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.
Keywords: Optimization, efficacy, safety, combination, capecitabine, docetaxel, modeling, population analysis
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