Brain Advance Access originally published online on September 10, 2009
Brain 2009 132(10):2712-2723; doi:10.1093/brain/awp219
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Oxaliplatin-induced neurotoxicity: changes in axonal excitability precede development of neuropathy
1 Prince of Wales Medical Research Institute and Prince of Wales Clinical School, University of New South Wales, NSW, Australia, 2031 2 School of Medical Sciences, University of New South Wales, NSW, Australia, 2052 3 Department of Medical Oncology, Prince of Wales Hospital, Sydney, NSW, Australia, 2031
Correspondence to: Matthew C. Kiernan, Prince of Wales Medical Research Institute, Barker Street, Randwick, Sydney, NSW 2031, Australia E-mail: m.kiernan{at}unsw.edu.au
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/m2), progressive abnormalities developed in sensory axons (refractoriness P 
0.001; superexcitability P < 0.001; hyperpolarizing threshold electrotonus 90–100 ms P 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/m2 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.
Key Words: oxaliplatin; neurotoxicity; neuropathy; excitability; channelopathy
Abbreviations: CMAP, compound motor action potential; CSAP, compound sensory action potential; FOLFOX, Treatment regimen including oxaliplatin, leucovorin and 5-fluorouracil; IQR, interquartile range; I/V, current–threshold relationship; NCI, National Cancer Institute; OSNS, Oxaliplatin-Specific Neurotoxicity Scale; RC, recovery cycle; TE, threshold electrotonus; TEh 90–100 ms, threshold electrotonus hyperpolarizing 90–100 ms; XELOX, Treatment regimen including oxaliplatin and capecitabine
Received May 12, 2009. Revised July 9, 2009. Accepted July 10, 2009.