PACLITAXEL BY 3-HOUR INFUSION IN COMBINATION WITH BOLUS DOXORUBICIN IN WOMEN WITH UNTREATED METASTATIC BREAST-CANCER - HIGH ANTITUMOR EFFICACY AND CARDIAC EFFECTS IN A DOSE-FINDING AND SEQUENCE-FINDING STUDY

Purpose: To define the maximum-tolerated dose (MTD) better tolerated s equence of paclitaxel by 3-hour infusion plus bolus doxorubicin (DOX) and to evaluate antitumor efficacy. Patients and Methods: Thirty-five women with metastases breast cancer (dominant visceral metastases in 5 6%, and involvement of greater than or equal to three sites in 67%) wh o never received chemotherapy of any type were studied. Paclitaxel eve ry 3 weeks (125 mg/m(2) starting dose) was increased by 25-mg/m(2) ste ps in subsequent cohorts of patients. DOX (60 mg/m(2) fixed dose) was administered 15 minutes before the start of or after the end of paclit axel for a maximum of eight cycles. Subsequently, patients in continuo us response could receive single-agent paclitaxel (175 to 200 mg/m(2) every 3 weeks). The drug sequence was alternated in consecutive patien ts and in the first two cycles. Results: Severe neutropenia that laste d greater than 7 days (n = 4), febrile neutropenia (n = 7) and grade I II oral mucositis (n = 6) defined the MTD of paclitaxel at 200 mg/m(2) in 34 assessable patients. Grade II peripheral neuropathy occurred in 33% of patients. Six women (18%) developed clinically reversible cong estive heart failure (CHF) after a median of 480 mg/m(2) total DOX. Dr ug sequence had no effect on toxicities. High efficacy on all metastat ic sites in 32 assessable patients accounted for a 41% complete respon se (CR) rate (95% confidence interval [CI], 24% to 59%) and 94% overal l-response rate (95% CI, 79% to 99%). After a median follow-up of 12 m onths (range 3 to 18), the median response duration is 8 months (range , 2+ to 18+) for complete responders and 11 months (range 1+ to 15+) f or partial responders. Conclusion: The rate of CR and incidence of CHF may be an expression of therapeutic and toxic enhancement due to the schedule used in this trial. Until clarification of this possibility, this promising combination should be used in investigational trials. ( C) 1995 by American Society of Clinical Oncology.