Dose-finding study of paclitaxel and cyclophosphamide in advanced breast cancer

Background: The toxicity profile of prolonged infusions of paclitaxel incombination with cyclophosphamide in metastatic breast cancer has already beendefined. The objective of this dose-finding study was to determine the maximumtolerable doses (MTDs) of shorter (three-hour) infusions of paclitaxel incombination with i.v. bolus cyclophosphamide in patients who had previouslyreceived a maximum of one chemotherapy for advanced breast carcinoma. The MTDof the same regimen with granulocyte colony-stimulating factor (G-CSF) supportwas then established.Patients and methods: Eighty women with metastatic breast cancer receiveda total of 352 fully evaluable courses of therapy. The starting doses werepaclitaxel 135 mg/m² and cyclophosphamide 750mg/m² given every three weeks. At least three patients weretreated at each dose level and if there were dose-limiting toxic effectsduring the first cycles three additional patients were entered. G-CSF support(5µg/kg s.c.) was added to the second cycle if specific dose-limitingtoxicitieshad occurred during the first cycle. The MTD was defined as the dose level atwhich more than two of six patients presented dose-limiting toxicities duringthe first cycle.Results: Febrile neutropenia (n = 4) and severe thrombocytopenia (n = 1)defined the MTDs of paclitaxel as 200 mg/m² and ofcyclophosphamide as 2,000 mg/m², with or without G-CSF inpatients with and, respectively, without prior chemotherapy for advanceddisease. Non-hematologic toxicity was moderate. Recommended doses were 200mg/m² of paclitaxel and 1,750 mg/m² ofcyclophosphamide with or without G-CSF in patients with and, respectively,without prior chemotherapy. The overall response rate was 25% and50%, respectively, in patients with and without prior chemotherapy formetastatic disease. Complete remissions (9%) were reported only inpatients without prior chemotherapy; antitumour activity in women withanthracycline-resistant disease, with an 8% response rate (95%CI: 1%–26%), was poor.Conclusions: Paclitaxel at 200 mg/m² and cyclophosphamideat 1,750 mg/m² can be safely administered every three weeksto women with advanced breast cancer. The moderate antitumour activityobserved with the schedule tested argues against its use as initial therapyfor advanced breast cancer.