Acute oxaliplatin-induced peripheral nerve hyperexcitability.
OBJECTIVE
Oxaliplatin is a novel platinum compound with clinical activity in several malignancies. Neurotoxicity is dose-limiting and occurs in two distinct forms, an acute neurologic symptom complex that occurs within hours or days of therapy and a chronic, cumulative sensory neuropathy.


METHODS
Patients were treated in a phase I study designed to establish the maximum-tolerated dose of capecitabine given with oxaliplatin. Because of the unusual neurosensory toxicity of oxaliplatin, detailed neurologic examination, needle electromyography (EMG), and nerve conduction studies (NCS) were performed before and the day after oxaliplatin in a subset of 13 patients. Carbamazepine therapy was tried in 12 additional patients to determine whether the neurologic effects might be relieved.


RESULTS
All patients experienced acute, reversible neurotoxicities with oxaliplatin. Symptoms included paresthesias, dysesthesias, cold hypersensitivity, jaw pain, eye pain, pain in the arm used for drug infusion, ptosis, leg cramps, and visual and voice changes. Serial EMG and NCS revealed striking signs of hyperexcitability in motor nerves after oxaliplatin. In patients who achieved therapeutic levels, carbamazepine did not alter the clinical or electromyographic abnormalities.


CONCLUSIONS
The acute neurotoxicity seen with oxaliplatin is characterized by peripheral-nerve hyperexcitability, and the findings are similar to the clinical manifestations of neuromyotonia. Carbamezepine, which provides symptomatic relief in acquired neuromytonia, did not seem to be beneficial. Efforts to identify a successful neuroprotectant strategy would have a major impact on improving patient quality of life and the ability to deliver full doses of oxaliplatin.
Wilson
Richard H
RH
Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Lehky
Tanya
T
Thomas
Rebecca R
RR
Quinn
Mary G
MG
Floeter
Mary Kay
MK
Grem
Jean L
JL
D000208:Acute Disease; D000368:Aged; D000927:Anticonvulsants / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D000069287:Capecitabine; D002220:Carbamazepine / Q000627:therapeutic use; D017321:Clinical Trials, Phase I as Topic; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004576:Electromyography / Q000187:drug effects; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives; D006801:Humans; D020386:Isaacs Syndrome / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009431:Neural Conduction / Q000187:drug effects*; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects*; D000077150:Oxaliplatin; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000188:drug therapy / Q000503:physiopathology*; D017211:Treatment Failure
D000927:Anticonvulsants; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D002220:Carbamazepine; D000069287:Capecitabine; D005472:Fluorouracil