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

Abstract

The objectives of the present study were to evaluate whether a schedule-dependent pharmacokinetic and/or pharmacodynamic interaction exists between two sequences of docetaxel and doxorubicin administration and to determine the maximal tolerated dose (MTD) of this combination. Patients with chemotherapy-naïve metastatic or recurrent advanced breast cancer were enrolled. In the crossover design, tandem dose escalation of docetaxel and doxorubicin was performed. Docetaxel, in doses ranging from 50-70 mg/m2, was administered 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/ m2. The sequence of drug administration was switched after the first course in each patient, and the sequence of drug administration thereafter depended on the patient's choice. Twenty-five patients were initially assessable for toxicity. The MTD in the sequence of doxorubicin after docetaxel was 40 and 50 mg/m2, respectively, 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/m2, respectively. The dose-limiting toxicities in this sequence were neutropenia and diarrhea. Duration of grade 4 neutropenia in the sequence of docetaxel followed by doxorubicin was significantly longer than that in the alternate sequence (P = 0.0062). However, there was no difference in pharmacokinetic parameters of docetaxel, doxorubicin, and doxorubicinol between the two sequences. The sequence of 50 mg/m2 doxorubicin followed by 60 mg/m2 docetaxel is recommended for subsequent clinical trials for practical reasons.

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@article{Itoh2000StudyOD, title={Study of dose escalation and sequence switching of administration of the combination of docetaxel and doxorubicin in advanced breast cancer.}, author={Kuniaki Itoh and Yu Sasaki and Hiromasa Fujii and Hitomi Minami and Tomoko Ohtsu and Hisasi Wakita and Tatsuo Igarashi and Yasuhiro Watanabe and Yusuke Onozawa and Masamichi Kashimura and Yasuo Ohashi}, journal={Clinical cancer research : an official journal of the American Association for Cancer Research}, year={2000}, volume={6 10}, pages={4082-90} }