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Phase I/II Trial of Cyclophosphamide, Mitoxantrone, and Escalated Doses of Carboplatin Supported by Peripheral-Blood Stem Cells in Women With Metastatic Breast Cancer

From the Department of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, Canada.

Address reprint requests to Michael Crump, MD, FRCPC, Department of Medical Oncology and Hematology, Princess Margaret Hospital, Room 5-108, Toronto, Canada M5G 2M9; email michael.crump{at}uhn.on.ca

PURPOSE: To intensify a regimen of high-dose cyclophosphamide, mitoxantrone, and carboplatin that had previously produced high complete and overall response rates in metastatic breast cancer (MBC).

PATIENTS AND METHODS: Forty-four patients with a median age of 43 years (range, 25 to 57 years) and previously untreated MBC who were responding to anthracycline-based or single-agent taxane chemotherapy received cyclophosphamide 1.5 g/m²/d and mitoxantrone 16 mg/m²/d combined with escalating doses of carboplatin 200 to 500 mg/m²/d, each given daily from days -6 to -3. Hematopoiesis was supported by mobilized peripheral-blood stem cells infused on day 0 and by use of granulocyte-macrophage colony-stimulating factor 300 µg/d subcutaneously starting on day 1.

RESULTS: A total of six dose levels of carboplatin were examined. Grades 3 and 4 toxicity occurred in 10 patients and one patient, respectively, with grade 3 toxicity occurring in only five of 31 patients treated with 400 mg/m² of carboplatin. Major dose-limiting toxicities were cardiac, pulmonary, and renal. Four patients developed congestive heart failure: two had persistently low ejection fraction 11 and 36 months after peripheral-blood stem-cell transplantation (PBSCT), and two recovered. Hematologic recovery to an absolute neutrophil count of greater than 0.5 x 10⁹/L occurred at a median of 11 days (range, 8 to 25 days) and to a platelet count of greater than 20 x 10⁹/L at a median of 10.5 days (range, 6 to 60 days). There were two toxic deaths from sepsis: one on day 27 (level 5) and one from cardiac arrest on day 42 (level 6).

CONCLUSION: The maximum-tolerated dose of carboplatin was 400 mg/m²/d in combination with mitoxantrone 16 mg/m²/d and cyclophosphamide 1,500 mg/m², all drugs given over 4 days. This regimen is being tested in a phase III trial of high-dose chemotherapy and PBSCT versus standard treatment.

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				M. Crump, S. Gluck, D. Tu, D. Stewart, M. Levine, P. Kirkbride, J. Dancey, S. O'Reilly, T. Shore, S. Couban, et al. Randomized Trial of High-Dose Chemotherapy With Autologous Peripheral-Blood Stem-Cell Support Compared With Standard-Dose Chemotherapy in Women With Metastatic Breast Cancer: NCIC MA.16 J. Clin. Oncol., January 1, 2008; 26(1): 37 - 43. [Abstract] [Full Text] [PDF]