Use of dexrazoxane and other strategies to prevent cardiomyopathy associated with doxorubicin-taxane combinations

Doxorubicin (DOX) plus paclitaxel is an active combination for patients with metastatic breast cancer, producing objective response in approximately 50% to 90% of patients. The drugs may be combined using different doses and schedules. When 60 mg/m² of DOX is given by intravenous bolus followed 15 to 30 minutes later by 200 mg/m² of paclitaxel (given as a 3-hour infusion), approximately 20% of patients will have a substantial decrease in their left ventricular ejection fraction below normal after four cycles of therapy (or a cumulative DOX dose of 240 mg/m²). Approximately 4% will have symptoms of congestive heart failure. After eight cycles of therapy, or a cumulative DOX dose of 480 mg/m², approximately 50% of patients will have a decrease in left ventricular ejection fraction below normal and 20% of patients will develop clinical evidence of congestive heart failure. This is a higher than expected incidence of congestive heart failure when compared with retrospectively derived historical data. Paclitaxel increases the area under the curve of DOX by approximately 30% when given before or after DOX, providing an explanation for this phenomenon. Several strategies seem to be associated with a reduced incidence of cardiac toxicity, including the use of dexrazoxane with the combination, restricting the cumulative DOX dose to ≤360 mg/m², increasing the interval between administration of the drugs, and use of other taxanes (eg, docetaxel) or other less cardiotoxic anthracyclines (eg, epirubicin or liposomal DOX). Most of these strategies were evaluated in noncomparative phase I/II trials, and further study will be required to determine the role of anthracycline-taxane combinations in the management of patients with operable and advanced breast cancer, and to determine a combination that has the most favorable therapeutic index.