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

Abstract

Purpose: Gemcitabine–cisplatin combinations are among the most active for the treatment of non-small cell lung cancer. Previous reports have suggested that the day of cisplatin administration affects both toxicity and drug delivery. We undertook this retrospective analysis to determine whether it also affects response and survival. Patients and Methods: This was a retrospective analysis of six studies of gemcitabine and cisplatin. Gemcitabine, 1000–1500 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 cisplatin 25–30 mg/m 2 was administered on day 1, 8 and 15. Standard prognostic factors including age, gender, stage, performance status, and histologic subtype were analyzed along with day of cisplatin administration. Single variable Cox proportional hazards regressions were performed. This was followed by multiple variable Cox proportional hazards regression, beginning with a full model containing terms for gender, age, performance status and stage. The 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 regression 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%). Survival was better for patients who received cisplatin on day 2 or 15 compared 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 for cisplatin on days 2 or 15 (hazard ratio=0.69, P=0.008) and female gender (hazard ratio=0.72, P=0.036). Only cisplatin delivery on day 2 or day 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 administration on day 2 or 15.