Paclitaxel by 24-hour infusion with doxorubicin by 48-hour infusion as initial therapy for metastatic breast cancer: Phase I results

Purpose: We and others have demonstrated the antineoplastic efficacy of pac litaxel as a single agent in metastatic breast cancer. We performed this ph ase I trial to evaluate the combination of paclitaxel with doxorubicin. Patients and methods: Eligible patients had measurable or evaluable metasta tic breast cancer for which this was the initial cytotoxic treatment. They may have received adjuvant chemotherapy with other drugs. The study had fou r parts. In part 1, the patients received paclitaxel by 24-hour infusion fo llowed by doxorubicin by 48-hour infusion. The paclitaxel dose was to be es calated from a starting dose of 125 mg/m(2), and the doxorubicin dose was t o remain constant at 60 mg/m(2) with treatment repeated every three weeks. The results of part 1 prompted part 2 which was a study of the reverse sequ ence. Part 3 was a formal study of pharmacology and has been reported (J Cl in Oncol 14: 2713-21, 1996). In part 4, patients received doxorubicin 50 mg /m(2) by bolus followed by paclitaxel 150 mg/m(2) by 24-hour infusion for c ourses 1 and 2. In all subsequent courses doxorubicin was administered by 4 8-hour infusion. All patients in all four parts of the study had baseline c ardiac scans. All patients received standard premedication for paclitaxel. Results: Forty-eight patients were treated in all four parts of the study. In part 1 (10 patients), the maximum tolerated dose (MTD) was paclitaxel 12 5 mg/m(2)/24 hours followed by doxorubicin 48 mg/m(2)/48 hours as defined b y dose-limiting mucositis and neutropenic fever which occurred at the start ing dose. For part 2 (21 patients), the MTD was doxorubicin 60 mg/m(2)/48 h ours followed by paclitaxel 160 mg/m(2)/24 hours. In part 4 (seven patients ), the MTD was doxorubicin 50 mg/m(2)/bolus followed by paclitaxel 135 mg/m (2)/24 hours. In parts 2 and 4, the dose-limiting toxic effect was neutrope nia. Of the entire cohort of 48 patients, seven (15%) had a complete respon se (one persists at five years without intervening therapy), 26 (54%) had a partial response for an objective response rate of 69% (95% confidence int erval (95% CI): 54%-81%). The median follow-up of all living patients is 38 + months (range 20+ to 62+); the median response duration is seven months ( range 2-33.7+); the median overall survival is 20.5 months (range 5-54+). T he median time to progression is 9.6 months (range 1-33.7+ months). Two pat ients developed congestive heart failure, one at 24 months after her final dose of doxorubicin which amounted to a cumulative lifetime total doxorubic in dose of 870 mg/m(2), one after a total of 660 mg/m(2). In both, cardiac symptoms were controlled with medications. Conclusions: The combination of paclitaxel/24 hours with doxorubicin/48 hou rs is an effective antineoplastic treatment for metastatic breast cancer. H owever, the incidence of complete response, the median overall survival, an d time to progression were not greater than for standard doxorubicin-based combinations. Additionally, a sequence-dependent interaction between paclit axel and doxorubicin, given in the schedule described here, was defined. Ot her strategies and schedules should be evaluated to maximize the antineopla stic efficacy of these two potent agents.