Dexrazoxane in Children With Cancer: From Evidence to Practice

Anthracyclines are used to treat different types of childhood cancer. Unfortunately, one of the most important adverse effects is cardiotoxicity, and the risk of developing cardiac disease is lifelong. The consequences of cardiac disease are extensive: it impairs the quality of life and can cause premature death. Prevention of cardiac disease is thus very important. One of the most widely investigated possible cardioprotective agents is dexrazoxane. For years, there has been extensive interest in whether it can be used to prevent heart failure in children with cancer treated with anthracyclines, focusing on cardioprotection, antitumor efficacy (ie, survival and treatment response), and adverse effects such as secondary malignant disease. The study by Chow et al adds important information to this discussion. The focus of their study was on late mortality after dexrazoxane treatment in three Children’s Oncology Group randomized controlled trials (RCTs) that included more than 1,000 children with leukemia or lymphoma. Median follow-up was 12.6 years. Overall mortality was similar in patients treated with or without dexrazoxane (hazard ratio, 1.03; 95% CI, 0.73 to 1.45). Dexrazoxane was not significantly associated with differential causes of death, including secondary malignant disease. Will this study change current clinical practice, that is, should dexrazoxane be used in children treated with anthracyclines? To give insight into the complexity of this question, we provide a short overview of the available evidence and discuss the translation to clinical practice. Although anthracyclines remain among the most widely used chemotherapeutic drugs in the treatment of childhood cancer, there is surprisingly sparse evidence from well-designed RCTs to support a survival benefit of these agents. Evidence supporting the use of anthracyclines is based mostly on noncontrolled trials or studies with a historical control group. In addition, a substantial amount of data from RCTs and observational studies showed the association between a higher dose of anthracyclines and a higher risk of both asymptomatic and symptomatic cardiac dysfunction. Cumulative doses of 100 mg/m or less have the lowest risk, whereas cumulative doses of 250 mg/m or higher have the highest. It is important to keep in mind that there is no safe anthracycline dose; cardiac disease can occur at low doses, suggesting that other factors like genetic variants might influence the risk of developing cardiotoxicity. Other risk factors are, for example, chest radiation (cumulative dose above 15 Gy) and the combination of anthracyclines and chest radiation, although the evidence for an increased risk with a lower age at anthracycline exposure is conflicting. A longer time from anthracycline exposure also seems to increase the risk of clinical heart failure. In the Childhood Cancer Survivor Study, the cumulative incidence of congestive heart failure 30 years after cancer diagnosis (as reported by the survivors themselves) was estimated to be 4.1% (95% CI, 3.2 to 5.0%); a substantial part of these survivors were treated with anthracyclines. In a study based on information from medical records, the cumulative incidence of clinical heart failure 30 years after primary cancer diagnosis was estimated to be 7.5% (95% CI, 3.6 to 11.2%) in childhood cancer survivors treated with anthracyclines. These are high risks, especially when we realize that these survivors are still young. Several strategies to prevent cardiotoxicity have been suggested. The most effective one would be to avoid the use of anthracyclines altogether if anthracyclines could be proven to have no added value with regard to antitumor efficacy. Although there is no safe dose, another option is to limit the cumulative anthracycline dose. Other strategies to consider include longer anthracycline infusion durations and different anthracycline analogs like doxorubicin, daunorubicin, epirubicin, and liposomal variants. However, although some of these strategies are promising in adults, high-quality evidence in pediatric patients with cancer is currently still lacking. Another approach to prevent cardiotoxicity is the use of cardioprotective agents such as dexrazoxane, N-acetylcysteine, and L-carnitine. Dexrazoxane has been described as one of the most promising preventive agents. For clinical decision making, the most important clinical outcomes to measure the cardioprotective effect of dexrazoxane seem to be clinical heart failure, both short and long term, and cardiac death. The protective effect of dexrazoxane on the development of clinical heart failure has been evaluated in several RCTs. The pooled analysis of available RCTs in a Cochrane systematic review showed a high cardioprotective effect in favor of dexrazoxane for the occurrence of clinical heart failure (risk ratio [RR], 0.18; 95% CI, 0.10 to 0.32). However, the included patients were mainly adults. In children, only a few RCTs have been performed, and these studies mainly analyzed the effect of dexrazoxane on surrogate markers for clinical heart failure. Until now, no studies have focused on outcomes such as very longterm clinical heart failure or cardiac death. Likewise, the most important potential harms of using dexrazoxane are mortality, possible influence on overall survival, and the occurrence of secondary malignant disease. The Cochrane review did not find evidence for a difference in overall survival (hazard ratio, 1.04; 95% CI, 0.88 to 1.23) or secondary malignant disease between the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 24 AUGUST 2