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

Purpose: Paclitaxel exposure, specifically the maximum concentration (Cmax) and amount of time the concentration remains above 0.05 µM (Tc>0.05), have been associated with the occurrence of paclitaxel-induced peripheral neuropathy (PN). The objective of this study was to validate the relationship between paclitaxel exposure and PN.  Experimental Design: Patients with breast cancer receiving paclitaxel 80 mg/m2 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 Cmax and Tc>0.05. Patient-reported PN 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 Tc>0.05. Secondary analyses were conducted using Cmax as an alternative exposure parameter and testing either parameter with a secondary endpoint of the occurrence of PN-induced treatment disruption.   Results: In the 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 Tc>0.05 (p=0.27) nor Cmax (p=0.99). In analyses of the secondary endpoint, cumulative dose (odds ratio (OR)=1.46, 95% confidence interval (CI): 1.18-1.80, p=0.0008) and Tc>0.05 (OR=1.79, 95% CI: 1.06-3.01, p=0.029) or Cmax (OR=2.74, 95% CI: 1.45-5.20, p=0.002) were associated with PN-induced treatment disruption. Conclusions: Paclitaxel exposure is predictive of the occurrence of treatment-limiting PN in patients receiving weekly paclitaxel for breast cancer. Studies are warranted to determine whether exposure-guided dosing enhances treatment effectiveness and/or prevents PN in these patients. 

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