title: 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.
authors.affiliation: Division of Oncology and Hematology, National Cancer Center Hospital East, Kashiwa, Japan. kaito@east.ncc.go.jp
authors.forename: K
authors.initials: K
authors.lastname: Itoh
authors.forename: Y
authors.initials: Y
authors.lastname: Sasaki
authors.forename: H
authors.initials: H
authors.lastname: Fujii
authors.forename: H
authors.initials: H
authors.lastname: Minami
authors.forename: T
authors.initials: T
authors.lastname: Ohtsu
authors.forename: H
authors.initials: H
authors.lastname: Wakita
authors.forename: T
authors.initials: T
authors.lastname: Igarashi
authors.forename: Y
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Y
authors.initials: Y
authors.lastname: Onozawa
authors.forename: M
authors.initials: M
authors.lastname: Kashimura
authors.forename: Y
authors.initials: Y
authors.lastname: Ohashi
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy*; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009503:Neutropenia; D017239:Paclitaxel / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D043823:Taxoids; D013997:Time Factors
chemical_list: D043823:Taxoids; D000077143:Docetaxel; D004317:Doxorubicin; D017239:Paclitaxel