A Phase I/II study of paclitaxel and doxorubicin in the treatment of advanced breast cancer.

We designed a clinical study in which fixed doses of doxorubicin were infused by intravenous bolus 16 hours before escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, princeton, NJ) for the treatment of patients with advanced breast cancer, an interval selected to allow systemic clearance of doxorubicin before administration of paclitaxel in an outpatient setting. Courses of fixed-dose doxorubicin 50 mg/m2 by intravenous bolus and paclitaxel (doses escalated from 130 mg/m2 to 250 mg/m2 via dose escalation of 30 mg/m2) were repeated every 21 days, to a maximum of eight cycles. Maximum tolerated dose was reached if two or more of six patients at a given dose level were affected by the following events: absolute neutrophil count less than 500/microliter for > or = 7 days, absolute neutrophil count less than 100/microliter for > or = 3 days, insufficient hematopoietic recovery with absolute neutrophil count less than 1,500/microliter on day 21, febrile neutropenia, grade 4 thrombocytopenia, any World Health Organization grade 3 nonhematologic toxicity for more than 7 days. There were 19 patients enrolled; the patients received a total of 128 treatment courses. Grade 4 neutropenia was the main side effect, occurring in 20% of courses but generally not associated with clinical events. No relevant clinical cardiac toxicity or alteration of left ventricular ejection fraction was observed. Other toxicities included complete alopecia, mild peripheral neuropathy, and mild myalgia. There was a reduction of one dose level for moderate myalgia in one patient (190 mg/m2 level). Complete alopecia was always present. Maximum tolerated dose was not reached at paclitaxel 250 mg/m2. Ultimately, the introduction of this combination in the adjuvant setting is warranted.