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A Phase I Study of Docetaxel Plus Cyclophosphamide in Solid Tumors followed by a Phase II Study as First-Line Therapy in Metastatic Breast Cancer¹

Departments of Sarcoma Medical Oncology [J. C. T., S. P.] and Breast Medical Oncology [V. V., D. J. B., L. T. E-G., N. I., Z. R., J. L. M., M. C., G. N. H.], and Division of Radiology [C. L. D.], The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030, and Aventis Pharmaceuticals, Bridgewater, New Jersey [L. V.]

Purpose: In Phase I, the purpose was to determine the maximum tolerated dose and pharmacokinetics of docetaxel plus cyclophosphamide (DC) with and without granulocyte colony-stimulating factor in the treatment of patients with solid tumors. For Phase II, the purpose was to determine the safety and efficacy of this combination as first-line treatment in patients with metastatic breast cancer (MBC).

Experimental Design: In Phase I (45 patients), docetaxel was escalated from 60 mg/m² to 85 mg/m², and cyclophosphamide from 600 mg/m² to 800 mg/m². Pharmacokinetic evaluation of docetaxel was performed in 19 patients with MBC. In Phase II (34 patients), patients received cyclophosphamide (600 mg/m²) followed by docetaxel (75 mg/m²), i.v.

Results: In Phase I, the dose-limiting toxicity was neutropenia-related events. The maximum tolerated dose for DC was 75 mg/m²/700 mg/m² in solid tumor patients treated previously and 75 mg/m²/800 mg/m² for patients not treated previously for MBC. Dose escalation of docetaxel >75 mg/m² was not tolerated, despite prophylactic granulocyte colony-stimulating factor treatment. In Phase II, 71% of patients received prior anthracycline therapy. Neutropenic fever requiring i.v. antibiotics occurred in 6 patients (19%). One patient had grade 3 neuropathy. There was no cardiotoxicity. The overall Phase II intent-to-treat objective response rate was 65% (complete responses, 12%). The median overall survival was 22 months, and the median time to progression was 6 months.

Conclusions: DC combination therapy is an active regimen with acceptable toxicity and is appropriate regardless of prior anthracycline therapy. In view of the high activity and lack of cardiotoxicity, this combination warrants additional investigation in early stage breast cancer and in combination with trastuzumab.