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

• Published in: Clinical cancer research 1999-04, Vol.5 (4), p.767-774
• Main Authors: ROWINSKY, E. K, JIROUTEK, M, BONOMI, P, JOHNSON, D, BAKER, S. D
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic agents; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - drug therapy; Chemotherapy; Cisplatin - administration & dosage; Cisplatin - toxicity; Demography; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms - drug therapy; Male; Medical sciences; Middle Aged; Multivariate Analysis; Paclitaxel - administration & dosage; Paclitaxel - blood; Paclitaxel - pharmacokinetics; Paclitaxel - toxicity; Pharmacology. Drug treatments; Treatment Outcome
• ISSN: 1078-0432; 1557-3265

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/m 2 cisplatin i.v. on day 1 and 100 mg/m 2 etopside i.v. on days 1–3 (EC arm) or 75 mg/m 2 cisplatin 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 demonstrated to be nearly equal to C ss s 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,avg s 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,avg s 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 wea