Cisplatin-associated neurotoxicity: can it be prevented?

Abstract

Neurotoxicity remains the major dose-limiting toxicity of cisplatin. Peripheral sensory neuropathy, the primary type of cisplatin neurotoxicity, has been reported in 30-100% of patients with clinical symptoms typically developing after cumulative cisplatin doses of > or = 300 mg/m2. Several clinical studies have established an important dose-response, dose intensity-response and cumulative total dose-response relationship for cisplatin in the treatment of head and neck, testicular, melanoma, and ovarian cancers. In patients with these tumor types, the occurrence of moderate or severe neuropathy presents an important therapeutic dilemma. Several types of agents--including micleophilic sulfur thiols, neurotrophic factors, phosphonic acid antibiotics and free oxygen radical scavengers--have been investigated for amelioration of cisplatin-related neurotoxicity. Of these, amifostine is likely to be the first neuroprotective agent widely used to enhance the clinical effectiveness of cisplatin. Recently reported results from a multicenter phase III trial of women with advance ovarian cancer receiving combination chemotheraphy with cisplatin plus cyclophosphamide showed that amifostine pretreatment was associated with moderate but significant reductions in cisplatin-associated peripheral neuropathy, tinnitus and nephrotoxicity, while achieving equivalent pathological response rates and median survival. Preclinical data suggest that several additional agents, especially the neurotropic factors nerve growth factor, insulin-like growth factor-I and neurotrophin-3, merit further investigation. Nerve growth factor is the only agent reported to prevent, rather than partially protect, cisplatin-induced neuropathy in an experimental model.