Carboplatin prescribed in mg/m2 in patients with advanced non small cell lung cancer (NSCLC): Is there an impact of the reached area under the curve (AUC) on response, survival and hematolo
摘要
From 4/1990 until 10/1995, the ELCWP, performed, in patients with advanced NSCLC, a large randomized phase III trial having as primary endpoint the comparison of the objective response rates reached with the chemotherapy combination of carboplatin (200 mg/m2) and cisplatin (30 mg/m2 d2-3) with or without ifosfamide (1.5 g/m2 d1, 2, 3), given every 3 weeks. After the planning of our study, it has been advocated that optimal carboplatin dosage should be performed using a target AUC. The purpose of this analysis was to look at the reached AUC (mg/ml × min) searching for an impact on response, survival and/or toxicity. We registered 505 eligible patients whose characteristics, well balanced according to treatment, were: sex M/F: 439/66, Karnofsky 60-70/80-100: 169/336, disease stage III/IV: 23/482, histology squamous/adeno/other: 196/212/97. During the first cycle, according to treatment arm, mean (SD) AUC was 2.65 (0.7) and 2.74 (0.7) using Chatelut approximation for creatinine clearance. With Cockroft approximation, the corresponding numbers were 3.34 (0.8) and 3.46 (0.7) (no difference between arms and excellent linear correlation, r = 0.91, for the two approximations). Grouped distribution for Chatelut approximations was: AUC <2.5: 203, AUC 2.5-3.5: 151, AUC >3.5: 142. For Cockroft formula, we had: AUC <3: 137, AUC 3-4: 260, AUC >4: 99. Three AUC dose-related variables were considered: received dose at cycle 1, cumulative dose and delivered dose intensity after 3 courses, assessed continuously or categorized into 3 classes. Using logistic regression models, with arm effect adjustment, we were not able to show any impact of any of these 3 variables on response. On survival, using Cox models, we obtained the same lack of statistical significance of dose effects. However, increased hematological toxicity (WHO grades 2-4), both on WBC and platelets counts, was seen after adjustment for treatment effect: at course 1, using Chatelut formula, estimated odds ratios were, (continuous assessment) 1.94, p = 0.001 (consistent results for Cockroft formula) for leucopenia and 2.19, p < 0.001 for thrombocytopenia. Looking at the categorical variable, effect was more marked in the highest dose level group. The observed effects remained statistically highly significant after three chemotherapy cycles, considering the cumulative doses but not when dose intensity was analyzed due to longer time intervals between two cycles. in case of hematological toxicity. In conclusion, in this large series of patients, we did not confirm the therapeutic benefit suggested in the literature when giving higher AUC carboplatin doses.