Optimize administration protocol of capecitabine plus docetaxel combination in metastatic breast cancer patients

Combining several cytotoxics is the current mainstay for treating breast cancer patients. The combination between capecitabine and docetaxel was found to be more efficient than capecitabine or docetaxel when both were used as single agents. However, the administration protocol for this combination has been empirically chosen from single-agent trials. Based on already available population analysis, we propose here to optimize the administration protocol of this association so as to enhance efficacy while limiting treatment-related toxicity. Efficacy parameters evaluated from population analysis using a disturbed tumor growth model and safety characteristics from the available databases evidenced that: 1) Docetaxel is more efficient than capecitabine at the start of the treatment, but becomes less efficient next because of acquisition of resistance; 2) Over a long period of time, capecitabine is better tolerated than docetaxel. These characteristics allowed the following recommendations for an optimized modality of combination: 1) The treatment has to be started at the maximum tolerated dose for docetaxel; this dose should be individualized right from the start of the second cycle of treatment; 2) In parallel, capecitabine has to be started at a dose lower than its maximum tolerated dose. 3) When docetaxel becomes less efficient than capecitabine because of resistance, docetaxel dose has to be reduced but not discontinued. 4) If adverse events show during the treatment, it is recommended to reduce docetaxel, rather than capecitabine dosage. Combining modeling and statistical analysis of clinical data permit to optimize combination treatments. This procedure could be extended to others treatments involving combination of several cytotoxics.