New directions with capecitabine combinations in advanced breast cancer.

Capecitabine (Xeloda) offers a unique mode of action. The drug is currently being combined with other active agents in the treatment of advanced breast cancer. The recent demonstration of improved disease-free and overall survival with the capecitabine/docetaxel (Taxotere) combination, for example, has encouraged investigation of additional capecitabine/taxane regimens and schedules. A unique aspect of the metabolic activation of capecitabine is the ability of several anticancer drugs to upregulate the critical activating enzyme thymidine phosphorylase. These preclinical findings have led to clinical trials of several active agents in combination with capecitabine demonstrating high response rates in early results. In combination studies, capecitabine has been associated with very manageable toxicity. The combination of docetaxel/epirubicin (Ellence)/capecitabine (TEX) has shown particular promise in advanced disease, and should be evaluated in earlier disease. TEX is currently in phase III trials of advanced disease. In preclinical studies, the combination of capecitabine with inhibitors of HER2/neu (or the epidermal growth factor pathway) appears to hold significant promise both in breast cancer treatment and in treatment of other tumors expressing these receptors. Continued evaluation of capecitabine combinations will help to define the roles of this valuable agent, the only oral fluoropyrimidine for treatment of breast cancer available in the United States.