Acute Abnormalities of Sensory Nerve Function Associated With Oxaliplatin-Induced Neurotoxicity

Abstract

Purpose Neurotoxicity is becoming increasingly recognized as the major dose-limiting toxicity of oxaliplatin. Because the mechanism of oxaliplatin-induced neurotoxicity remains unclear, the present study investigated the potential of axonal excitability techniques in identifying pathophysiologic mechanisms and early markers of nerve dysfunction. Patients and Methods Measures of sensory axonal excitability were recorded before and after infusion over 88 treatment cycles in 25 patients with colorectal cancer, who received a total oxaliplatin dose of 766 ± 56 mg/m2. Neurologic assessment, clinical rating scales, and routine nerve conduction studies were performed. Results By completion of treatment, 16% of patients had developed severe (grade 3) neurotoxicity, and oxaliplatin dose reduction or cessation as a result of neurotoxicity was required in 40% of patients. Changes in axonal excitability occurred after infusion and could be explained on the basis of alterations in axonal membrane sodium (Na+) channel function (refractoriness: 7.6% ± 1.7% before infusion v 4.5% ± 1.4% after infusion; P = .03; superexcitability: −22.8% ± 0.8% before infusion v −20.1% ± 1.1% after infusion; P = .0002). Changes became less pronounced in later treatment cycles, suggesting that chronic nerve dysfunction and sensory loss masked acute effects at higher cumulative doses. Importantly, patients who demonstrated reductions in superexcitability in early treatment were subsequently more likely to develop moderate to severe neurotoxicity. The findings suggest that the degree of acute nerve dysfunction may relate to the development of chronic neurotoxicity. Conclusion Sensory axonal excitability techniques may facilitate identification of Na+ channel dysfunction in oxaliplatin-induced neurotoxicity and thereby provide a method to identify patients at risk for neurotoxicity to target those most likely to benefit from future neuroprotective strategies.