title: 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.
authors.affiliation: Prince of Wales Medical Research Institute, Barker Street, Randwick, Sydney, NSW 2031, Australia. m.kiernan@unsw.edu.au.
authors.forename: Susanna B
authors.initials: SB
authors.lastname: Park
authors.forename: Cindy S-Y
authors.initials: CS
authors.lastname: Lin
authors.forename: Arun V
authors.initials: AV
authors.lastname: Krishnan
authors.forename: David
authors.initials: D
authors.lastname: Goldstein
authors.forename: Michael L
authors.initials: ML
authors.lastname: Friedlander
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Kiernan
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001369:Axons / Q000187:drug effects* / Q000502:physiology*; D015415:Biomarkers; D002908:Chronic Disease; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000150:complications / Q000188:drug therapy; D004594:Electrophysiology; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000187:drug effects; D009431:Neural Conduction / Q000187:drug effects; D009460:Neurologic Examination; D020258:Neurotoxicity Syndromes / Q000503:physiopathology*; D009944:Organoplatinum Compounds / Q000009:adverse effects* / Q000627:therapeutic use; D000077150:Oxaliplatin; D011984:Sensory Receptor Cells / Q000187:drug effects; D015222:Sodium Channels / Q000187:drug effects; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D009944:Organoplatinum Compounds; D015222:Sodium Channels; D000077150:Oxaliplatin