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Paclitaxel Steady-State Plasma Concentration as a Determinant of Disease Outcome and Toxicity in Lung Cancer Patients Treated with Paclitaxel and Cisplatin¹

The Institute for Drug Development, Cancer Therapy and Research Center, San Antonio Texas and The University of Texas Health Science Center, San Antonio, Texas 78229 [E. K. R., S. D. B.]; Dana Farber Cancer Institute, Boston, Massachusetts 02115 [M. J.]; Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Illinois 60612 [P. B.]; and Vanderbilt University Medical Center, Nashville, Tennessee 37232 [D. J.]

The principal purpose of this study was to evaluate relationships between paclitaxel plasma steady-state concentration (C_ss) and both disease outcome and toxicity in patients with non-small cell lung cancer (NSCLC) treated with 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/m² cisplatin i.v. on day 1 and 100 mg/m² etopside i.v. on days 1–3 (EC arm) or 75 mg/m² cisplatin i.v. combined with either a low dose of paclitaxel (135 mg/m², 24-h i.v. infusion; PC arm) or a higher dose of paclitaxel (250 mg/m² i.v., 24-h i.v. infusion) with granulocyte colony-stimulating factor (PCG arm). End-of-24-h-infusion paclitaxel concentrations, which have been demonstrated to be nearly equal to C_sss on this schedule, were obtained during the first and second courses in patients on the PC and PCG arms. Relationships between the average paclitaxel C_ss (C_ss,avg) and the best response to treatment, time to treatment failure (TTF), survival, and worst grade of leukopenia and neurotoxicity were evaluated by univariate analysis. A multivariate model was used to assess the influence of paclitaxel C_ss in conjunction with other potentially relevant patient variables that may affect disease outcome, including the paclitaxel treatment arm, age, sex, performance status, weight loss during the previous 6 months, and disease stage. Paclitaxel 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,avgs in patients treated with PC and PCG were significantly different (median, 0.32 versus 0.81 µmol/liter; P < 0.0001), response rates were not (33.8 versus 26.7%; P = 0.3719). 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 concentrations from both treatment arms revealed no significant difference in paclitaxel C_ss,avg between responders and nonresponders [median, 0.40 (range, 0.16–1.6) µmol/liter versus 0.55 (range, 0.11–3.6)], and C_ss,avgs were similar in patients segregated according to whether they had a complete response, partial response, stable disease, or progressive disease as their best response to treatment (P = 0.7612). In addition, the relationship between C_ss,avg and TTF was weak (r² = 0.00003, P = 0.94), as was the relationship between C_ss,avg and survival (P = 0.1267). With regard to the principal toxicities, neither the propensity to develop neuromuscular and neurosensory toxicity nor the worst grade of these adverse effects were related to C_ss,avg (P = 0.5000 and 0.2033, respectively); however, the relationship between C_ss,avg and the worst grade of leukopenia experienced was marginally significant (P = 0.0796). In a multivariate model, neither the combined effect of relevant demographic and stratification variables nor paclitaxel 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 positive determinant of survival (P = 0.0121) in the multivariate model. In summary, paclitaxel C_ss,avg was not a determinant of response, TTF, or survival 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 patients with advanced NSCLC with paclitaxel on a 24-h i.v. schedule at doses of >135 mg/m² in combination with cisplatin, although higher doses are associated with higher paclitaxel C_sss.

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