Affiliations of authors: E. Winquist, M. Vincent, Division of Medical Oncology, London Regional Cancer Centre and University of Western Ontario, London, Ontario, Canada; W. Stadler, Department of Medicine, University of Chicago, Chicago. IL.
Correspondence to: Eric Winquist, M.D., London Regional Cancer Centre, 790 Commissioners Rd. East, London, Ontario, Canada N6A 4L6 (e-mail: eric.winquist{at}lrcc.on.ca).
Oxaliplatin (trans-l-1,2-diaminocyclohexane oxalatoplatinum) inhibits DNA synthesis by cross-linking DNA (1). Oxaliplatin also interferes with the DNA mismatch repair enzyme complex by decreasing replicative bypass of platinum-DNA adducts, making it of possible therapeutic interest for cisplatin-resistant tumors. Oxaliplatins principal dose-limiting toxicity is sensory neuropathy, with both acute and chronic components. Acute neurotoxicity is often cold-induced and typically consists of distal paresthesias or dysesthesias. Laryngopharyngeal dysesthesia, which causes a distressing sensation of difficulty in breathing or swallowing, may also occur. Chronic peripheral neuropathy intensifies with cumulative exposure but resolves when treatment is stopped (2). Unequivocal acute motor neuropathy has not been reported (3,4).
A 68-year-old man with metastatic transitional cell carcinoma of the renal pelvis with a retroperitoneal mass and hepatic metastases was treated with oxaliplatin (130 mg/m2 intravenously [iv] over 2 hours) preceded by dexamethasone (10 mg iv) and ondansetron (8 mg iv). Ten minutes after completing the first oxaliplatin infusion, the patient complained of dyspnea and diplopia. Vital signs were normal, and the patient was alert, oriented, and did not appear to be in respiratory distress. Cranial nerve testing demonstrated persistent diplopia only on horizontal outward gaze affecting both eyes. There were no other findings on neurologic examination except for pre-existing grade 1 peripheral sensory neuropathy. The patient was warmed with blankets, treated with thiamine, and admitted to the hospital for observation. Three hours after symptoms began, all had resolved completely, and the patient was discharged the next day asymptomatic. Subsequent doses of oxaliplatin were reduced by 25% (infused over 4 hours) and were uneventful. A computed tomography scan of the brain and orbits showed no evidence of stroke or intracranial malignancy. Oxaliplatin treatment was stopped after three cycles because of disease progression, and the patient died 3 months after starting treatment without further indications of neurologic disease.
Lateral rectus muscle weakness may result from disease affecting either the abducens nucleus and nerve or the muscle itself (5). In the absence of other cranial nerve abnormalities, midbrain and myopathic processes are quite unlikely. The abducens nerve may be affected by mass effect (e.g., tumor, aneurysm, skull fracture, cavernous sinus thrombosis), meningeal disease (e.g., carcinoma, meningitis, hemorrhage), raised intracranial pressure, infarction, infection, or demyelination. None of these diagnoses suitably explains the self-limited and isolated weakness of both lateral rectus muscles observed in this patient. The close temporal relationship between oxaliplatin treatment and simultaneous acute laryngopharyngeal dysesthesia make a diagnosis of bilateral acute abducens neuropathy due to oxaliplatin the most likely explanation. The patient was rechallenged with oxaliplatin, and symptoms were not reproduced; however, the drug dose had been modified. Acute oxaliplatin-induced neuropathy is associated with striking signs of hyperexcitability in motor nerves similar to neuromyotonia (4). Thus, occurrence of acute motor neuropathy due to oxaliplatin should not be surprising; however, it is rarely seen. Our patient may have been predisposed to acute motor neuropathy because of prior cisplatin exposure (total dose = 700 mg/m2). The length of the abducens nerve may render it more susceptible to neuropathy than other cranial nerves.
This case confirms that oxaliplatin can have clinically significant acute motor nerve effects in patients previously treated with cisplatin. An adequately warm environment, dose modification, and the use of protective agents, such as glutathione or calcium gluconate/magnesium chloride infusions, should be considered in these patients (6,7).
NOTES
Supported by contract N01-CM-17107 and Public Health Service grant L98-0128 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.
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6 Cascinu S, Catalano V, Cordella L, Labianca R, Giordani P, Baldelli AM, et al. Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: a randomized, double-blind, placebo-controlled trial. J Clin Oncol 2002;20:347883.
7 Gamelin E, Gamelin L, Delva R, Guerin-Meyer V, Morel A, Boisdron-Celle M, et al. Prevention of oxaliplatin peripheral sensory neuropathy by Ca+ gluconate/Mg+ chloride infusions: a retrospective study [abstract]. Proc ASCO 2002;20:157a.
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