[Oxaliplatin neurotoxicity]

Abstract

Oxaliplatin is a reference drug in the treatment of digestive-tract tumors, especially colorectal cancer. Its toxicity profile is dominated by a peripheral sensitive neuropathy, with neuromuscular manifestations. This neurotoxicity has 2 components: an acute toxicity characterized by a rapid onset of cold-induced distal dysesthesia and/or paresthesia, muscular contractions, numbness, stiffness, usually transient but able to evolve into a chronic, persistent sensory peripheral neuropathy that eventually causes functional impairment. A persistent sensory peripheral neuropathy may develop with prolonged treatment, eventually causing superficial and deep sensory loss, sensory ataxia and functional impairment. This neurotoxicity is frequent, 80%of the patients and becomes chronic in 15 to 20%of the patients, sometimes irreversible. The mechanism of this neurotoxicity has been elucidated: an increased neuronal excitability is due to the action of oxaliplatin on voltage-gated sodium channels through chelation of calcium by the oxaliplatin metabolite. The prevention of this neurotoxicity is a major goal, taking in account the wide indications of this drug. Different approaches have been or are evaluated, based on pathogenic or practical concepts: 1) modifications of the administration schedule; 2) substances acting upon sodium channels : calcium-magnesium, carbamazepine, gabapentine, venlafaxin; 3) detoxifying agents and antioxydants: glutathion, amifostine, alphalipoic acid, tocopherol ; 4) substances used in other kinds of neuropathy: glutamine, alphalipoic acid; 5) neurotrophic factors: NGF, LIF; 6) oxaliplatin analogs, with a DACH platin, without oxalate. Calcium-magnesium infusion seem to be an efficient and safe approach. Further studies are necessary for a better understanding and prevention of this neurotoxicity, potentially severe.