Phase II Evaluation of Methotrexate, Vinblastine, Doxorubicin, and Cisplatin (M-VAC) in Advanced, Measurable Breast Carcinoma

Abstract

The purpose of this study was to determine whether methotrexate, vinblastine, doxorubicin, and cisplatin, each individually active in metastatic breast cancer (MBC), could, in combination, produce an overall response rate, median survival, and long-term survival sufficiently promising to merit its consideration for phase 111 trials in MBC and as induction therapy prior to autologous bone marrow transplant. From July 1986 through February 1990,30patients with stage IV, measurable breast carcinoma received M-VAC: methotrexate–30 mglm days 1,15, 22; vinblastine–3 mg/m² days 2, 15, 22; doxorubicin–30 mglm day 2; cisplatin–70 mglm day 2. Cycles were repeated at 4-week intervals for up to six courses. Median age was 53 years (range 34–64 years). Prior treatment included adjuvant cyclophosphamide, methotrexate, and 5-Fluorouracil in 12 patients, radiotherapy in 13 patients, and hormonal therapy in 14 patients. Eleven patients were ER (+) at the time of initial diagnosis. Five patients had disease restricted to bone and/or nodes; the other 25 had visceral-dominant sites of metastases, with or without bone involvement, or evidence of rapid, inflammatory chest wall relapse. Twenty-nine of 30 patients were evaluablefor toxicity and response; all were evaluablefor survival. The major overall response rate was 83%, with a 21% complete remission rate. The chief toxicity was bone marrow suppression, with grade 4 granulocytopenia in 20 patients, grade 3 in 7 patients, and grade 3 and 4 thrombocytopenia in 5 patients. Grade 3 stomatitis occurred in 9 patients. Renal insufficiency was clinically insignificant, and neurotoxicity mild, with 7patients sustaining grade I or 2 paresthesias. Median time to progression was 9 months and median survival 19 months (range, 5–84+ months) with 4 patients still alive at least 45 + months or more from the start of treatment and 2 presently free of progressive disease. Although highly toxic, M-VAC produces a response rate and survival duration in visceral-dominant MBC competitive with, if not superior to, conventional regimens such as CAF (Cytoxan, doxorubicin, 5-fluorouracil); it therefore merits further investigation in conjunction with hematopoietic growth factors and as cytoreductive therapy prior to autologous bone marrow transplantation.