Oxaliplatin‐induced neurotoxicity and the development of neuropathy

Abstract

The pathophysiology of oxaliplatin-induced neurotoxicity remains unclear, although in vitro studies suggest involvement of voltage-gated Na+ channels. In the present study, clinical assessment was combined with nerve conduction studies (NCS) and nerve excitability studies in 16 patients after completion of oxaliplatin therapy. Chronic neuropathic symptoms persisted in 50% of patients. NCS confirmed abnormalities in symptomatic patients: sensory potentials were significantly low, whereas motor studies remained essentially normal. At 12-month follow-up of symptomatic patients, positive sensory symptoms improved but NCS abnormalities persisted. Cumulative oxaliplatin dose was a predictor of neuropathy, and long-term effects appeared to be minimized by low single-infusion dosages. Nerve excitability measures in symptomatic patients established that axons were of high threshold. Refractoriness was significantly greater in patients (symptomatic group, 56.3 +/- 24.9%; entire patient group, 46.3 +/- 12.5%; controls, 27.1 +/- 1.9%; P < 0.05). Thus, although positive sensory symptoms of oxaliplatin-induced neuropathy improved, negative sensory symptoms and abnormalities of sensory nerve conduction persisted. Differences in nerve excitability measures, particularly refractoriness, support in vitro studies indicating involvement of voltage-gated transient Na+-channel dysfunction in the development of oxaliplatin-induced neurotoxicity.

Impact of Oxaliplatin-Induced Neuropathy in Patients with Colorectal Cancer: A Prospective Evaluation at a Single Institution

“…The presence of comorbidities in our patient population therefore did not seem to significantly influence the rates of dose reduction and treatment cessation-a finding that supports the hypothesis that comorbidities are not associated with a greater risk of oxaliplatin-induced neuropathy. In fact, earlier trials had not found an association of comorbidities such as diabetes with a greater incidence of oxaliplatin-induced persistent peripheral sensory neuropathy [14][15][16] . On the other hand, our lower proportion of participants with grade 3 neuropathy, treatment cessation, and dose reduction might be explained by the inclusion of participants taking pain medications.…”

Long-Term Neuropathy After Oxaliplatin Treatment: Challenging the Dictum of Reversibility

“…Objective measures of nerve function reveal further lasting deficits in sensory nerves [11,14,34], suggesting that, rather than recovery, patients undergo adaptation to chronic symptoms [35].…”

“…Neurophysiological assessment of nerve function was undertaken using conventional nerve conduction studies [14,26] and axonal excitability studies [12,27]. A Medelec Synergy system (Oxford Instruments, Oxfordshire, U.K.) was used for nerve conduction studies of upper and lower limb nerves.…”

“…Although it has been reported that oxaliplatin-induced neurotoxicity is reversible upon treatment cessation [1,3,5], other reports suggest that oxaliplatin-induced neurotoxicity may be long lasting [6, 10,11]. Recently, axonal excitability studies [12,13] provided evidence for striking progressive changes in peripheral nerve function that developed across oxaliplatin treatment, predicting the development of neuropathy [6,8,14,15]. In the present study, prospective and longitudinal assessments of oxaliplatin-treated patients were undertaken to determine the extent to which oxaliplatin treatment induces long-standing alterations in peripheral nerve function.…”

In Reply

“…In addition, the findings of nerve conduction studies do not always correlate with the severity of sensory neuropathy. For example, it has been shown that the abnormalities of sensory NCV may persist even though the symptoms of oxaliplatininduced neuropathy have been remarkably reduced after discontinuation of oxaliplatin treatment [6].…”