Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy

Abstract

Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics. It can lead to detrimental dose reductions and discontinuation of treatment, and severely affects the quality of life of cancer survivors. Clinically, chemotherapy-induced peripheral neuropathy presents as deficits in sensory, motor, and autonomic function which develop in a glove and stocking distribution due to preferential effects on longer axons. The pathophysiological processes are multi-factorial and involve oxidative stress, apoptotic mechanisms, altered calcium homeostasis, axon degeneration and membrane remodeling as well as immune processes and neuroinflammation. This review focusses on the commonly used antineoplastic substances oxaliplatin, cisplatin, vincristine, docetaxel, and paclitaxel which interfere with the cancer cell cycle—leading to cell death and tumor degradation—and cause severe acute and chronic peripheral neuropathies. We discuss drug mechanism of action and pharmacokinetic disposition relevant to the development of peripheral neuropathy, the epidemiology and clinical presentation of chemotherapy-induced neuropathy, emerging insight into genetic susceptibilities as well as current understanding of the pathophysiology and treatment approaches.

Searching for analgesic drug candidates alleviating oxaliplatin‐induced cold hypersensitivity in mice

“…As shown in the prevention protocol involved in our study, in oxaliplatin-treated mice, duloxetine attenuated the development of early-phase cold allodynia, but it had no prophylactic effect against the development of late-phase allodynia. This finding seems to confirm that the development of early-phase and late-phase CIPN in oxaliplatin-treated mice might be mediated by distinct mechanisms (Furgała, Fijałkowski, et al, 2018;Sałat et al, 2019;Starobova & Vetter, 2017). Of note, in this prevention protocol, we noted decreased latencies to pain reaction in vehicle-treated non-neuropathic mice on day 7.…”

“…There is a large body of evidence showing that oxaliplatin induces two forms of neuropathy-acute and chronic (reviewed in Starobova & Vetter, 2017), and these two phases are thought to be mediated by distinct mechanisms: altered neuronal excitability, TRPA1 channel activation (Nakagawa & Kaneko, 2017), impaired calcium homeostasis-all involved mainly in the development of the early phase, and mitochondrial dysfunction, glial cell activation, oxidative stress, axon degeneration, neuroinflammation underlying the late one (Nakagawa & Kaneko, 2017;Sisignano et al, 2014;Starobova & Vetter, 2017). Therefore, the efficacy of analgesics used for pain relief in these two phases of CIPN might be also different (Furgała, Fijałkowski, et al, 2018;Sałat et al, 2019).…”

Carboplatin and vincristine neurotoxicity in the treatment of pediatric low‐grade gliomas

“…In our study, we did not identify risk factors predisposing patients to peripheral neuropathy. For example, age did not influence vincristine‐induced neuropathy as it did in other studies . Prior treatment may predispose to peripheral neuropathy but no patients in this cohort received other chemotherapeutic agents before initiating CV .…”

“…Despite the fact that Previous studies have shown that most patients develop some degree of peripheral neuropathy at a cumulative dose of more than 4 mg/m 2 . 17,18 In our study, patients developed peripheral neuropathy after receiving, on average, a cumulative dose of 2.90 mg/m 2 of vincristine, suggesting that the intensity of vincristine infusion during induction increases the risk of developing neuropathy. Neurotoxicity was most marked during induction, but decreased during the maintenance phase of therapy in tandem with reduced vincristine intensity.…”

“…For example, age did not influence vincristineinduced neuropathy as it did in other studies. 18 Prior treatment may predispose to peripheral neuropathy but no patients in this cohort received other chemotherapeutic agents before initiating CV. 17 Genetic factors such as polymorphisms could be responsible for intraindividual differences.…”