Dexrazoxane and Prevention of Anthracycline-Related Cardiomyopathy

PROJECT SUMMARY Five-year survival among children with cancer now exceeds 80%. Late cardiovascular disease, including cancer therapy-related cardiomyopathy/heart failure (CHF), has now become the leading non-cancer cause of premature morbidity and mortality among childhood cancer survivors. Anthracycline and related drugs have been well-documented to be the single most important risk factor associated with subsequent development of CHF among cancer survivors. Anthracyclines, despite their known cardiotoxicity, continue to be an integral part of many contemporary pediatric cancer treatment protocols. Dexrazoxane (DRZ) is an EDTA-like bisdioxopiperazine that decreases oxygen free radicals via intracellular iron chelation, and is FDA-approved for use as a cardioprotectant in adults being treated with high-dose anthracyclines for breast cancer. The American Society of Clinical Oncology recommends considering its use for all adults exposed to high doses of anthracyclines. However, concerns regarding DRZ?s safety and efficacy have limited its use in children. Four national phase 3 clinical trials that featured upfront DRZ randomization were conducted among more than 1,200 children with leukemias and lymphomas from 1995-2001. Patients were treated with a range of anthracycline (specifically, doxorubicin) doses still commonly used today. While some short- and intermediate- term data up to 5-years from these trials suggest that DRZ-exposed children had less acute cardiotoxicity and pathologic left ventricular remodeling, longer term data are lacking. The proposed research will attempt to ascertain long-term cardiovascular health in this population of childhood cancer survivors now that 15-20 years have elapsed since cancer diagnosis. Specifically, we will leverage the study infrastructure we have developed within the Children?s Oncology Group (COG; a member of the NCI?s National Clinical Trials Network) in order to prospectively ascertain current cardiac function via echocardiography and overall cardiovascular health among at least 200 survivors. This sample size will allow us to definitively determine if survivors randomized to DRZ have decreased markers of CHF compared with those treated on the standard non-DRZ arms. We will then combine prospective echocardiographic data with archived data collected by the original clinical trialists and those available from participating COG institutions to examine whether DRZ exposure is associated with a differential trajectory of echocardiographic change over time. Finally, we will deploy a variety of approaches, including use of administrative and insurance databases, to capture long-term adverse health outcomes from almost the entire study population. We believe successful completion of the proposed research will allow us to determine whether DRZ provides long-term cardioprotection, with immediate clinical implications for current patients and drug regulatory policy.