chemotherapy was significantly poorer than that of the United States population, survivors who did not have recurrence of disease during the first 5 years after diagnosis had an excellent prognosis for survival for up to 20 years after diagnosis.2 Others reported that survival of 3-year4 or 5-year5-8 survivors of childhood cancer was inferior to that of control populations. Only one study examined the relationship between treatment exposures and mortality rate. The exposures evaluated included only alkylating agent exposure and treatment with radiation therapy.8 One previous study examined the long-term survival of 10-year survivors.9 None has examined the outcome of 15-year survivors of pediatric cancer after modern treatment. The present study was undertaken to evaluate sex-specific, all-cause, and cause-specific mortality rates and risk factors for late mortality in a large cohort of 15-year survivors of cancer diagnosed during childhood or adolescence whose treatment exposures were well characterized.
The Department of Pediatrics at Roswell Park Cancer Institute (RPCI) was founded in 1956 by Donald Pinkel, MD. Patients were treated by department members using studies developed by Cancer and Leukemia Group B. More recently, patients have been treated using Pediatric Oncology Group protocols. Megavoltage radiation therapy has been used for the treatment of patients at RPCI since 1954. The Long-Term Follow-Up Project is a comprehensive study of a cohort of consecutive, previously untreated patients who were younger than 20 years of age at diagnosis. A list of all patients younger than 20 years of age at diagnosis who were referred to RPCI between January 1, 1960, and December 31, 1989, was prepared by the medical records department. Previously untreated patients who were referred for treatment of their first tumor were identified. Patients referred for treatment of recurrent disease, for a second opinion, and for treatment of a second malignant tumor were excluded. The above procedures resulted in the identification of 1,441 consecutive, previously untreated patients with cancer. The hospital number, patient name, date of birth, sex, race, diagnosis, date of diagnosis, primary tumor site, presence of metastatic disease, treatment (surgery, radiation therapy, or chemotherapy), date of splenectomy, date of first treatment, total dose and treatment volume for the first two orthovoltage and the first two megavoltage radiation-therapy fields, date of first treatment with dactinomycin, doxorubicin, daunorubicin, etoposide and teniposide, an alkylating agent, the specific alkylating agents used (cyclophosphamide, 1-(2-chloroethyl)-3 cyclohexyl-1-nitrosourea [CCNU], 1,3-bis(2-chloroethyl)-1-nitrosourea [BCNU], nitrogen mustard, procarbazine, cis-diammine-dichloro-platinum(II), and chlorambucil), date of relapse, date of diagnosis of second (and subsequent) malignant neoplasm(s), primary tumor site and histology of second (and subsequent) malignant neoplasm(s), and date and cause of death or date of last follow-up were entered into a computerized database using commercially available software (VisualDbase; Inprise Corp, Scotts Valley, CA). All second malignant neoplasms were confirmed histologically. Annual contact with those patients who survived was maintained through clinic visits or by mail, either through participation in the Long-Term Follow-Up Project or by contact by the central follow-up clerk of the medical records department of RPCI, who maintained a file of contact persons for each patient. Of the 474 15-year survivors, two were last contacted in 1993, two in 1995, three in 1996, and 21 through March 18, 1997. Thirty were last contacted between March 19, 1997, and March 18, 1998, and 416 between March 19, 1998, and March 18, 1999.
