Originally published as JCO Early Release 10.1200/JCO.2008.19.3425 on January 21 2009

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

From the Prince of Wales Medical Research Institute, Prince of Wales Clinical School, and School of Medical Sciences, University of New South Wales; Department of Medical Oncology, Prince of Wales Hospital, Sydney, Australia.

Corresponding author: Matthew C. Kiernan, PhD, Prince of Wales Medical Research Institute, Barker St, Randwick, Sydney, New South Wales 2031; e-mail: M.kiernan{at}unsw.edu.au.

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.

Supported by the National Heath and Medical Research Council of Australia (Project Grant No. 400938), the Sydney Foundation for Medical Research, and an Australian Postgraduate Award (S.B.P.).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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