Cardiotoxicity is a dose-limiting and potentially lethal complication of anthracycline administration. Previous studies failed to determine definitive toxic doses or cardioprotective factors. Current dosing strategies may utilize unnecessarily high anthracycline doses, such that survival benefit may not outweigh increased toxicity rates. A systematic review of randomized controlled trials and prospective/retrospective studies investigating anthracycline treatment in pediatric solid tumors was performed from PubMed/MEDLINE and Cochrane databases. Generalized linear models mapping survival, cardiotoxicity, and cardiotoxicity-free survival adjusted for male-to-female ratio, follow-up time, and concomitant chemotherapeutic drugs or cardioprotective agents (dexrazoxane) were generated using R. Survival rose linearly with increasing cumulative anthracycline dose whereas cardiotoxicity demonstrated exponential increases both without (dose, >200 mg/m2) and with (dose, >400 mg/m2) dexrazoxane. Maximum cardiotoxicity-free survival was 268.2 mg/m2 without and 431.8 mg/m2 with dexrazoxane. Despite increasing cardiotoxicity-free dose by >150 mg/m2, dexrazoxane minimally improved projected survival (71.9% vs. 75.4%). Cardiotoxicity increased linearly as a function of follow-up time with rates doubling from 5 to 20 years, without evidence of plateau. On the basis of our model, current dosing regimens—doxorubicin doses >375 mg/m2 without dexrazoxane—overvalue increased anthracycline administration and may contribute to devastating cardiotoxicity. The linear increase of cardiotoxicity without evidence of plateau confirms the necessity for lifelong cardiac monitoring.
*Department of Surgery, University of Illinois College of Medicine
†Department of Surgery, Rush University Medical Center
‡Department of Pediatrics, Division of Pediatric Hematology/Oncology
§Department of Surgery, Division of Pediatric Surgery, University of Illinois, Chicago, IL
Supported by National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number R01NS094218.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
The authors declare no conflict of interest.
Reprints: Bill Chiu, MD, Department of Surgery, Division of Pediatric Surgery, University of Illinois at Chicago, 840 S. Wood Street, Suite 416, Chicago, IL 60612 (e-mail: firstname.lastname@example.org).
Received August 17, 2017
Accepted November 30, 2017