Chemotherapy-induced peripheral neuropathy: Prevention and treatment strategies

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose limiting side effect of many commonly used chemotherapeutic agents, including platinum drugs, taxanes, epothilones and vinca alkaloids, and also newer agents such as bortezomib and lenolidamide. Symptom control studies have been conducted looking at ways to prevent or alleviate established CIPN. This manuscript provides a review of studies directed at both of these areas. New evidence strongly suggests that intravenous calcium and magnesium therapy can attenuate the development of oxaliplatin-induced CIPN, without reducing treatment response. Accumulating data suggest that vitamin E may also attenuate the development of CIPN, but more data regarding its efficacy and safety should be obtained prior to its general use in patients. Other agents that look promising in preliminary studies, but need substantiation, include glutamine, glutathione, N-acetylcysteine, oxcarbazepine, and xaliproden. Effective treatment of established CIPN, however, has yet to be found. Lastly, paclitaxel causes a unique acute pain syndrome which has been hypothesised to be caused by neurologic injury. No drugs, to date, have been proven to prevent this toxicity.

Introduction

Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose limiting side effect of many older commonly used chemotherapeutic agents, including platinum drugs, taxanes, epothilones and vinca alkaloids, but also newer agents such as bortezomib and lenolidamide (Table 1).1, 2 The incidence of CIPN can be variable, but often ranges from 30 to 40% of patients receiving chemotherapy. A number of factors influence the incidence of CIPN in patients receiving neurotoxic chemotherapy, including patient age, dose intensity, cumulative dose, therapy duration, coadministration of other neurotoxic chemotherapy agents, and pre-existing conditions such as diabetes and alcohol abuse. While symptoms may resolve completely, in some instances CIPN is only partly reversible, and in other cases it does not appear to be reversible at all.1, 3

CIPN can be extremely painful and/or disabling, causing significant loss of functional abilities and decreasing quality of life. Neurotoxic chemotherapeutic agents may cause structural damage to peripheral nerves resulting in aberrant somatosensory processing of the peripheral and/or central nervous system.⁴ This resultant peripheral neuropathy can potentially affect both small fibre axons (temperature, pin prick) and large fibre sensory axons (vibration, proprioception). A common clinical course begins with paraesthesias (tingling) and dysaesthesias, commonly located in the toes and fingers. These symptoms then spread proximally to affect both lower and upper extremities in a characteristic ‘glove and stocking’ distribution.⁵ CIPN has not been adequately characterised nor the pain quantified clinically and can occur at various points in the pathogenic process. Further details regarding how these different agents cause CIPN and the resultant symptoms have been discussed in recent review articles.1, 2

Compared to other neuropathies or neuropathic pain syndromes, there is a resemblance to diabetic neuropathy with similar glove and stocking distribution and other characteristics, such as pain, paraesthesias, and dysaesthesias. However, treatments for diabetic neuropathies are not necessarily helpful for preventing or treating neuropathies associated with chemotherapy.

Given the prevalence of CIPN, and that it can be dose-limiting for several cytotoxic drugs, symptom control studies have been conducted looking at ways to prevent or alleviate established CIPN. Studies directed at both of these areas are reviewed below, with randomised trials being summarised in Table 2, Table 3.