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The development of effective antineoplastic therapies for childhood cancer is a great success in modern medicine. Five year survival rates of children diagnosed with cancer in the USA and Western Europe in excess of 70% make long term survivors of childhood cancer a steadily increasing population. Although there is much to celebrate, new challenges lie ahead in treating the systemic sequelae of chemotherapy.1 Results from the Childhood Cancer Survivor Study (CCSS) showed that 30 years after treatment, the cumulative incidence of chronic health conditions in long term survivors reaches 73%, with a cumulative incidence of 42% for severe, disabling, or life threatening conditions or death.2 Severe conditions, that are significantly more common in childhood cancer survivors than in their siblings, include: major joint replacement (relative risk (RR) 54.0), congestive heart failure (RR 15.1), second malignant neoplasm (RR 14.8), severe cognitive dysfunction (RR 10.5), coronary artery disease (RR 10.4), cerebrovascular accident (RR 9.3), and renal failure (RR 8.9).2 Previous CCSS results found that patients who had survived at least 5 years after diagnosis had 10.8-fold increased rates of all cause mortality.3 The standardised mortality ratio for cardiac causes was 8.2 times higher than expected and the cumulative probability of cardiac death increased 15–25 years after cancer diagnosis. A similar study in a large Nordic cohort documented a standardised mortality ratio of 5.8 for cardiac death and elevated rates of sudden, presumed arrhythmic, deaths.4
Chief among adverse late effects is the cardiovascular toxicity of anthracyclines.5–11 Unfortunately, despite well documented dose related toxicity, the superior disease-free survival rates of regimens including anthracyclines leave limited viable treatment alternatives and the majority of long term paediatric cancer survivors in the Pediatric Oncology Group received an anthracycline during treatment.12
NATURAL HISTORY OF ANTHRACYCLINE CARDIOTOXICITY
Mechanism of cardiotoxicity
Several cytotoxic biochemical changes follow anthracycline exposure in …
Funding: This paper has been supported in part by grants from the National Cancer Institute (CA68484-SL, CA34183-SL, CA79060-SL, CA06516-SL, CA127642-SL), National Heart, Lung, and Blood Institute (HL69800-SL, HL53392-SL, HL59837-SL, HL53392-SL), the Lance Armstrong Foundation (SL), the Children’s Cardiomyopathy Foundation (SL), and the Women’s Cancer Association (SL).
Competing interests: In compliance with EBAC/EACCME guidelines, all authors participating in Education in Heart have disclosed potential conflicts of interest that might cause a bias in the article. Dr Lipshultz has investigator-initiated research grants from Pfizer and Novartis and has been a consultant to Chiron, all of whom manufacture dexrazoxane. The other authors indicated no potential financial conflicts of interest.
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