Background: Variability of chemotherapy exposure may cause severe toxicity or lack of efficacy. Paclitaxel (PTX) exposure (time above a plasma concentration of 0.05mM, Tc > 0.05) has been shown to predict toxicity. Whereas carboplatin dose is adapted to kidney function, PTX dosing only accounts for body-surface area. We developed a PTX dosing algorithm for avoidance of supra- or subtherapeutic PTX exposure based on Tc > 0.05 determined from a single blood sample drawn 18 – 30 hours after starting PTX infusion. This study was initiated to validate PK-guided PTX dosing in advanced NSCLC patients.
Methods: 304 patients with advanced NSCLC were randomly assigned to receive up to 6 cycles of first-line 3-weekly carboplatin AUC 6 combined with PTX either at a standard dose of 200 mg/m2 (Arm A) or at a PK-guided dose (Arm B).
Initial PTX dose in Arm B was between 150 to 200 mg/m2 based on age and sex, and subsequent PTX doses were adjusted according to the previous cycle PTX Tc > 0.05 to target a Tc > 0.05 between 26 and 31 hours. Dose reductions were permitted in both arms for chemotherapy-associated toxicity. The study had a power of 90% to detect a 11% reduction of grade 4 neutropenia with PK-guided PTX dosing.
Results: Major patient characteristics were male gender in 67%, current smokers in 38%, ≥65 years of age in 50%, performance status of 2 in 8%, squamous-cell histology in 21%. Compared to standard dosing, PK-guided dosing of PTX reduced the incidence of grade 4 neutropenia (measured on day 15 of each cycle) (15% v 21%, P = 0.029), grade ≥2 neuropathy (14% v 27%, P < 0.001), and grade ≥3 neuropathy (1% v 8%, P < 0.001). Median PTX dose at cycle 6 was significantly lower with PK-guided dosing (132 v 197 mg/m2, P < 0.001), and the proportion of patients with supratherapeutic PTX exposure was reduced from 41% in cycle 1 to 2% in cycle 6. Objective response rate was 32% and 29% in Arms A and B (P = 0.70). Progression-free survival was 5.2 and 4.7 months in Arms A and B (hazard ratio 1.1, 95% CI 0.8 – 1.4, P = 0.54).
Conclusions:
PK-guided dosing of PTX improves the risk-benefit profile in patients with advanced NSCLC, primarily by a substantial reduction of PTX-associated neuropathy.
