Paclitaxel Plasma Concentration after the First Infusion Predicts Treatment-Limiting Peripheral Neuropathy

Purpose: Paclitaxel exposure, specifically the maximum concentration (C-max) and amount of time the concentration remains above 0.05 mu mol/L (T-c>0.05), has been associated with the occurrence of paclitaxel-induced peripheral neuropathy. The objective of this study was to validate the relationship between paclitaxel exposure and peripheral neuropathy. Experimental Design: Patients with breast cancer receiving paclitaxel 80 mg/m(2) x 12 weekly doses were enrolled in an observational clinical study (NCT02338115). Paclitaxel plasma-concentration was measured at the end of and 16-26 hours after the first infusion to estimate C-max and T-c>0.05. Patient-reported peripheral neuropathy was collected via CIPN20 at each dose, and an 8-item sensory subscale (CIPN8) was used in the primary analysis to test for an association with T-c>0.05. Secondary analyses were conducted using C-max as an alternative exposure parameter and testing each parameter with a secondary endpoint of the occurrence of peripheral neuropathy-induced treatment disruption. Results: In 60 subjects included in the analysis, the increase in CIPN8 during treatment was associated with baseline CIPN8, cumulative dose, and relative dose intensity (P < 0.05), but neither T-c>0.05 (P = 0.27) nor C-max (P = 0.99). In analyses of the secondary endpoint, cumulative dose (OR = 1.46; 95% confidence interval (CI), 1.18-1.80; P = 0.0008) and T-c>0.05 (OR = 1.79; 95% CI, 1.06-3.01; P = 0.029) or C-max (OR = 2.74; 95% CI, 1.45-5.20; P = 0.002) were associated with peripheral neuropathy-induced treatment disruption. Conclusions: Paclitaxel exposure is predictive of the occurrence of treatment-limiting peripheral neuropathy in patients receiving weekly paclitaxel for breast cancer. Studies are warranted to determine whether exposure-guided dosing enhances treatment effectiveness and/or prevents peripheral neuropathy in these patients. (C) 2018 AACR.