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

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/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 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.

Figure 1:. Increase in Self-Reported Neuropathy during Paclitaxel Treatment:

Self-reported sensory peripheral neuropathy (CIPN8) gradually increased from baseline to the end of treatment in the overall patient cohort, as expected. The thick black line represents the smoothed average of CIPN8 at that dose of treatment. Note that patients who discontinued treatment were assigned their final CIPN8 score for the remaining doses of treatment when estimating the average CIPN8 curve within this figure and that CIPN20 forms were collected at dose 12 from most patients, therefore, few patients have CIPN8 data for dose 12.

Figure 2:. Increase in Self-Reported Neuropathy During Treatment, Stratified by Paclitaxel Exposure.

Self-reported sensory peripheral neuropathy (CIPN8) gradually increased from baseline to the end of treatment. The cohort was stratified by tertiles of T_c>0.05 (Figures 2A) or C_max (Figures 2B). There was no significant difference in increase in CIPN8 in the cohort stratified by either paclitaxel exposure parameter. The thick black line represents the smoothed average of CIPN8 at that treatment dose. Note that patients who discontinued treatment were assigned their final CIPN8 score for the remaining doses of treatment in order to estimate the average CIPN8 curve within these figures and that CIPN20 forms were collected at dose 12 from most patients, therefore, few patients have CIPN8 data for dose 12.

Figure 3:. Probability of Treatment Disruption by Paclitaxel Exposure.

The probability of experiencing PN-Induced Treatment Disruption Increases as exposure (T_c>0.05 or C_max) during the first dose increases. Assuming a patient has a baseline CIPN8=0 and receives the full dose (80 mg/m²) for 12 scheduled weekly doses, she would have a 25% risk of treatment disruption if her T_c>0.05=14.06 hours (Figure 3A) or C_max=2,885 ng/mL (Figure 3B)).