Cisplatin, gemcitabine and vinorelbine in locally advanced or metastatic non-small-cell lung cancer: A phase I study

Purpose: The objective of this study was to determine the maximally tolerable doses (MTDs) of vinorelbine (VNR) and gemcitabine (GEM) when combined with a fixed dose of cisplatin (CDDP).Patients and methods: Chemotherapy-naïve patients with stage IIIB–IV non-small-cell lung cancer (NSCLC) received a fixed dose of CDDP (50 mg/m²) and escalating doses of VNR (starting from 20 mg/m²) and GEM (starting from 800 mg/m²) on days 1 and 8, every three weeks. The single escalation of GEM alone, by 200 mg/m² at each step, was initially planned up to a dose of 1,200 mg/m², to be followed by increments of the VNR dose of 5 mg/m² at each step.Results: Thirty-one patients were enrolled at five different dose levels. The escalation was stopped at level 4 (GEM 1,200 mg/m² and VNR 25 mg/m²) since two of six patients of this cohort showed dose-limiting neutropenia at treatment cycle 1. Two different dose levels, GEM 1,200 mg/m² + VNR 20 mg/m², and GEM 1,000 mg/m² + VNR 25 mg/m², were fairly well tolerated. No treatment-related deaths occurred. Neutropenia was the main toxic effect, occurring in 76% of the total of 116 cycles delivered, and in 24% of them was of grades 3 or 4. A total of eight patients (26%) experienced grade 4 neutropenia lasting more than seven days; in five of them it occurred in the first course. Neutropenic fever was observed in four cases. Grade 4 thrombocytopenia occurred in only two patients. Non-hematologic toxicity was a minor problem in all patients but was never dose-limiting. No complete responses were obtained, but sixteen out of 31 (52%) patients achieved partial responses. The median duration of response was 20 (range 6–56+) weeks, while at a nine-month median follow-up, the median survival time has not yet been reached. To date, 18 patients are still alive. The one-year projected survival for all patients was 51%.Conclusions: Our results show that CDDP, VNR and GEM can be safely given together without substantial reductions in their individual dose intensities. In our opinion, the dose level of GEM 1,000 mg/m² + VNR 25 mg/m² given in combination with CDDP 50 mg/m² on days 1 and 8 of a three-week cycle can be recommended for phase II trials, since it provides a better balance in dose intensity of GEM and VNR. A phase II randomised study is underway to establish the activity of this new regimen (at the above-cited dose level) in chemo-naïve NSCLC patients.