High-dose paclitaxel in combination with doxorubicin, cyclophosphamide andperipheral blood progenitor cell rescue in patients with high-risk primaryand responding metastatic breast carcinoma: toxicity profile, relationshipto paclitaxel pharmacokinetics and short-term outcome

We assessed the feasibility and pharmacokinetics of high-dose infusional pa clitaxel in combination with doxorubicin, cyclo phosphamide, and peripheral blood progenitor cell rescue. Between October 1995 and June 1998, 63 patie nts with high-risk primary [stage II with greater than or equal to 10 axill ary nodes involved, stage IIIA or stage IIIB inflammatory carcinoma (n = 53 )] or with stage IV responsive breast cancer (n = 10) received paclitaxel 1 50-775 mg/m(2) infused over 24 hours, doxorubicin 165 mg/m(2) as a continuo us infusion over 96 hours, and cyclophosphamide 100 mg kg(-1). There were n o treatment-related deaths. Dose-limiting toxicity was reversible, predomin antly sensory neuropathy following administration of paclitaxel at the 775 mg/m(2) dose level. Paclitaxel pharmacokinetics were non-linear at higher d ose levels; higher paclitaxel dose level, AUC, and peak concentrations were associated with increased incidence of paraesthesias. No correlation betwe en stomatitis, haematopoietic toxicities, and paclitaxel dose or pharmacoki netics was found. Kaplan-Meier estimates of 30-month event-free and overall survival for patients with primary breast carcinoma are 65% (95% CI; 51-83 %) and 77% (95% CI; 64-93%). Paclitaxel up to 725 mg/m(2) infused over 24 h ours in combination with with doxorubicin 165 mg/m(2) and cyclophosphamide 100 mg kg-l is tolerable. A randomized study testing this regimen against h igh-dose carboplatin, thiotepa and cyclophosphamide (STAMP V) is currently ongoing. (C) 2001 Cancer Research Campaign.