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

Abstract

<b>Purpose:</b> Paclitaxel exposure, specifically the maximum concentration (<i>C</i>_max) and amount of time the concentration remains above 0.05 μmol/L (<i>T_c</i>_>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.<b>Experimental Design:</b> Patients with breast cancer receiving paclitaxel 80 mg/m² × 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 <i>C</i>_max and <i>T_c</i>_>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 <i>T_c</i>_>0.05 Secondary analyses were conducted using <i>C</i>_max as an alternative exposure parameter and testing each parameter with a secondary endpoint of the occurrence of peripheral neuropathy-induced treatment disruption.<b>Results:</b> In 60 subjects included in the analysis, the increase in CIPN8 during treatment was associated with baseline CIPN8, cumulative dose, and relative dose intensity (<i>P</i> < 0.05), but neither <i>T_c</i>_>0.05 (<i>P</i> = 0.27) nor <i>C</i>_max (<i>P</i> = 0.99). In analyses of the secondary endpoint, cumulative dose (OR = 1.46; 95% confidence interval (CI), 1.18-1.80; <i>P</i> = 0.0008) and <i>T_c</i>_>0.05 (OR = 1.79; 95% CI, 1.06-3.01; <i>P</i> = 0.029) or <i>C</i>_max (OR = 2.74; 95% CI, 1.45-5.20; <i>P</i> = 0.002) were associated with peripheral neuropathy-induced treatment disruption.<b>Conclusions:</b> 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. <i>Clin Cancer Res; 24(15); 3602-10. ©2018 AACR</i>.