Statistical Procedures Three primary statistical analyses were conducted: (1) standardized mortality ratios (SMRs) were calculated to determine whether cohort members were at a greater risk of dying than the general population; (2) log-rank tests were performed to determine the statistical significance of factors that may have modified the risk of death; and (3) Cox proportional hazards models were estimated to determine whether particular predictor variables were associated with increased survival time. Sex-specific SMRs were calculated using commercially available software (Epilog Plus: Statistical Package for Epidemiology and Clinical Trials, Windows Version; Epicenter Software, Pasadena, CA). Sex-specific person-years at risk were accumulated from the date of initial diagnosis until the date of death or last follow-up and were partitioned into 5-year age categories. The first 15 years of patient follow-up were excluded from the calculation to avoid artifactual improvement in survival. The expected number of all-cause and cause-specific (cardiac and cancer) deaths was obtained by multiplying the specified mortality rate by the population size for each of the sex/age category. The mortality and population data are for New York State, excluding New York City, for the years 1960, 1965, 1970, 1975, 1980, 1985, 1990, and 1995. The SMR for a particular disease cause is calculated as the number of observed deaths divided by the number of expected deaths. Ninety-five percent confidence intervals were calculated around each point estimate under the assumption that the number of observed deaths follows a Poisson distribution.11 Because multiple comparisons were being made, the significance level was adjusted using the Bonferroni method.12 The adjusted significance levels were (a) log-rank comparisons of various prognostic factors (P < .0042; .05/12) and (b) log-rank comparisons of various alkylating agents (P < .0071; .05/7). Overall survival time was estimated from the date of diagnosis to the date of death or date of last follow-up using the Kaplan-Meier method.13 The log-rank test was used to determine the statistical significance of factors that may have been associated with the risk of death.14
Cox proportional hazards modeling was used to evaluate the effects of several predictor variables on survival by sex using the SPSS software package (SPSS Advanced Statistics, Version 8.0; SPSS Inc, Chicago, IL). The variables examined were initial diagnosis (acute lymphoblastic leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, osteosarcoma, neuroblastoma, CNS tumors, and other), age at diagnosis (< 10 years,
The distribution of diagnoses of all patients diagnosed between January 1, 1960, and December 31, 1989, is shown in Table 1, in comparison to data from the National Cancer Institute Surveillance, Epidemiology, and End Results Program distribution for patients younger than 20 years of age at diagnosis.15 The demographic data for the entire cohort of patients and for those who survived for 15 years after diagnosis are shown in Table 2. The mean age (± SD) at follow-up was 34.55 ± 8.06 years (median, 33.9 years; range, 18.5 to 57.3 years) for males and 35.57 ± 8.97 years (median, 35.00 years; range, 17.8 to 56.4 years) for females.
The distribution of treatment modalities is shown in Table 3. Fifty-seven of 1,441 were treated using both the orthovoltage and megavoltage techniques, 79 using only the orthovoltage technique, and 692 using only the megavoltage technique. Four were treated with iodine-131.
Four hundred seventy-four patients survived for 15 or more years. The mean follow-up (± SD) of these patients was 24.13 ± 6.13 years (median, 23.39 years; range, 15.04 to 38.54 years). Twenty-five of these patients died. The actuarial survival percentage was 88% ± 2% at 35 years after diagnosis. The causes of death are listed in Table 4.
Five patients died as the result of second malignant neoplasms. The histology of the initial cancer, histology and primary site of the second malignant neoplasm, elapsed time in years between the diagnosis of the initial cancer and second malignant neoplasm, and duration of survival are shown in Table 5.
Five patients died as the result of cardiac disease. Three men, two of whom were treated with mediastinal irradiation, had fatal acute myocardial infarctions 20.9 to 27.6 years after diagnosis. The mediastinal radiation therapy doses were 21 Gy (neck, axilla, and mediastinum) and 20.5 Gy (mediastinum). A fourth patient, who received radiation therapy to a mantle (36 Gy), and subsequently to the left lung (20 Gy) and left lower lobe (10 Gy), and doxorubicin (cumulative dose, 223 mg/m2), died of congestive heart failure after mitral valve replacement and coronary artery bypass grafting. One unirradiated patient died of doxorubicin cardiomyopathy (cumulative dose, 537 mg/m2).
SMRs
The mortality rate from second malignant neoplasms was not increased among either male (Table 8) or female (Table 9) 15-year survivors. The SMRs for males (Table 8) were not increased for any of the variables examined. The SMRs for females (Table 9) were increased for those treated with radiation therapy, for those treated with an alkylating agent, and for those whose initial duration of remission was less than 15 years.
The cardiac mortality rate was significantly increased among males (Table 10). The SMRs for cardiac mortality among males were significantly increased among those with the diagnosis of Hodgkin's disease, those treated with doxorubicin, and those whose initial duration of remission was less than 15 years. There were no deaths caused by cardiac disease among females.
