From the Department of Pediatric Oncology, Dana-Farber Cancer Institute, Division of Hematology/Oncology, Department of Medicine, Children's Hospital, and Harvard Medical School, Boston, Massachusetts; and Department of Pediatrics, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Stephen E. Sallan, MD, Dana-Farber Cancer Institute , 44 Binney Street, Boston, MA 02115; e-mail: stephen_sallan{at}dfci.harvard.edu
Overview: Improved therapies for childhood cancers have greatly increased the number of survivors; however, they are associated with long-term adverse effects. One of the most common and problematic late effects of treatment is cardiac dysfunction resulting from previous therapy with anthracyclines. Risk factors of anthracycline-induced cardiotoxicity include a higher total cumulative dose, younger age at administration, and female sex; however, these risk factors do not identify all patients who will show evidence of anthracycline-associated cardiac damage. Because patients with asymptomatic idiopathic dilated cardiomyopathy have a 7-year mortality rate of 50%, the importance of understanding the natural history of anthracycline-induced cardiotoxicity is clear. Keeping the total cumulative dose of doxorubicin less than 550 mg/m2 reduces late toxicity but even survivors who received low cumulative doses develop echocardiographic abnormalities long after therapy. Minimizing high peak concentrations with continuous intravenous administration reduces cardiotoxicity for adults but has not been confirmed for children. Dexrazoxane prevents acute cardiac deterioration during anthracycline chemotherapy without compromising efficacy, but its long-term effect is unknown. More than 20% of children treated with dexrazoxane still show serologic evidence of acute cardiac injury, indicating that dexrazoxane does not offer complete protection. Anthracycline interacts with iron in the heart muscle, and as such, conditions leading to higher tissue levels of iron may predispose patients to cardiotoxicity. Mutations of the hemochromatosis gene or other genes linked to increased iron stores may increase susceptibility to doxorubicin cardiotoxicity. Several misconceptions have contributed to the current practice of withholding dexrazoxane from children treated with doxorubicin.
