Study of dose escalation and sequence switching of administration of the combination of docetaxel and doxorubicin in advanced breast cancer

The objectives of the present study mere to evaluate whether a schedule-dep endent pharmacokinetic and/or pharmacodynamic interaction exists between tw o sequences of docetaxel and doxorubicin administration and to determine th e maximal tolerated dose (MTD) of this combination. Patients with chemother apy-naive metastatic or recurrent advanced breast cancer were enrolled. In the crossover design, tandem dose escalation of docetaxel and doxorrbicin w as performed. Docetaxel, in doses ranging from 50-70 mg/m(2), was administe red for 1 h by drip infusion either just before or after a 5-min bolus i.v, injection of doxorubicin at dosages from 40-50 mg/m(2). The sequence of dr ug administration was switched after the first course in each patient, and the sequence of drug administration thereafter depended on the patient's ch oice. Twenty-five patients were initially assessable for toxicity. The MTD in the sequence of doxorubicin after docetaxel was 40 and 50 mg/m(2), respe ctively, with the dose-limiting toxicity of neutropenia. On the other hand, the MTD of the sequence of docetaxel after doxorubicin was 70 and 50 mg/m( 2), respectively. The dose-limiting toxicities in this sequence were neutro penia and diarrhea, Duration of grade 4 neutropenia in the sequence of doce taxel followed by doxorubicin was significantly longer than that in the alt ernate sequence (P = 0,0062), However, there was no difference in pharmacok inetic parameters of docetaxel, doxorubicin, and doxorubicinol between the two sequences. The sequence of 50 mg/m(2) doxorubicin followed by 60 mg/m(2 ) docetaxel is recommended for subsequent clinical trials for practical rea sons.