Inability to escalate vinorelbine dose intensity using a daily x3 schedulewith and without filgrastim in patients with metastatic breast cancer

Purpose: Vinorelbine (Navelbine) is a semisynthetic vinca alkaloid with doc umented activity in breast cancer. The major dose-limiting toxicity (DLT) w hen given weekly is myelosuppression with minimal neurologic toxicity. This phase I study attempted to define the maximally tolerated dose (MTD) and t he DLT of vinorelbine on a daily x3 schedule with and without filgrastim su pport, Methods: A total of 19 patients with stage IV breast cancer were enr olled in separate studies at Duke University Medical Center (DUMC) and the Dana-Farber Cancer Institute (DFCI). Eligible patients could have received up to two prior chemotherapy regimens in the metastatic setting and had to have an ANC > 1500/mm(2), PLT > 100000 m(3), creatinine < 2.0 mg/dl, biliru bin < 2.0 mg/dL, SGOT not more than three times normal, and performance sta tus 0-1. Vinorelbine was administered using a daily x3 schedule every 3 wee ks. The protocols were designed to study dose escalation with and without g rowth factor support. At DUMC, in the initial phase of the study, the start ing dose was 15 mg/m(2) per day and dose escalations of 5 mg/m(2) were plan ned until DLT developed and the MTD was defined. DLT was defined as granulo cytopenia < 500/mm(3) for > 7 days, grade IV thrombocytopenia, febrile neut ropenia, or grade III or greater nonhematologic toxicity. In the second pha se of the study, growth factor support was given with vinorelbine at the MT D. Filgrastim at a dose of 5 mu g/kg was started on day 4 of the 21-day cyc le and was continued until the neutrophil count exceeded 10000 cells/mm(3). At DFCI, all patients received growth factor starring on day 4 and the sta rting dose of vinorelbine was 25 mg/m(2). Results: At DUMC, DLT was seen at 20 mg/m(2) in three of three patients and included febrile neutropenia, gr ade IV neutropenia > 7 days, grade III neurotoxicity, and grade III vomitin g. Despite the addition of filgrastim, DLT was again seen at 20 mg/m(2) and included grade III neurotoxicity (law pain, abdominal pain, constipation. ileus) and grade IV mucositis. Three patients at DFCI were treated with vin orelbine at a dose of 25 mg/m(2) with growth factor support, and two develo ped DLT including febrile neutropenia, neutropenia > 7 days, and grade III stomatitis. Conclusions: Our effort to escalate the dose intensity of vinor elbine on this schedule was not successful and was complicated by hematolog ic and nonhematologic toxicity. A daily x3 schedule of vinorelbine should n ot be pursued as an alternative treatment regimen in patients with previous ly treated metastatic breast cancer.