Abstract P6-11-03: Association of systemic paclitaxel concentrations with severity and progression of paclitaxel-induced peripheral neuropathy
Authors: DL Hertz, KM Kidwell, K Vangipuram, D Sun, NL Henry
Journal: Cancer Research (2018)

Abstract Background: Paclitaxel is commonly used in combination regimens in patients with early stage breast cancer, but its use is often limited by the development of severe paclitaxel-induced peripheral neuropathy (PIPN). Paclitaxel pharmacokinetics (PK), specifically the maximum paclitaxel concentration (Cmax) and amount of time the concentration remains above 0.05 µM (Tc&amp;gt;0.05), have been associated with occurrence of severe, clinician-documented (NCI CTCAE) neuropathy. Patient-reported outcomes are more reliable, sensitive, and responsive than clinician-documented neuropathy, particularly for subjective toxicities. The objective of this study was to confirm that paclitaxel PK predicts occurrence and progression of patient-reported PIPN. Methods: This observational trial enrolled patients with early stage breast cancer receiving adjuvant/neoadjuvant weekly 1-hour paclitaxel infusions (80 mg/m2 x 12 cycles) at the University of Michigan Comprehensive Cancer Center. Patients with existing neuropathy or previous neuropathic chemotherapy treatment were excluded. Paclitaxel concentration was measured via liquid chromatograph/mass spectrometry (LC/MS) in plasma samples collected at the end of (Cmax) and 16-24 hours after (Tc&amp;gt;0.05) first infusion. Patient-reported neuropathy was collected (EORTC CIPN20) at baseline and each treatment cycle. The 8-item sensory subscale of the CIPN20 (CIPN8, range 8-32) was estimated for each patient and cycle of treatment to calculate the change from baseline (ΔCIPN8, range 0-24). The analysis was conducted using two approaches. In the first analysis, the cohort was stratified into cases and controls by the median ΔCIPN8 and in the second, each patient was described by the rate of change of CIPN8 per treatment cycle. The association of Cmax and Tc&amp;gt;0.05 with case/control definition was tested using Wilcoxon rank sum and t-tests. Associations with rate of change of CIPN8 were tested using linear regression. Results: 60 patients were enrolled in this observational clinical study. The mean age was 52.4 years, 93% of patients were Caucasian, and 5% had diabetes diagnosis. At baseline there was very little patient-reported neuropathy (mean baseline CIPN8=8.3). The median ΔCIPN8 was 4. Patients with ΔCIPN8&amp;gt;4 had greater Cmax than patients with ΔCIPN8≤4 (p=0.010). In the regression modeling, there was a significant correlation between patient's Tc&amp;gt;0.05 and the rate of increase in ΔCIPN8 (r=0.28, p=0.03). Conclusions: Our preliminary findings suggest that a single PK sample collected at the end of the first cycle (Cmax) or 16-24 hours later (Tc&amp;gt;0.05) are indicative of a patient's risk of experiencing PIPN during paclitaxel treatment. Ongoing modeling that accounts for dosing decreases, delays, and discontinuations will further characterize the contribution of paclitaxel pharmacokinetics to PIPN development and enable identification of genetic and metabolomic biomarkers that predict which patients experienced more severe PIPN than would be anticipated based on their paclitaxel PK. Citation Format: Hertz DL, Kidwell KM, Vangipuram K, Sun D, Henry NL. Association of systemic paclitaxel concentrations with severity and progression of paclitaxel-induced peripheral neuropathy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-11-03.