Mitoxantrone plus vinorelbine with granulocyte-colony stimulating factor (G-CSF) support in advanced breast cancer patients. A dose and schedule finding study

Summary Mitoxantrone (MTZ) and vinorelbine (VNR) have shown a good efficacy in advanced breast cancer. We conducted a phase I-II trial to determine the MTDs and best schedule of these drugs, in advanced breast cancer patients, when granulocyte-colony stimulating factor (G-CSF) support was given. The starting dose-intensity level was MTZ 3 mg/m²/week + VNR 15 mg/m²/week; dose was escalated at each step by 1 mg/m²/week for MTZ and 5 mg/m²/week for VNR, until dose limiting toxicity (DLT) developed in 33% or more of the patients at the first course. G-CSF 5 µg/kg/day d 3–13 was administered at each cycle from dose level 2 on. For each dose step we planned 3 different schedules (a = total dose of MTZ on day 1; b = total dose d 1 and 8; c = weekly schedule). At the time of this analysis (December 1993) 43 patients with locoregionally advanced or metastatic breast cancer have entered this study, 23 of whom had received prior chemotherapy other than adjuvant. Toxicity has been primarily hematologic. Non hematologic toxicity never caused interruption of dose escalation.Overall 8 patients developed DLT at the first course. Dose escalation was stopped at level 3 in patients receiving schedules a or b, and in those receiving schedule c the dose was escalated until level 5. The MTD was MTZ 6 mg/m² and VNR 30 mg/m² weekly. Age, dose level, and PS were found to be correlated with neutrophil and platelet nadirs, but dose level was the only independent variable predictive of myelotoxicity at multiple regression analysis.Forty-one patients were evaluable for response. Five complete and 16 partial responses were recorded for a 51% [35–67] overall response rate. This was 67% (12/18) in chemotherapy naive patients as compared to 39% (9/23) in those who had been pretreated.Seven of 21 (33%) patients receiving dose level 1 and 2 responded as compared to 14/20 (70%) patients who received higher dose-intensity (p = 0.02). Dose level and pretreatment were the only variables significantly associated with response rate at multiple logistic analysis.The median TTP was 9.5 months for the entire group. It was significantly better in patients who received a dose level > 2 (15 vs. 7; p = 0.015). However, the chemotherapy dose level did not significantly predict outcome after correction for pretreatment (yes vs. no), at multivariate Cox analysis.In conclusion, G-CSF support allows us to achieve a high dose-intensity of MTZ and VNR. Weekly administration of mitoxantrone is recommended to achieve the maximum dose level.Dose escalation seems to provide a significant gain in terms of response rate, although the low number of patients enrolled and the short follow-up prevents us from drawing any conclusion on its effects on TTP and survival. Further controlled trials of this combination in unpretreated patients with advanced breast cancer are needed to determine whether dose escalation can really improve prognosis.