Paclitaxel steady-state plasma concentration as a determinant of disease outcome and toxicity in lung cancer patients treated with paclitaxel and cisplatin

The principal purpose of this study was to evaluate relationships between p aclitaxel plasma steady-state concentration (C-ss) and both disease outcome and toxicity in patients with non-small cell lung cancer (NSCLC) treated w ith paclitaxel and cisplatin in an Eastern Cooperative Oncology Group (ECOG ) Phase III study E5592. Chemotherapy-naive patients with stage IIIb and IV NSCLC were randomized to treatment with either 75 mg/m(2) cisplatin i.v. o n day 1 and 100 mg/m(2) etopside i.v. on days 1-3 (EC arm) or 75 mg/m(2) ci splatin i.v. combined with either a low dose of paclitaxel (135 mg/m(2), 24 -h i.v. infusion; PC arm) or a higher dose of paclitaxel (250 mg/m(2) i.v., 24-h i.v. infusion) with granulocyte colony-stimulating factor (PCG arm). End-of-24-h-infusion paclitaxel concentrations, which have been demonstrate d to be nearly equal to C(ss)s on this schedule, were obtained during the f irst and second courses in patients on the PC and PCG arms. Relationships b etween the average paclitaxel C-ss (C-ss,(avg)) and the best response to tr eatment, time to treatment failure (TTF), survival, and worst grade of leuk openia and neurotoxicity were evaluated by univariate analysis. A multivari ate model was used to assess the influence of paclitaxel C-ss in conjunctio n with other potentially relevant patient variables that may affect disease outcome, including the paclitaxel treatment arm, age, sex, performance sta tus, weight loss during the previous 6 months, and disease stage. Paclitaxe l C-ss in both courses 1 and 2 were obtained in 71 patients treated with PC and 75 patients treated with PCG. Although C-ss,(avg)s in patients treated with PC and PCG were significantly different (median, 0.32 versus 0.81 mu mol/liter; P < 0.0001), response rates were not (33.8 versus 26.7%; P = 0.3 719). In addition, there were no differences between the PC and PCG arms in TTF (median, 5.1 versus 5.5 months, P = 0.6201) or survival (median, 11.6 versus 11.3 months, P = 0.7173). Combined analysis of paclitaxel concentrat ions from both treatment arms revealed no significant difference in paclita xel C-ss,(avg) between responders and nonresponders [median, 0.40 (range, 0 .16-1.6) mu mol/liter versus 0.55 (range, 0.11-3.6)], and C-ss,(avg)s were similar in patients segregated according to whether they had a complete res ponse, partial response, stable disease, or progressive disease as their be st response to treatment (P = 0.7612). In addition, the relationship betwee n C-ss,(avg) and TTF was weak (r(2) = 0.00003, P = 0.94), as was the relati onship between C-ss,(avg) and survival (P = 0.1267). With regard to the pri ncipal toxicities, neither the propensity to develop neuromuscular and neur osensory toxicity nos the worst grade of these adverse effects were related to C-ss,(avg) (P = 0.5000 and 0.2033, respectively); however, the relation ship between C-ss,(avg) and the worst grade of leukopenia experienced was m arginally significant (P = 0.0796). In a multivariate model, neither the co mbined effect of relevant demographic and stratification variables nor pacl itaxel C-ss,(avg) predicted for either response (P = 0.1544) or TTF (P = 0. 2574), whereas the combined effect of all covariates predicted for survival (P = 0.0249). With regard to individual covariates, a lower disease stage (stage IIIb) was the only significant positive determinant of response (P = 0.0173), female sex was the only significant favorable predictor for TTF ( P = 0. 0195), and a lower ECOG performance status (= 0) was the only significant p ositive determinant of survival (P = 0.0121) in the multivariate model. In summary, paclitaxel C-ss,(avg) was not a determinant of response, TTF, or s urvival in patients with advanced NSCLC treated with paclitaxel as a 24-h i .v. infusion combined with cisplatin. On the basis of both the clinical and pharmacodynamic results of E5592, there is no compelling reason to treat p atients with advanced NSCLC with paclitaxel on a 24-h i.v. schedule at dose s of >135 mg/m(2) in combination with cisplatin, although higher doses are associated with higher paclitaxel C(ss)s.