PHASE I II STUDY OF 72-HOUR INFUSIONAL PACLITAXEL AND DOXORUBICIN WITH GRANULOCYTE-COLONY-STIMULATING FACTOR IN PATIENTS WITH METASTATIC BREAST-CANCER/

Purpose: We conducted a phase I/II trial of concurrently administered 72-hour infusional paclitaxel and doxorubicin in combination with gran ulocyte colony-stimulating factor (G-CSF) in patients with previously untreated metastatic breast cancer and bidimensionally measurable dise ase. Patients and Methods: We defined the maximum-tolerated dose (MTD) of concurrent paclitaxel and doxorubicin administration and then stud ied potential pharmacokinetic interactions between the two drugs. Fort y-two patients who had not received prior chemotherapy for metastatic breast cancer received 296 total cycles of paclitaxel and doxorubicin with G-CSF. Results: The MTD was determined to be paclitaxel 180 mg/m( 2) and doxorubicin 60 mg/m(2) each by 72-hour infusion with G-CSF. Dia rrhea was the dose-limiting toxicity (DLT) of this combination, with t hree of three patients developing abdominal computed tomographic (CT) scan evidence of typhlitis (cecal thickening) at the dose level above the MTD. All patients developed grade 4 neutropenia (absolute neutroph il count [ANC] < 500/mu L), generally less than 5 days in duration. Th is combination was generally safely administered at dose levels at or below the MTD. The overall response rate was 72% (28 of 39 patients; 9 5% confidence interval [CI], 55% to 85%), with 8% complete responses ( CRs) (three of 39; 95% CI, 2% to 21%) and a median response duration o f 9 months. The median overall survival time for all patients is 23 mo nths, with a median follow-up duration of 28 months. Pharmacokinetic s tudies showed that administration of paclitaxel and doxorubicin togeth er by 72-hour infusion did not affect the steady-state concentrations of either drug. Conclusion: Concurrent 72-hour infusional paclitaxel n d doxorubicin can be administered safely, but is associated with signi ficant toxicity. The overall response rate of this combination in untr eated metastatic breast cancer patients is similar to that achieved wi th other doxorubicin-based combination regimens. The modest complete r esponse rate achieved suggests that this schedule of paclitaxel and do xorubicin administration does not produce significant additive or syne rgistic cytotoxicity against breast cancer.