Anthracylines are widely used in childhood cancer and have significantly contributed to the increased survival rates. However, their use is limited by a dose-dependent toxicity.18 The mechanism for this toxicity is not clear. Among possible mechanisms are the formation of toxic free radicals through mitochondrial pathways19 and direct damage to cardiac myocytes.20 Clinically, anthracycline induced cardiac toxicity is either acute, early- or late-onset. Acute toxicity, occurring immediately or during an infusion of anthracy-cline, is rare (<1%) in children. Early-onset chronic progressive anthracycline induced cardiotoxicity is seen within the first year after treatment and can occur in about 2% of children who have received anthracy-clines.21,22 Late-onset toxicity occurs within 1 year of completion of therapy. At 6 years after anthracycline therapy, 65% of children have been reported to have altered cardiac function.23 The risk of heart failure in these patients, 15-20 years after the start of the therapy is estimated to be 4-5%.22,24 The risk of death due to cardiac related events is eight times higher for long-term survivors than for the normal population.24,25
In both adults and children, the risk of clinical car-diotoxicity increases with the cumulative dose. In children the cumulative toxic dose is around 250-300 mg/m2.26 Most treatment protocols in children limit the maximum cumulative dose of anthracyclines. However, there is no absolute safe dose below which cardiotoxic-ity does not occur.23 Continuous infusion of anthracy-clines reduces peak levels, but also prolongs exposure and as reported in Study 3, there is no evidence to suggest that this decreases the incidence of cardiac toxic-ity.27,28 At the moment, therefore, we have no evidence that prolonging the duration of infusiondecreases car-diotoxicity and the current Medical Research Council trials in childhood leukemia have reduced the duration of infusion of anthracyclines from 6 to 1 hour.
A number of agents have been used to protect the heart from anthracycline induced damage. They include, probucol;29 amifostine,30 carvedilol31 and sildenafil.32 However none of these have been evaluated in context of a randomized trial and it is unclear as to whether they interfere with the anti-tumor activity of anthra-cyclines. The most studied agent is dexrazoxane or ICRF-187.33 A number of randomized controlled trials have reported on the cardioprotectant effect of dexrazoxane. One study, in adults with breast cancer, suggested that the concomitant use of dexrazoxane though cardioprotective, diminished the tumoricidal activity of doxorubicin.34 Study 1 reports that in children with ALL, randomized to receive or not dexrazoxane, cardioprotection is achieved without compromising the anti-tumor effect of doxorubicin.35 Similarly Study 2 suggests that dexrazoxane may be beneficial in decreasing anthracycline induced car-diotoxicity without compromising outcome in childhood sarcoma. It should now be used in the setting of research protocols to evaluate the balance of cardioprotection and possible reduction of anthracycline induced tumoricidal activity.
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