Docetaxel–ifosfamide combination in patients with HER2-non-overexpressing advanced breast cancer failing prior anthracyclines

The feasibility of the docetaxel–ifosfamide combination, as well as the definition of maximum tolerated doses (MTD) in a previous phase I study, led us to continue evaluating the regimen in an extended phase II study in patients with HER2-non-overexpressing, anthracycline pre-treated advanced breast cancer. Patients with histologically confirmed metastatic breast cancer failing prior anthracycline-based chemotherapy were treated with docetaxel 100 mg/m² over 1 h on day 1 followed by ifosfamide 5 g/m² divided over days 1 and 2 (2.5 g/m²/day over 1 h), and recycled every 21 days with prophylactic granulocyte-colony stimulating factor (G-CSF) administration from day 3—until a neutrophil count >10,000/μl. Between March 1999 and June 2002, 71 patients with a median age of 55 years (range, 28–72) and performance status (World Health Organization; WHO) of 1 (range, 0–2) were treated; all were assessable for toxicity and 70 patients for response. Clinical response rates (RRs), on an intention-to-treat basis were: 41/71 [58%; 95% CI, 46.5–69.5%]; 7 complete remissions (CRs), 34 partial remissions (PRs), 15 stable disease (SD) and 15 progressive disease (PD). The median response duration was 7.5 months (2–28 months), median time-to-progression (TTP) 6 months (0.1–30 months), and median overall survival (OS) 12 months (0.1–36 months). Grade 3/4 toxicities included; neutropenia in 63% of patients—with 52% developing grade 4 neutropenia (≥7 days) and in 11% of these febrile neutropenia (FN), while no grade 3/4 thrombocytopenia was observed. Other toxicities included; peripheral neuropathy grade 2 only in 7%, grade 1/2 reversible central nervous system (CNS) toxicity in 11%, no renal toxicity, grade 2 myalgias in 7%, grade 3 diarrhea in 4%, skin/nail toxicity in 11%, and grade 1/2 fluid retention in 28% of patients. The present report has demonstrated encouraging activity of the docetaxel–ifosfamide combination in anthracycline-pretreated, HER2-negative advanced breast cancer. Therefore, future randomized phase III studies versus single-agent docetaxel or currently established combinations of the latter with other agents in this setting with established clinical activity, such as capecitabine or gemcitabine, will be warranted.