Paclitaxel in the treatment of metastatic breast cancer: M.D. Anderson Cancer Center experience.
Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) 250 mg/m2 by 24-hour infusion at 21-day intervals was evaluated at M.D. Anderson Cancer Center as a single agent in patients who had received one prior chemotherapy regimen either as adjuvant therapy or for metastatic disease. Of 25 patients treated, 12% had a complete remission and 44% had a partial response. The median time to progression was 9 months (range, 1 to 20 months). In the next phase of development, a phase I trial evaluated sequentially administered paclitaxel and doxorubicin as initial therapy for metastatic disease. Granulocyte colony-stimulating factor also was administered in each cycle. The dose-limiting toxicity was either stomatitis or neutropenic fever. The maximum tolerated dose (MTD) was 125 mg/m2 for paclitaxel and 48 mg/m2 for doxorubicin. Because of much lower than anticipated MTDs of both drugs in this schedule, it was hypothesized that there may be a schedule-dependent toxicity; therefore, in the second phase I study the schedule of administration was reversed (ie, doxorubicin followed by paclitaxel infusion). The MTDs of this schedule were 60 mg/m2 and 150 mg/m2 for doxorubicin and paclitaxel, respectively. Pharmacokinetic studies subsequently have confirmed that administration of paclitaxel before doxorubicin impairs the elimination of doxorubicin by some unknown mechanism. In an ongoing phase II study, paclitaxel is being evaluated in patients who have received three or more treatments with chemotherapy. Paclitaxel is administered at doses of 135 and 150 mg/m2 (for poor- and good-risk patients, respectively) without granulocyte colony-stimulating factor. Six patients (19%) have shown objective partial responses. Our initial phase II study showed significant antitumor activity for paclitaxel in patients who had received limited prior chemotherapy. Our phase I studies established that initial administration of paclitaxel alters the pharmacokinetics of doxorubicin and increases morbidity. The reverse sequence of administration was associated with better tolerance and a higher MTD. In heavily treated patients this drug also has significant antitumor activity.
Buzdar
A U
AU
Department of Breast and Gynecologic Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Holmes
F A
FA
Hortobagyi
G N
GN
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002986:Clinical Trials as Topic; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012074:Remission Induction; D016019:Survival Analysis
D016179:Granulocyte Colony-Stimulating Factor; D004317:Doxorubicin; D017239:Paclitaxel