Doxorubicin/taxane combinations: cardiac toxicity and pharmacokinetics

Doxorubicin and the taxanes, paclitaxel and docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA), are among the most active cytotoxic agents for the treatment of metastatic breast cancer. Given their activity, relative non-cross-resistance, partially non-overlapping toxicities, and differing mechanisms of action, there is a clear rationale for combining these agents for both advanced and early stage disease. Phase I and II trials have been reported for both doxorubicin/paclitaxel and doxorubicin/docetaxel. Response rates have been generally high for both combinations. Some groups have reported an unacceptably high risk of congestive heart failure in patients treated with some schedules of doxorubicin/paclitaxel if the cumulative doxorubicin dose exceeded 360 mg/m2. A similar effect has not been observed with doxorubicin/docetaxel combinations. This is likely explained by a pharmacokinetic interference of doxorubicin elimination by paclitaxel, an effect that is highly dependent on the interval between administration of the drugs and the duration of the paclitaxel drug infusion. Such an interaction has not been observed with doxorubicin/docetaxel, providing an explanation for the lack of enhanced cardiotoxicity with docetaxel-containing combination. Phase III trials comparing doxorubicin/taxane combinations with standard regimens have been completed and are in progress, and should help define whether the use of these drugs in combination offers any advantage over their use in a sequential fashion in both early and advanced disease.