Risk factors for early anthracycline clinical cardiotoxicity in children: the pediatric oncology group experience

Purpose: To evaluate risk factors for clinical cardiotoxicity from anthracycline chemotherapy in children with cancer and to estimate the relative risk associated with each factor singly and with different combinations of risk factors. Patients and Methods: The study population consisted of 6493 children with cancer who had received anthracycline chemotherapy on Pediatric Oncology Group protocols during the period from 1974 to 1990. Cardiotoxicity, defined as congestive heart failure not due to other causes, abnormal measurements of cardiac function that prompted the discontinuation of therapy, or sudden death from presumed cardiac causes, was determined by a review of protocol records. Results: Cardiotoxicity was confirmed in 106 patients (1.6%): 58 had congestive heart failure, 43 had changes in measures of cardiac function that prompted the discontinuation of therapy and five died suddenly from presumed cardiac causes. In a multivariate analysis, factors contributing to the relative risk (RR) of toxicity were a cumulative dose of anthracycline≥550 mg/m 2 of body-surface area (RR=5.2), a maximal dose of 50 mg/m 2 (RR=2.8), female sex (RR=1.9), black race (RR=1.7), the presence of trisomy 21 (RR=3.4) and exposure to amsacrine (RR=2.6). The relative risk of early clinical cardiotoxicity increased with increasing numbers of risk factors and was projected to exceed 405 when all six statistically significant risk factors were present. Conclusion: Early clinical cardiotoxicity in children treated with anthracycline is rare. A high maximal dose, or cumulative dose of anthracycline, female sex, black race, the presence of trisomy 21 and treatment with amsacrine increase the risk for anthracycline-associated cardiotoxicity. The cumulative effect of multiple risk factors can be estimated as the product of the relative risks associated with each.