Randomized study of individualized pharmacokinetically-guided dosing of paclitaxel compared with body-surface area dosing in Chinese patients with advanced non-small cell lung cancer.

Abstract

This prospective, randomized study was initiated to assess the impact of pharmacokinetically (PK)-guided paclitaxel (PTX) dosing on toxicity and efficacy compared with body-surface area (BSA)-based dosing in Chinese non-small cell lung cancer patients. A total of 319 stage IIIB/IV non-small cell lung cancer patients receiving first-line chemotherapy were enrolled. Patients were randomized to receive 3-weekly carboplatin plus PTX at a starting dose of 175mg/m2 with subsequent PTX dosing based on either BSA or PK-guided dosing targeting time above a PTX plasma concentration of 0.05μmol/L (PTXTc>0.05 ) between 26 and 31hours. The primary safety endpoint was grade 4 haematological toxicity. The secondary endpoints were neuropathy, objective response rate, progression-free survival and overall survival. In total, 275 (86%) patients completed ≥2cycles of chemotherapy (140 in BSA arm and 135 in PK arm). In cycle 1, with the same PTX dose, average PTXTc>0.05 was 37hours (range=18-57hours). Over cycles 2-4, patients in the PK arm had significantly lower average PTX doses and exposure compared with the BSA arm (128 vs 161mg/m2 , P < .0001 and 29 vs 35hours, P < .0001). PK-guided dosing significantly reduced the cumulative incidence of grade 4 haematological toxicity (15% vs 24%, P=.004), grade 4 neutropenia (15% vs 23%, P=.009) and grade≥2 neuropathy (8% vs 21%, P=.005). Objective response rate (32% vs 26%, P=.28) and overall survival (21.0 vs 24.0months, P=.815) were similar in PK and BSA arms. Progression-free survival was slightly improved in PK arm (4.67 vs 4.17months, P=.026). PK-guided PTX dosing significantly reduced grade 4 haematological toxicities and grade≥2 neuropathy without an adverse impact on clinical outcomes.