Platinum‐induced peripheral neurotoxicity: From pathogenesis to treatment

Abstract

Platinum-induced peripheral neurotoxicity (PIPN) is a common side effect of platinum-based chemotherapy that may cause dose reduction and discontinuation, with oxaliplatin being more neurotoxic. PIPN includes acute neurotoxicity restricted to oxaliplatin, and chronic non-length-dependent sensory neuronopathy with positive and negative sensory symptoms and neuropathic pain in both upper and lower limbs.Chronic sensory axonal neuropathy manifesting as stocking-and-glove distribution is also frequent. Worsening of neuropathic symptoms after completing the last chemotherapy course may occur. Motor and autonomic involvement is uncommon. Ototoxicity is frequent in children and more commonly to cisplatin. Platinum-based compounds result in more prolonged neuropathic symptoms in comparison to other chemotherapy agents. Patient reported outcomes questionnaires, clinical evaluation and instrumental tools offer complementary information in PIPN. Electrodiagnostic features include diffusely reduced/abolished sensory action potentials, in keeping with a sensory neuronopathy. PIPN is dependent on cumulative dose but there is a large variability in its occurrence. The search for additional risk factors for PIPN has thus far yielded no consistent findings. There are currently no neuroprotective strategies to reduce the risk of PIPN, and symptomatic treatment is limited to duloxetine that was found effective in a single phase III intervention study. This review critically examines the pathogenesis, incidence, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of PIPN.

Oxaliplatin rechallenge in metastatic colorectal cancer patients with clinically significant oxaliplatin‐induced peripheral neurotoxicity

“…grade 1 OXAIPN in two patients (8%), grade 2 in 19 patients (76%), and grade 3 neuropathy in 4 (16%) patients Worsening of pre-existing OXAIPN was documented in seven (28%) patients and was significantly associated with higher OXA delivered cumulative dose (P < .001). Median TNSc scores following treatment (10; range [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] were significantly increased (P < .001), when compared to the scores recorded at the end of first line treatment (8; range [2][3][4][5][6][7][8][9][10][11][12]. Rechallenging OXA appears to relatively worsen the severity of existing OXAIPN.…”

“…1 However, the applicability of OXA is limited by the evidence of the chronic OXA-induced peripheral neurotoxicity (OXAIPN), which represents its most common and severe nonhematological and dose limiting toxicity, affecting up to 80% of OXA-treated patients. 2,3 The chronic form of OXAIPN is a pure sensory neuronopathy, closely resembling the typical characteristics of platinum compoundinduced peripheral neurotoxicity. Pathologically, there is evidence of dorsal root ganglia (DRG) neurons apoptosis generated by oxidative stress, mitochondrial dysfunction and formation of DNA adducts and cross-links.…”

“…7,8 Moreover, it is considered that the pre-existing neurotoxicity as a result of exposure to previous OXA-based chemotherapy is considered as a significant risk factor of developing more severe chronic OXAIPN in patients requiring OXA rechallenge. 2 Despite the significant clinical relevance of therapeutic OXA rechallenge in the metastatic setting of CRC, the safety profile of this therapeutic strategy in terms of neurotoxicity is poorly documented.…”

Co‐expression gene modules involved in cisplatin‐induced peripheral neuropathy according to sensitivity, status, and severity

“…With higher cumulative doses and longer cisplatin exposure times, the probability of occurrence and severity of cisplatin-induced peripheral neuropathy will increase. 7 Individuals' sensitivity to cisplatin treatment can differ during clinical treatment. 8 Some patients experience relatively mild symptoms, but others suffer from serious symptoms that can lead to limits on or cessation of treatment.…”

“…The neurotoxicity caused by cisplatin varies greatly among patients, and few predictors of appearance, duration of symptoms, susceptibility, or severity are available. With higher cumulative doses and longer cisplatin exposure times, the probability of occurrence and severity of cisplatin‐induced peripheral neuropathy will increase 7 . Individuals' sensitivity to cisplatin treatment can differ during clinical treatment 8 .…”