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Dose-Escalation Study of Docetaxel in Combination With Mitoxantrone as First-Line Treatment in Patients With Metastatic Breast Cancer

From the Departments of Medical Oncology and Biostatistics, School of Medicine, University of Crete, Heraklion, Crete, Greece.

Address reprint requests to Vassilis Georgoulias, MD, Department of Medical Oncology, University General Hospital of Heraklion, P.O. Box 1352, 711.10 Heraklion, Crete, Greece; email georgsec@ danae.med.uch.gr.

PURPOSE: To define the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of docetaxel in combination with mitoxantrone in patients with metastatic breast cancer (MBC).

PATIENTS AND METHODS: Forty-one chemotherapy-naive patients with MBC (median age, 61 years) were enrolled. Thirty-eight (93%) had performance status (World Health Organization [WHO]) 0, 29 (71%) were postmenopausal, and 21 (51%) had estrogen receptor–negative tumors. Patients received escalated doses of docetaxel (75 to 100 mg/m²) on day 1 and mitoxantrone (8 to 22 mg/m²) on day 8. Treatment was repeated every 3 weeks.

RESULTS: A total of 217 chemotherapy cycles were administered. Without recombinant human granulocyte colony-stimulating factor (rhG-CSF) support, the MTD1 occurred at the first dose level (docetaxel 75 mg/m² and mitoxantrone 8 mg/m²); DLTs were febrile neutropenia, grade 4 neutropenia lasting more than 5 days, and grade 3 diarrhea. With prophylactic rhG-CSF, the MTD2 was docetaxel 100 mg/m² and mitoxantrone 20 mg/m²; DLTs were febrile neutropenia and grade 4 neutropenia. Nine (22%) patients developed neutropenia after the first cycle of treatment. A total of 19 episodes of febrile neutropenia (9% of the cycles) occurred during the whole period of the study; there were no toxic deaths. At high docetaxel (100 mg/m²) and mitoxantrone (> 12 mg/m²) dose levels, a significant decrease of the absolute lymphocyte number was observed; immunophenotyping revealed that all lymphocyte subpopulations were reduced. Grades 2 and 3 neurosensory toxicity occurred in six patients (15%) and one patient (2%), respectively. No cardiac toxicity was observed. Nine complete responses (22%) and 23 partial responses (56%) were achieved (overall response rate, 78%; 95% confidence interval, 62.5% to 88.8%). The median duration of response was 12.5 months, and the median time to tumor progression was 14.5 months.

CONCLUSION: The reported combination of docetaxel and mitoxantrone with G-CSF support is a safe, intensified, well-tolerated, and effective regimen as first-line treatment in patients with MBC.

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