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 to lerable doses (MTDs) of vinorelbine (VNR) and gemcitabine (GEM) when c ombined with a fixed dose of cisplatin (CDDP). Patients ann methods. C hemotherapy-naive patients with stage IIIB-IV non-small-cell lung canc er (NSCLC) received a fixed dose of CDDP (50 mg/m(2)) and escalating d oses of VNR (starting from 20 mg/m(2)) and GEM (starting from 800 mg/m (2)) on days 1 and 8, every three weeks. The single escalation of GEM alone, by 200 mg/m(2) at each step, was initially planned up to a dose of 1,200 mg/m(2), to be followed by increments of the VNR dose of 5 m g/m(2) at each step. Results: Thirty-one patients were enrolled at fiv e different dose levels. The escalation was stopped at level 4 (GEM 1, 200 mg/m(2) and VNR 25 mg/m(2)) since two of six patients of this coho rt showed dose-limiting neutropenia at treatment cycle 1. Two differen t dose levels, GEM 1,200 mg/m(2) + VNR 20 mg/m(2), and GEM 1,000 mg/m( 2) + VNR 25 mg/m(2) were fairly well tolerated. No treatment-related d eaths occurred. Neutropenia was the main toxic effect, occurring in 76 % of the total of 116 cycles delivered, and in 24% of them was of grad es 3 or 4. A total of eight patients (26%) experienced grade 4 neutrop enia lasting more than seven days in five of them it occurred in the f irst course. Neutropenic fever was observed in four cases. Grade 4 thr ombocytopenia occurred in only two patients. Non-hematologic toxicity was a minor problem in all patients but was never dose-limiting. No co mplete responses were obtained, but sixteen out of 31 (52%) patients a chieved partial responses. The median duration of response was 20 (ran ge 6-56+) weeks, while at a nine-month median follow-up, the median su rvival time has not yet been reached. To date, 18 patients are still a live. The one-year projected survival for all patients was 51%. Conclu sions. Our results show that CDDP, VNR and GEM can be safely given tog ether without substantial reductions in their individual dose intensit ies. In our opinion, the dose level of GEM 1,000 mg/m(2) + VNR 25 mg/m (2) given in combination with CDDP 50 mg/m(2) on days 1 and 8 of a thr ee-week cycle can be recommended for phase II trials, since it provide s a better balance in dose intensity of GEM and VNR. A phase II random ised study is underway to establish the activity of this new regimen ( at the above-cited dose level) in chemo-naive NSCLC patients.