The influence of gemcitabine and cisplatin schedule on response and survival in advanced non-small cell lung cancer

Purpose: Gemcitabine-cisplatin combinations are among the most active for t he treatment of non-small cell lung cancer. Previous reports have suggested that the day of cisplatin administration affects both toxicity and drug de livery. We undertook this retrospective analysis to determine whether it al so affects response and survival. Patients and Methods: This was a retrospe ctive analysis of six studies of gemcitabine and cisplatin. Gemcitabine, 10 00-1500 mg/m(2) was administered on days 1, 8, and 15 of a 28 day cycle. In four studies cisplatin 100 mg/m(2) was administered with mannitol diuresis every four weeks on either day 1, day 2 or day 15. In two studies cisplati n 25-30 mg/m(2) was administered on day 1, 8 and 15. Standard prognostic fa ctors including age, gender, stage, performance status, and histologic subt ype were analyzed along with day of cisplatin administration. Single variab le Cox proportional hazards regressions were performed. This was followed b y multiple variable Cox proportional hazards regression, beginning with a f ull model containing terms for fender, age, performance status and stage. T he least statistically significant terms were subsequently dropped from the model to reach a final model with only statistically significant variables . A similar approach was followed to fit a multiple variable logistic regre ssion model to overall response data. Results: Overall response rates were highest (36-46%) in the three studies that administered cisplatin on days 2 or 15, and these studies had the highest 1-year survival rates (52-58%). S urvival was better for patients who received cisplatin on day 2 or 15 compa red to those treated on either day 1 or weekly on days 1, 8, 15 (P = 0.020) . In the final model of the Cox regression analysis, survival was better fo r cisplatin on days 2 or 15 (hazard ratio = 0.69, P = 0.008) and female gen der (hazard ratio = 0.72, P = 0.036). Only cisplatin delivery on day 2 or d ay 15 predicted for significantly better response (42 vs. 29%, P = 0.036). Conclusion: In a 28 day cycle in which gemcitabine is administered day 1, 8 and 15. the best therapeutic index is achieved with cisplatin administrati on an day 2 or 15. (C) 2000 Elsevier science Ireland Ltd. All rights reserv ed.