The mortality rate was increased among males 35 to 39 years of age (data not shown). Excess mortality was due to cardiac disease among the 40- to 44-year-old males (data not shown). No significant relationship between all-cause or cause-specific mortality was identified among females when the P values were adjusted for the nine age groups examined.
Univariate Analysis Treatment with doxorubicin (P = .0015) was associated with significantly greater risk of death due to cardiac disease. Sex (P = .0325), race (P = .7136), age group (0 to 9 years, 10 to 19 years; P = .0365), treatment with radiation therapy (P = .987), treatment with chemotherapy (P = .2521), treatment with splenectomy (P = .4313), treatment with any alkylating agent (P = .7416 ), treatment with daunorubicin (P = .6988), and relapse during the first 15 years after diagnosis (P = .0514) were not significantly associated with an increased mortality rate due to cardiac disease.
Multivariate Analysis Males. Duration of remission for less than 15 years was highly significant (P < .01) in a Cox regression model of survival time, which included all of the predictor variables (see Patients and Methods under Statistical Procedures). Treatment with doxorubicin was of borderline significance (P = .08) in a Cox regression model of survival time, which included all of the predictor variables. No variable achieved statistical significance in the Cox regression models of death due to cancer (second malignant neoplasms) or cardiac disease, which included all of the predictor variables. Females. No variable achieved statistical significance in the Cox regression models of survival time or death due to cancer (second malignant neoplasms), which included all of the predictor variables.
We undertook the present study to evaluate further survival, cause-specific mortality rates, and risk factors for late mortality of patients who were younger than 20 years of age when diagnosed with cancer and who survived for 15 years after receiving modern treatment, which may have included megavoltage radiation therapy and/or combination chemotherapy, for their cancer. We found excess mortality in 15-year survivors of childhood cancer. No previous study evaluated mortality in this group of patients. Those who survived relapse-free for the first 15 years after diagnosis did not have excess mortality, compared with the New York State population. There was no suggestion of a difference in mortality risk by sex among 15-year survivors in the present study. Previous studies demonstrated that there was excess mortality among 5-year survivors of childhood cancer. Nicholson et al7 reported that the SMR, using a sibling control group, was increased for all age groups examined except the oldest (41 to 55 years of age, SMR = 2.1; 95% confidence interval, 0.8 to 5.5). Green et al reported that the SMR was 4.8 (95% confidence interval, 2.8 to 7.5) for men who did not experience disease recurrence or progression during the first 5 years after diagnosis, and 29.2 (95% confidence interval, 20.3 to 40.7) for men who experienced disease recurrence during the first 5 years after diagnosis. The SMR was 6.1 (95% confidence interval, 2.8 to 11.7) for those women who did not relapse during the first 5 years after diagnosis, and 58.9 (95% confidence interval, 38.0 to 86.9) for women who experienced disease recurrence or progression during the first 5 years after diagnosis.8 Hudson et al reported that the mortality rate exceeded that for the general population for both eras of treatment (1962 to 1970 and 1971 to 1983) for all patients and for those who survived relapse-free for the first 5 years (n = 2,053) after diagnosis. The SMR was 15 among all 5-year survivors and was seven among all 5-year survivors who remained relapse-free for the first 5 years after diagnosis.9 One prior study evaluated the outcome of 10-year survivors of childhood cancer. Hudson et al reported that the SMR was 8 among all 10-year survivors and 4 to 6 among all 10-year survivors who remained relapse-free for the first 10 years after diagnosis. The sex-specific mortality rate and the relationship between treatment exposures and subsequent all-cause or cause-specific mortality rates were not evaluated in this study.9 Few prior studies examined cause-specific mortality rates in surviving patients. Robertson et al6 reported an SMR due to cardiovascular disease of 5 among 5-year survivors, with six of the deaths related to doxorubicin cardiomyopathy. Hudson et al9 reported