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Time-to-Event Analysis of Paclitaxel-Associated Peripheral Neuropathy in Advanced Non-Small-Cell Lung Cancer Highlighting Key Influential Treatment/Patient Factors

Francis W Ojara, Andrea Henrich, Nicolas Frances, Wilhelm Huisinga, Niklas Hartung, Markus Joerger & Charlotte Kloft

abstract Paclitaxel-associated peripheral neuropathy (PN), a major dose-limiting toxicity, significantly impacts patients' quality of life/treatment outcome. Evaluation of risk factors often ignores time of PN onset, precluding the impact of time-dependent factors, e.g., drug exposure, needed to comprehensively characterize PN. We employed parametric time-to-event (TTE) analysis to describe the time course of risk of first occurrence of clinically relevant PN grades ≥2 (PN2+, = 105, common terminology criteria v4.0) and associated patient/treatment characteristics, leveraging data from 365 patients (1454 cycles) receiving paclitaxel every 3 weeks (plus carboplatin AUC = 6 or cisplatin 80 mg/m) for ≤6 cycles. Paclitaxel was intravenously administered (3 hours) as standard 200-mg/m doses ( = 182) or as pharmacokinetic-guided dosing ( = 183). A cycle-varying hazard TTE model linking surge in hazard of PN2+ to paclitaxel administration [PN2+ proportions (i.e., cases per 1000 patients), 1 day, cycle 1: 4.87 of 1000; cycle 6: 7.36 of 1000] and linear decline across cycle (last day, cycle 1: 1.64 of 1000; cycle 6: 2.48 of 1000) adequately characterized the time-varying hazard of PN2+. From joint covariate evaluation, PN2+ proportions (1 day, cycle 1) increased by 1.00 per 1000 with 5-μmol·h/l higher paclitaxel exposure per cycle (AUC between the start and end of a cycle, most relevant covariate), 0.429 per 1000 with 5-year higher age, 1.31 per 1000 (smokers vs. nonsmokers), and decreased by 0.670 per 1000 (females vs. males). Compared to 200 mg/m dosing every 3 weeks, model-predicted cumulative risk of PN2+ was significantly higher (42%) with 80 mg/m weekly dosing but reduced by 11% with 175 mg/m dosing every 3 weeks. The established TTE modeling framework enables quantification and comparison of patient's cumulative risks of PN2+ for different clinically relevant paclitaxel dosing schedules, sparing patients PN2+ to improve paclitaxel therapy. SIGNIFICANCE STATEMENT: Characterization of risk factors of paclitaxel-associated peripheral neuropathy (PN) typically involves time-independent comparison of PN odds in patient subpopulations, concealing the impact of time-dependent factors, e.g., changing paclitaxel exposure, required to comprehensively characterize PN. We developed a parametric time-to-event model describing the time course in risk of clinically relevant paclitaxel-associated PN, identifying the highest risk in older male smokers with higher paclitaxel area under the plasma concentration-time curve between the start and end of a cycle. The developed framework enabled quantification of patient's risk of PN for clinically relevant paclitaxel dosing schedules, facilitating future dosing decisions.
   
citation Ojara F W, Henrich A, Frances N, Huisinga W, Hartung N, Joerger M, Kloft C. Time-to-Event Analysis of Paclitaxel-Associated Peripheral Neuropathy in Advanced Non-Small-Cell Lung Cancer Highlighting Key Influential Treatment/Patient Factors. J Pharmacol Exp Ther 2020; 375:430-438.
   
type journal paper/review (English)
date of publishing 02-10-2020
journal title J Pharmacol Exp Ther (375/3)
ISSN electronic 1521-0103
pages 430-438
PubMed 33008871
DOI 10.1124/jpet.120.000053