Multi-center study of two dose levels of paclitaxel with carboplatin in locally advanced and metastatic non-small cell lung cancer (NSCLC)

Background: The efficacy and toxicity of the combination of two cytotoxic c ompounds that are active as single agents in non-small cell lung cancer (NS CLC), paclitaxel (Taxol((R))) and carboplatin (Paraplatin((R)) was investig ated in a multicenter, community-based setting. Materials and Methods: Two consecutive cohorts of chemonaive patients with stages IIIA/B and IV NSCLC received two dose levels of paclitaxel. The first cohort received 200 mg/m( 2) over 3 hours (HD) and the second cohort 175 mg/m(2) oiler 3 hours (LD) i n combination with a fixed dose of carboplatin. The dose of carboplatin was calculated according to the Calvert formula with an area under the concent ration versus time curve (AUC) value of 6 mg/ml/minute. The carboplatin cle arance, calculated by the Chatelut formula rather than the glomerulation fi ltration rate (GFR) + 25, was introduced into the Calvert formula. The elig ibility criteria were identical for both cohorts throughout the study. Trea tment was administered every three weeks. The study endpoints were response rate (RR) toxicity, time to progression (TTP) and survival (S). Results: O ne hundred and thirty consecutive eligible patients from 36 Belgian institu tions were fully evaluable for all study parameters (99 in the HD and 31 in the LD cohort). Myelosuppression was the most prominent side-effect of tre atment with comparable results for both cohorts. The wont gr:ade 3-4 leucop enia and neutropenia pel patient in the HD versus LD cohort was 34.4 vs 19. 3% and 59.2 vs 51.6%, respectively 10.4% of patients in the HD cohort requi red hospitalisation for febrile neutropenia (6.2% with and 4.2% without doc umented bacterial infection), while in the LD cohort the respective figures were 13.7, 10.3 and 3.4%. The most prominent non-hematologic toxicities we re alopecia and polyneuropathy, with no major difference between the HD and LD cohort (grade 2 alopecia in 78.1 vs. 83.9% and grade 3 neuropathy in 14 .3 vs. 9.7%, respectively). The overall best clinical RR was 31 out of 130 (23.8%) with one complete (CR) and 30 partial responses (PR). The respectiv e RR in the HD and LD cohort was 23.2 and 258%. Median TTP and S for all pa tients was 120 and 248 days, with no apparent difference between the HD and the LD cohort (119 and 254 versus 128 and 222, respectively). The one year survival was 34% in the HD cohort. The 95% confidence intervals for effica cy and toxicity parameters overlapped in both cohorts. Conclusion: In this multicenter study, the combination of paclitaxel and carboplatin produced a moderate RR of 23.8% in stages IIIA/B & TV NSCLC. The therapy was generall y well tolerated at both doses of paclitaxel. Myelosuppression, neurotoxici ty and alopecia were the major therapy-related side-effects. The difference s between the two paclitaxel dose cohorts with respect to activity and toxi city were minimal. The use of the Chatelut formula to calculate the carbopl atin clearance is feasible, but might have lead to the apparent excess in m yelotoxicity in our study compared to other studies which used other method s for estimating renal function.