Ninety-six-hour paclitaxel infusion after progression during short taxane exposure: A phase II pharmacokinetic and pharmacodynamic study in metastatic breast cancer

Purpose: A phase II trial of paclitaxel infused over 96 hours in patients with metastatic breast cancer with demonstrated disease progression (PD) during short-infusion taxane treatment was performed to evaluate schedule-dependent activity with prolonged drug exposure. The tolerability of this strategy and its pharmacokinetic profile and pharmacodynamic correlates were also investigated. Patients and Methods: Paclitaxel was administered to 26 patients with metastatic breast cancer at 120 to 140 mg/m(2) intravenously over 96 hours. Twenty-three patients had demonstrated PD while receiving prior 3-hour paclitaxel, two during 1-hour docetaxel, and one during infusions of docetaxel and then paclitaxel. Twenty-one patients (81%) had no prior response to the short taxane infusion (primary resistance) and five (19%) had prior partial responses (PRs) of brief duration before PD (secondary resistance). Plasma paclitaxel concentrations were assessed at 24, 48, 72, and 96 hours. Results: After delivery of 195 cycles, seven of 26 assessable patients (26.9%; 95% confidence interval, 11.6% to 47.8%) had major objective responses, with a median response duration of 6 months (range, 1 to 13). The predomi-nant toxicities were neutropenia (76% grade greater than or equal to 3) and stomatitis (15% grade greater than or equal to 3). Despite omission of premedications, no significant hypersensitivity reactions occurred. The median steady-state paclitaxel concentration (Css) in 23 assessable patients wets 0.047 mu mol/L (range, .023 to .176). Patients who experienced grade 4 neutropenia had significantly decreased paclitaxel clearance and higher Css than those with grade 1 to 3 neutropenia (P < .05). Pretreatment elevation of hepatic transaminases was associated with delayed clearance (P < .01)and increased myelosuppression and mucosal toxicity. Conclusion: Paclitaxel demonstrates activity against metastatic breast cancer when administered over 96 hours to patients with disease that recently had progressed during short taxane exposure. Delayed paclitaxel clearance and consequent increased toxicity occured in patients with hepatic dysfunction. The activity observed supports preclinical data that suggest variability in efficacy and resistance patterns to paclitaxel based on duration of exposure. (C) 1996 by American Society of Clinical Oncology.