Abstract
Oxaliplatin-induced peripheral neurotoxicity (OIPN) is a severe and potentially permanent side effect of cancer treatment affecting the majority of oxaliplatin-treated patients, mostly with the onset of acute symptoms, but also with the establishment of a chronic sensory loss that is supposed to be due to dorsal root ganglia neuron damage. The pathogenesis of acute as well as chronic OIPN is still not completely known, and this is a limitation in the identification of effective strategies to prevent or limit their occurrence. Despite intense investigation at the preclinical and clinical levels, no treatment can be suggested for the prevention of OIPN, and only limited evidence for the efficacy of duloxetine in the treatment setting has been provided. In this review, ongoing neuroprotection clinical trials in oxaliplatin-treated patients will be analyzed with particular attention paid to the hypothesis leading to the study, to the trial strengths and weaknesses, and to the outcome measures proposed to test the efficacy of the therapeutic approach. It can be concluded that (1) prevention and treatment of OIPN still remains an important and unmet clinical need, (2) further, high-quality research is mandatory in order to achieve reliable and effective results, and (3) dose and schedule modification of OHP-based chemotherapy is currently the most effective approach to limit the severity of OIPN.
Highlights
Oxaliplatin (OHP)-induced peripheral neurotoxicity (OIPN) is a severe and potentially permanent side effect of cancer treatment [1,2]
Calmangafodipir (PledOx® ), a compound derived from the contrast agent used in magnetic resonance imaging mangafodipir, possessing antioxidant and MnSOD-mimetic activities [41,42], was evaluated in a clinical trial of 173 patients with colorectal cancer treated with OHP-based chemotherapy and in this phase II randomized, placebo-controlled, double blind-trial, pre-treatment with PledOx significantly reduced the neurotoxicity of the treatment, without reducing its antineoplastic efficacy [43]
The primary outcome measure of this study focused on the acute symptoms of Oxaliplatin-induced peripheral neurotoxicity (OIPN) is the cold detection threshold assessed on day 42 of treatment
Summary
Oxaliplatin (OHP)-induced peripheral neurotoxicity (OIPN) is a severe and potentially permanent side effect of cancer treatment [1,2]. Unlike nuclear DNA, mitochondrial DNA does not have any DNA repair system (e.g., base excision repair, nucleotide excision repair pathways) and, platinum adducts cannot be removed causing problems in mitochondrial protein synthesis, impairing the mitochondrial respiratory chain functionality and, eventually, leading to energy failure and oxidative stress These observations were subsequently extended and in a rat model of OIPN reported by Xiao and Bennet [24] it was shown an increase in swollen and vacuolated mitochondria in saphenous nerves of treated animals compared to controls. Animal evidence of different susceptibility in different mice strains suggested a genetic background to explain this difference [4], but the several studies performed in OHP-treated patients failed so far to provide firm confirmation [30,31]
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