Oxaliplatin-induced neurotoxicity: changes in axonal excitability precede development of neuropathy

Abstract

Administration of oxaliplatin, a platinum-based chemotherapy used extensively in the treatment of colorectal cancer, is complicated by prominent dose-limiting neurotoxicity. Acute neurotoxicity develops following oxaliplatin infusion and resolves within days, while chronic neuropathy develops progressively with higher cumulative doses. To investigate the pathophysiology of oxaliplatin-induced neurotoxicity and neuropathy, clinical grading scales, nerve conduction studies and a total of 905 axonal excitability studies were undertaken in a cohort of 58 consecutive oxaliplatin-treated patients. Acutely following individual oxaliplatin infusions, significant changes were evident in both sensory and motor axons in recovery cycle parameters (P < 0.05), consistent with the development of a functional channelopathy of axonal sodium channels. Longitudinally across treatment (cumulative oxaliplatin dose 776 +/- 46 mg/m(2)), progressive abnormalities developed in sensory axons (refractoriness P < or = 0.001; superexcitability P < 0.001; hyperpolarizing threshold electrotonus 90-100 ms P < or = 0.001), while motor axonal excitability remained unchanged (P > 0.05), consistent with the purely sensory symptoms of chronic oxaliplatin-induced neuropathy. Sensory abnormalities occurred prior to significant reduction in compound sensory amplitude and the development of neuropathy (P < 0.01). Sensory excitability abnormalities that developed during early treatment cycles (cumulative dose 294 +/- 16 mg/m(2) oxaliplatin; P < 0.05) were able to predict final clinical outcome on an individual patient basis in 80% of patients. As such, sensory axonal excitability techniques may provide a means to identify pre-clinical oxaliplatin-induced nerve dysfunction prior to the onset of chronic neuropathy. Furthermore, patients with severe neurotoxicity at treatment completion demonstrated greater excitability changes (P < 0.05) than those left with mild or moderate neurotoxicity, suggesting that assessment of sensory excitability parameters may provide a sensitive biomarker of severity for oxaliplatin-induced neurotoxicity.

Long-Term Neuropathy After Oxaliplatin Treatment: Challenging the Dictum of Reversibility

“…Symptom severity scores and clinical and nerve function parameters were correlated within individual patients with Spearman rank correlation coefficients. To determine the relationship between excitability measures during oxaliplatin treatment and follow-up measures, a sum score of composite excitability was determined by combining the measures refractoriness, superexcitability, and threshold electrotonus [8,15] and was correlated within individual patients' clinical neurotoxicity scores (TNSc and TNSr). To compare assessments across multiple time points (pre-oxaliplatin, post-oxaliplatin, and follow-up), assessments were paired and compared within patients using Wilcoxon signed rank tests (two-tailed).…”

“…To compare assessments across multiple time points (pre-oxaliplatin, post-oxaliplatin, and follow-up), assessments were paired and compared within patients using Wilcoxon signed rank tests (two-tailed). Results are expressed as the mean Ϯ standard error of the mean (SEM) or, alternatively, as the median and interquartile range (IQR) as a measure of variability [15]. Significance was defined as p Յ .05.…”

“…The median nerve was stimulated at the wrist with a reference electrode placed 10 cm distal over bone and compound sensory action potentials (CSAPs) were recorded from the second digit. Using established protocols [12,27], multiple excitability parameters were recorded, as in prior studies of oxaliplatin-induced neurotoxicity [8,15], as indirect measures of resting axonal membrane potential. The recovery of excitability following impulse conduction, marking the function of voltage-gated Na ϩ channels, was assessed with the parameters refractoriness and superexcitability, calculated as the percent change in threshold 2.5 msec and 7 msec after supramaximal stimulation [12,29,30].…”

“…Although it has been reported that oxaliplatin-induced neurotoxicity is reversible upon treatment cessation [1,3,5], other reports suggest that oxaliplatin-induced neurotoxicity may be long lasting [6, 10,11]. Recently, axonal excitability studies [12,13] provided evidence for striking progressive changes in peripheral nerve function that developed across oxaliplatin treatment, predicting the development of neuropathy [6,8,14,15]. In the present study, prospective and longitudinal assessments of oxaliplatin-treated patients were undertaken to determine the extent to which oxaliplatin treatment induces long-standing alterations in peripheral nerve function.…”

Transient Receptor Potential Channels in Chemotherapy-Induced Neuropathy

“…Cold hypersensitivity is a typical feature observed in acute oxaliplatin-induced neurotoxicity. It has been shown that acute modulation of sodium channels influences the severity of oxaliplatin-induced neurotoxicity [39,40]. The involvement of sodium channels is also reported in paclitaxel-induced neuropathic pain, where low doses of tetrodotoxin result able to prevent pain induced by taxane [41].…”