that the SMR due to cardiac disease was 6, with one death related to mantle radiation therapy, one to doxorubicin cardiomyopathy, and two to doxorubicin and chest irradiation. This figure is similar to that (SMR, 7.9; 95% confidence interval, 3.1 to 16.6) observed among male 15-year survivors in the present study, although fatal ischemic heart disease occurred more frequently in the present study than did fatal doxorubicin cardiomyopathy. The sex-specific cardiac mortality rate was not evaluated in any prior study. In the present study, cardiac mortality was more frequent among the male survivors. We evaluated several risk factors for late mortality among 15-year survivors. The risk factors differed with sex. Treatment with doxorubicin and relapse during the first 15 years after diagnosis were associated with excess mortality among males. None of the examined variables (eg, treatment with or without doxorubicin) was associated with a significantly higher risk of mortality among females, as the 95% confidence intervals for all of the variables overlapped. However, several variables were associated with a significant increase in the risk of mortality, compared with the New York State population. Nicholson et al7 reported that the diagnosis of CNS tumors and treatment with radiation therapy and alkylating agents were associated with an increased risk of mortality among 5-year survivors of childhood cancer, but they did not evaluate the effect of duration of initial remission or treatment with doxorubicin on all-cause or cause-specific mortality rates. The results of the present study demonstrate that both treatment with specific chemotherapeutic agents and the duration of initial remission may be significant risk factors for excess all-cause mortality. None of the examined variables was associated with a higher SMR for death due to a second malignant neoplasm among males, and only treatment with an alkylating agent was associated with a higher SMR for death due to a second malignant neoplasm among females. Both older age group10-19 at diagnosis and treatment with doxorubicin were associated with a higher SMR for death due to cardiac disease among males. There were no deaths due to cardiac disease among the female members of the cohort. The small number of events limits the power of the present analysis to detect differences in the SMRs for the various risk factors examined. Changes in overall and cause-specific mortality rates may be related to changes in supportive care, changes in treatment intensity, and/or changes in referral patterns and may lead to decreases in mortality rates among patients treated during more recent periods. Hudson et al9 reported that the SMRs for the period from 1962 to 1970 and the period from 1971 to 1983 were not significantly different, although there was a significant difference in the actuarial survival rate for those diagnosed during the earlier, compared with the later, period. This difference is most likely the result of the more advanced age, and therefore greater crude mortality rate, among those in the 1962 to 1970 cohort. The present study demonstrated no difference in SMRs or actuarial survival of 15-year survivors treated during the early (1960 to 1970) and more recent (1971 to 1984) periods. This suggests that as death due to the original cancer, the primary cause of death among 5-year survivors, becomes a less prevalent cause of death, as among 15-year survivors, differences in the mortality rate across treatment eras become less significant. The most frequent cause of death in the cohort of 15-year survivors was the original cancer. This is consistent with the findings of several earlier cohort studies of less intensively treated patients. Li et al2 reported that 11% of 5-year survivors who were treated between 1947 and 1969 at the Dana-Farber Cancer Institute subsequently died. The most frequent cause of death among the Dana-Farber Cancer Institute patients was their original cancer. Hawkins et al5 reported that the original cancer was the cause of 74% of deaths and a second malignant neoplasm caused 8% of deaths among 5-year survivors of childhood cancer diagnosed between 1940 and 1982. Robertson et al6 reported that the original cancer was the cause of 74% of deaths, and second malignant neoplasms were the cause of 7% of the deaths among 5-year survivors of childhood cancer diagnosed between 1971 and 1985. Nicholson et al reported excess mortality among a cohort of 5-year survivors of childhood cancer treated