DOSE-FINDING STUDY OF PACLITAXEL AND CYCLOPHOSPHAMIDE IN ADVANCED BREAST-CANCER

Background: The toxicity profile of prolonged infusions of paclitaxel in combination with cyclophosphamide in metastatic breast cancer has a lready been defined. The objective of this dose-finding study was to d etermine the maximum tolerable doses (MTDs) of shorter (three-hour) in fusions of paclitaxel in combination with i.v. bolus cyclophosphamide in patients who had previously received a maximum of one chemotherapy for advanced breast carcinoma. The MTD of the same regimen with granul ocyte colony-stimulating factor (G-CSF) support was then established. Patients and methods: Eighty women with metastatic breast cancer recei ved a total of 352 fully evaluable courses of therapy. The starting do ses were paclitaxel 135 mg/m(2) and cyclophosphamide 750 mg/m(2) given every three weeks. At least three patients were treated at each dose level and if there were dose-limiting toxic effects during the first c ycles three additional patients were entered. G-CSF support (5 mu g/kg s.c.) was added to the second cycle if specific dose-limiting toxicit ies had occurred during the first cycle. The MTD was defined as the do se level at which more than two of six patients presented dose-limitin g toxicities during the first cycle. Results: Febrile neutropenia (n = 4) and severe thrombocytopenia (n = 1) defined the MTDs of paclitaxel as 200 mg/m(2) and of cyclophosphamide as 2,000 mg/m(2) with or witho ut G-CSF in patients with and, respectively, without prior chemotherap y for advanced disease. Non-hematologic toxicity was moderate. Recomme nded doses were 200 mg/m(2) of paclitaxel and 1,750 mg/m(2) of cycloph osphamide with or without G-CSF in patients with and, respectively, wi thout prior chemotherapy. The overall response rate was 25% and 50%, r espectively, in patients with and without prior chemotherapy for metas tatic disease. Complete remissions (9%) were reported only in patients without prior chemotherapy; antitumour activity in women with anthrac ycline-resistant disease, with an 8% response rate (95% CI: 1%-26%), w as poor. Conclusions: Paclitaxel at 200 mg/m(2) and cyclophosphamide a t 1,750 mg/m(2) can be safely administered every three weeks to women with advanced breast cancer. The moderate antitumour activity observed with the schedule tested argues against its use as initial therapy fo r advanced breast cancer.