Abstract
Purpose: Paclitaxel exposure, specifically the maximum concentration (C(max)) and amount of time the concentration remains above 0.05 μmol/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) × 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. Clin Cancer Res; 24(15); 3602-10. ©2018 AACR.