between 1945 and 1974, approximately 47.7% of whom were treated with surgery only. Only 20.5% of the members of this cohort received any chemotherapy. The original cancer was the cause of death for 67.5% of the 5-year survivors. Second malignant neoplasms were the cause of 6.8% of the deaths, and cardiac disease was the cause of 3.4% of the deaths.7 Green et al reported that the original cancer was the cause of 84.5% of the deaths, and second malignant neoplasms were responsible for four (5.6%) of the deaths in a cohort of patients treated between 1960 and 1985. Only 10.1% of the members of this cohort were treated with surgery only, and 75.5% received treatment that included chemotherapy.8 In the present study, the most common cause of death, when death was not caused by the original cancer, was a second malignant neoplasm. This finding is consistent with those of studies of 5- and 10-year survivors of childhood cancer.5-7,9 In the present series, as in others,16,17 prior cranial irradiation was associated with the later occurrence of CNS malignancies. Several patients successfully treated for Hodgkin's disease developed second malignant neoplasms. One was characteristic of those observed among individuals who smoked and were treated with thoracic radiation therapy for Hodgkin's disease or breast cancer.18-23 The majority of irradiated patients in the present cohort were treated using a megavoltage radiation source. Treatment with megavoltage irradiation is associated with a lower absorbed bone dosage, and thus with a lower frequency of second malignant bone sarcoma.24 The second most frequent cause of death, excluding the original cancer, was cardiac disease. Some,7 but not all,6,9 other studies have also documented a high frequency of death due to cardiac disease in childhood cancer survivors. Mediastinal irradiation using megavoltage technique is associated with a significant risk of death due to myocardial infarction.25 In addition, modern treatment with combination chemotherapy regimens that include an anthracycline may cause fatal cardiomyopathy, the manifestations of which may only be apparent in the course of a pregnancy or with initiation of a vigorous physical training program.26-29 Several studies have demonstrated that the risk of late cardiac dysfunction is significantly higher among anthracycline-treated females than among anthracycline-treated males.30,31 In addition, experimental32,33 and clinical34-37 findings have documented modulation of effective radiation dose by administration of doxorubicin. In the present study, only one cardiac death was solely attributable to prior anthracycline therapy, and none occurred among the female members of the cohort. A second death occurred in a patient who had received a modest cumulative anthracycline dose and extensive left ventricular irradiation. We conclude that 15-year survivors of cancer diagnosed during childhood or adolescence experience excess mortality. The original cancer is the most frequent cause of death. More successful treatment strategies for the original cancer have the potential to significantly decrease the late mortality rate. The present study demonstrated, in addition, that second malignant neoplasms and cardiac disease were significant causes of late mortality. Thus, strategies to decrease the frequency of exposures associated with an increased risk of second malignant neoplasms, such as the adolescent breast to radiation therapy, strategies to decrease risk-taking behaviors, such as tobacco use,38-43 and strategies to reduce risk factors for ischemic heart disease, such as weight reduction, reduced saturated fat intake and increased exercise, may decrease the rate of late mortality due to treatment-associated complications. These possibilities should be evaluated in well-designed, prospective studies.
Supported in part by a 1997 Developmental Funds Award from the Roswell Park Alliance Foundation and by grant no. R25 CA18201-22 from the Cancer Research Education Training Program, National Cancer Institute, National Institutes of Health. The authors thank Diane Piacente for her assistance with this research.
