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.
Highlights
Chemotherapy-induced peripheral neuropathy (CIPN) is an adverse effect of many chemotherapeutic agents and a major cause of ongoing pain in cancer survivors (FarguharSmith and Brown, 2016)
Several other single nucleotide polymorphisms (SNPs), including in CAMKK1 (Calcium/Calmodulin Dependent Protein Kinase 1, involved in regulation of apoptosis), CYP2C8 (Cytochrome P450 Form 1) and CYP2C9 (Cytochrome P450 PB-1, both involved in hepatic drug clearance), NFATC2 (Nuclear Factor of Activated T-Cells 2), ID3 (Inhibitor Of Differentiation 3) and SLC10A2 have been suggested to be involved in vincristine-induced neuropathy (Johnson et al, 2011)
The phenotype of pain behaviors induced by oxalate differs significantly from oxaliplatin-induced neuropathy, which is characterized by cold allodynia and a lack of spontaneous nocifensive behavior (Deuis et al, 2013)
Summary
Chemotherapy-induced peripheral neuropathy (CIPN) is an adverse effect of many chemotherapeutic agents and a major cause of ongoing pain in cancer survivors (FarguharSmith and Brown, 2016). The histopathological changes associated with CIPN commonly involve large myelinated fibers, bortezomibinduced neuropathy involves small fibers (Cata et al, 2007; Wilkes, 2007; Gutierrez-Gutierrez et al, 2010) These changes to the morphological and molecular physiology of peripheral nerves result in the development of sensory and motoric symptoms such as hypersensitivity to mechanical stimuli or distal weakness due to mechanisms which are not entirely understood. The mechanism of action of chemotherapeutic agents that lead to potent effects on tumor cell proliferation and cell death are well-studied and relatively well understood (Figure 1) It is not entirely clear whether these (mostly) desirable effects on rapidly proliferating cells are responsible for causing undesirable effects on non-proliferating sensory neurons, or whether additional pharmacological effects contribute to the development of CIPN. The pathophysiology of CIPN is likely multifactorial and contribution of at least some specific anti-cancer mechanisms, discussed below, is probable
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