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New Strategies May Protect Against Oxaliplatin-Induced Neurotoxicity

Oxaliplatin (Eloxatin, Sanofi-Synthelabo), a third-generation platinum drug active in colorectal and other cancers, has neurotoxicity as its dose-limiting toxicity; however, various strategies can be used to manage this adverse effect, according to a review article.

In his report, Axel Grothey, MD, with the Martin-Luther University Halle-Wittenberg, Germany, describes the neuropathy and neurotoxicity associated with oxaliplatin and the underlying mechanisms and strategies for counteracting this side effect.

Oxaliplatin induces 2 forms of neuropathy, 1 that is transient and occurs in up to 95% of patients and another that is chronic and cumulative and occurs at a grade 3/4 level in less than 20% of patients.

Transient neuropathy is completely reversible within a few hours or days and is generally triggered or aggravated by exposure to cold. Prolonging infusion rates and lowering peak plasma concentrations may prevent pharyngolaryngeal dysesthesias, one of the more common symptoms.

In contrast, chronic neuropathy consists of sensory impairment of peripheral neural function with distally pronounced dysesthesias and paraesthesias of the extremities of gradually prolonged duration. These eventually persist between treatment cycles and increase in intensity with the cumulative dose.

Data from 2 phase III trials (MOSAIC and NSABP C07) suggest that oxaliplatin-based chemotherapy can be safely administered in the adjuvant setting up to a comparatively high cumulative dose without persistence of severe neurotoxicity.

In addition, Dr. Grothey points out that "it is clinically important to note that onset of tumour response with oxaliplatin-based therapy usually occurs before a cumulative oxaliplatin dose of 700 mg/m² has been reached. This allows for a clinical decision to continue or stop oxaliplatin therapy in view of the observed efficacy of treatment."

According to Dr. Grothey, acute neurotoxicity may be clinically similar to voltage-gated ion channel disorders. Furthermore, no morphologic signs of neurotoxicity have been found in sural nerve biopsies. In contrast, neurophysiologic findings of chronic morphologic damage have been found with cumulative oxaliplatin-induced neurotoxicity.

Strategies for prophylaxis or treatment of oxaliplatin-induced neurotoxicity include a "stop-and-go strategy" (OPTIMOX), which involves increasing the cumulative oxaliplatin dose that can be given to individual patients until the neurotoxic threshold is reached.

Other strategies currently being tested involve use of neuromodulatory agents, such as calcium and magnesium ions, glutathione, carbamazepine, gabapentin, amifostine, and alpha-lipoic acid.

"Prospective trials investigating various therapeutic and prophylactic strategies are underway or have recently been completed, so that the actual value of these different approaches for clinical practice will soon be understood," Dr. Grothey notes.

Dr Grothey has received research grant support and honoraria, and has served as a consultant to Sanofi-Synthelabo.



Semin Oncol 2003;30:4 Suppl 15:5-13. "Oxaliplatin-safety profile: Neurotoxicity"

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