Vincristine-Induced Peripheral Neuropathy (VIPN) in Pediatric Tumors: Mechanisms, Risk Factors, Strategies of Prevention and Treatment

Abstract

Vincristine-induced peripheral neurotoxicity (VIPN) is a very common side effect of vincristine chemotherapy among pediatric patients with cancer. Neuropathy may be sensory, motor and/or autonomic, with consequent reduction, delay or discontinuation of vincristine-chemotherapy, but also pain, disability, reduced quality of life of patients and an increase in medical costs. Vincristine acts out its antineoplastic function by altering the normal assembly and disassembly of microtubules, with their consequent mitosis block and death. Vincristine leads to VIPN through a complex mechanism of damage, which occurs not only on the microtubules, but also on the endothelium and the mitochondria of nerve cells. Furthermore, both patient-related risk factors (age, race, ethnicity and genetic polymorphisms) and treatment-related risk factors (dose, time of infusion and drug–drug interactions) are involved in the pathogenesis of VIPN. There is a lack of consensus about the prophylaxis and treatment of VIPN among pediatric oncologic patients, despite several molecules (such as gabapentin, pyridoxine and pyridostigmine, glutamic acid and glutamine) having been already investigated in clinical trials. This review describes the molecular mechanisms of VIPN and analyzes the risk factors and the principal drugs adopted for the prophylaxis and treatment of VIPN in pediatric patients with cancer.

A Brief Review of In Vitro Models for Injury and Regeneration in the Peripheral Nervous System

“…Chemotherapy-induced peripheral neuropathies (CIPN) are a set of clinical conditions observed in patients administered with chemotherapeutics. CIPN commonly occurs as an undesirable, dose-limiting effect of several chemotherapeutics such as cisplatin, paclitaxel [ 143 , 144 ], vinblastine, and vincristine [ 145 ], mainly due to chemically induced damage to axons and cell bodies of peripheral neurons. Though the underlying mechanism of CIPN is not completely known, axonal degeneration or ‘dying back’ is a well-recognized histopathological hallmark [ 27 , 146 ], and understanding the molecular mechanism behind such pathogenesis is crucial to develop therapeutic strategies.…”

Mechanisms, Characteristics, and Treatment of Neuropathic Pain and Peripheral Neuropathy Associated with Dinutuximab in Neuroblastoma Patients

“…Oxaliplatin accumulates in dorsal root ganglion neurons and causes functional changes in nerve excitability to undergo severe neuropathy [ 63 ]. Vincristine determines a compromission of microtubule function and axonal transport with mitochondrial toxicity [ 7 , 64 ]. Another pathway observed in the chemotherapeutic drugs neurotoxicity is the stimulation of NK cells by upregulation of stress related proteins in tumor and/or downregulation of inhibitory self-ligands on the target cell surface [ 65 , 66 , 67 ].…”

“…The treatment strategy for high-risk neuroblastoma patients includes induction chemotherapy, surgery, consolidation with myeloablative high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (SCT), and maintenance therapy. Better tumor responses after induction therapy appear to be critical to improve the percentage of long-term survival, but the dose intensity of traditional drugs such as platin compounds, cyclophosphamide, etoposide, doxorubicin, vincristine, topotecan, and temozolomide cannot be increased because of their hematological and non-hematological toxicities [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. Moreover, some new combinations of agents active against neuroblastoma have been developed with encouraging results, but none of them have yet been adopted in large randomized trials [ 14 , 15 , 16 ].…”

Peripheral Nervous System Involvement in Non-Primary Pediatric Cancer: From Neurotoxicity to Possible Etiologies

“…Of the potential neuroprotective agents, the only ones that have been trialed in the pediatric population are carbamazepine, glutamic acid and amifostine for the prevention of CIPN, and intravenous immunoglobulin, pyridoxine/pyridostigmine and gabapentin for treatment, with limited evidence (Level C) for benefit [ 3 ]. However, in a recent review of VIPN (probably, the most well studied CIPN in the pediatric population) has been reported that pyridoxine and pyridostigmine may induce an improvement in symptoms while glutamic acid and glutamine may have a good preventive role [ 113 ].…”