Longitudinal assessment of oxaliplatin-induced neuropathy

Abstract

Objectives: To characterize the natural history of oxaliplatin-associated neuropathy (ON) and determine whether intraepidermal nerve fiber density (IENFD) is a sensitive measure of neuropathy progression. In addition, we sought to assess the potential of ON as a neuroprotection model and gain insight into the relationship between axon loss and neuropathic symptoms.

Methods: Eight subjects receiving oxaliplatin for advanced colorectal cancer were prospectively followed prior to starting chemotherapy and at 30, 90, 180, and 360 days (180 days after completing treatment). Electrophysiology, punch biopsies, symptom assessment, and examinations with calculation of a reduced total neuropathy score (rTNS) were performed at each time point. Changes over time were assessed through Poisson regression for IENFD and a mixed effects model for rTNS and electrophysiology measures.

Results: The distal leg IENFD, rTNS, peroneal, and sural amplitudes were all significantly reduced over time, while conduction velocity (peroneal and sural) and distal thigh IENFD were not. Measures of axon loss continued to worsen following discontinuation of oxaliplatin. Five of 8 subjects reported prominent symptoms associated with oxaliplatin administration.

Conclusions: This study demonstrates that oxaliplatin is associated with mild, sensory, and motor axon loss that may not be reversible. Axonal loss was detected by electrophysiology, rTNS, and distal leg IENFD. Several subjects reported prominent sensory symptoms that were not associated with axon loss, and that may or may not represent neuropathy. ON is an attractive paradigm for neuroprotection studies and the distal leg IENFD is an objective measure that requires minimal subject participation or study site expertise.

Figure 1. Spaghetti plots of reduced total neuropathy score (rTNS) (A) and intraepidermal nerve fiber density (IENFD) (B) at baseline, 30 days, 90 days, 180 days, and 360 days in each subject

Numbers on graphs correspond to subject number in table 1. Dark black lines represent the predicted regression line for all data. Stars indicate dates of oxaliplatin administration.

Figure 2. Spaghetti plots of peroneal (A) and sural nerve (B) amplitudes across time

Numbers on graphs correspond to subject number in table 1. Dark black lines represent the predicted regression line for all data. Stars indicate dates of oxaliplatin administration.