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Hudson MM, Jones D, Boyett J, et al: Late mortality of long-term survivors of childhood cancer. J Clin Oncol15:2205-2213, 1997 10. International Classification of Diseases 9th Revision: Basic Tabulation With Alphabetical Index. Ann Arbor, MI, World Health Organization, 1978 11. Breslow NE, Day NE: Rates and rate standardization, in Statistical Methods in Cancer Research: The Design and Analysis of Cohort Studies, Volume 2. Lyon, France, International Agency for Research on Cancer, 1987, pp 69-72 12. Neter J, Wasserman W, Kutner MH: Applied Linear Statistical Models: Simultaneous Inferences and Other Topics in Regression Analysis (ed 3). Homewood, IL, Richard D. Irwin, Inc, 1990 13. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc53:457-481, 1958 14. Kalbfleisch JD, Prentice RL: The Statistical Analysis of Failure Time Data. New York, NY, Wiley, 1980, p 159 15. SEER Cancer Incidence Public-Use Database, 1973-1995 August 1997 Submission. Bethesda, MD, U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute, Cancer Statistics Branch, 1998 16. Neglia JP, Meadows AT, Robison LL, et al: Second neoplasms after acute lymphoblastic leukemia in childhood. N Engl J Med325:1330-1336, 1991[Abstract] 17. Ron E, Modan B, Boice JD Jr, et al: Tumors of the brain and nervous system after radiotherapy in childhood. N Engl J Med319:1033-1039, 1988[Abstract] 18. Neugut AI, Robinson E, Lee WC, et al: Lung cancer after radiation therapy for breast cancer. Cancer71:3054-3057, 1993[Medline]
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Inskip PD, Stovall M, Flannery JT: Lung cancer risk and radiation dose among women treated for breast cancer. J Natl Cancer Inst86:983-988, 1994 20. Neugut AI, Murray T, Santos J, et al: Increased risk of lung cancer after breast cancer radiation therapy in cigarette smokers. Cancer73:1615-1620, 1994[Medline]
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Hancock SL, Donaldson SS, Hoppe RT: Cardiac disease following treatment of Hodgkin's disease in children and adolescents. J Clin Oncol11:1208-1215, 1993 26. Goorin AM, Chauvenet AR, Perez-Atayde AR, et al: Initial congestive heart failure six to ten years after doxorubicin chemotherapy for childhood cancer. J Pediatr116:144-147, 1990[Medline] 27. Davis LE, Brown CEL: Peripartum heart failure in a patient treated previously with doxorubicin. Obstet Gynecol71:506-507, 1988[Medline] 28. Katz A, Goldenberg I, Maoz C, et al: Peripartum cardiomyopathy occurring in a patient previously treated with doxorubicin. Am J Med Sci314:399-400, 1997[Medline] 29. Steinherz LJ, Steinherz PG, Tan C: Cardiac failure and dysrhythmias 6-19 years after anthracycline therapy: A series of 15 patients. Med Pediatr Oncol24:352-361, 1995[Medline] 30. Silber JH, Jakacki RI, Larsen RL, et al: Increased risk of cardiac dysfunction after anthracyclines in girls. Med Pediatr Oncol21:477-479, 1993[Medline]
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Lipshultz SE, Lipsitz SR, Mone SM, et al: Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med332:1738-1743, 1995 32. Phillips TL, Wharam MD, Margolis LW: Modification of radiation injury to normal tissues by chemotherapeutic agents. Cancer35:1678-1684, 1975[Medline] 33. Redpath JL, Colman M: The effect of Adriamycin and actinomycin D on radiation induced skin reactions in mouse feet. Int J Radiat Oncol Biol Phys5:483-486, 1979[Medline] 34. Cassady JR, Richter MP, Piro AJ, et al: Radiation Adriamycin interactions: Preliminary clinical observations. Cancer36:946-949, 1975[Medline] 35. Bhanot P, Cushing B, Phillipart A, et al: Hepatic irradiation and Adriamycin cardiotoxicity. J Pediatr95:561-563, 1979[Medline] 36. Pinkel D, Camitta B, Kun L, et al: Doxorubicin cardiomyopathy in children with left-sided Wilms' tumor. Med Pediatr Oncol10:483-488, 1982[Medline] 37. Gerber MA, Gilbert EM, Chung KJ: Adriamycin cardiotoxicity in a child with Wilms tumor. J Pediatr87:629-632, 1975[Medline] 38. Mulhern RK, Tyc VL, Phipps S, et al: Health-related behaviors of survivors of childhood cancer. Med Pediatr Oncol25:159-165, 1995[Medline]
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Troyer H, Holmes GE: Cigarette smoking among childhood cancer survivors. Am J Dis Child142:123, 1988 (letter) 40. Corkery JC, Li FP, McDonald JA, et al: Kids who really shouldn't smoke. N Engl J Med300:1279, 1979 (letter) [Medline] 41. Haupt R, Byrne J, Connelly RR, et al: Smoking habits in survivors of childhood and adolescent cancer. Med Pediatr Oncol20:301-306, 1992[Medline] 42. Green DM, Zevon MA, Hall B: Cigarette smoking among survivors of cancer diagnosed during childhood or adolescence. Proc Am Soc Clin Oncol 16:519a, 1997 (abstr)
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
10 years), treatment era (1960 to 1970, 1971 to 1984), years of initial remission (< 15 years, 
