Chemotherapy-Induced Peripheral Neuropathy: Epidemiology, Pathomechanisms and Treatment

Abstract

Purpose: This review provides an update on the current clinical, epidemiological and pathophysiological evidence alongside the diagnostic, prevention and treatment approach to chemotherapy-induced peripheral neuropathy (CIPN).

Findings: The incidence of cancer and long-term survival after treatment is increasing. CIPN affects sensory, motor and autonomic nerves and is one of the most common adverse events caused by chemotherapeutic agents, which in severe cases leads to dose reduction or treatment cessation, with increased mortality. The primary classes of chemotherapeutic agents associated with CIPN are platinum-based drugs, taxanes, vinca alkaloids, bortezomib and thalidomide. Platinum agents are the most neurotoxic, with oxaliplatin causing the highest prevalence of CIPN. CIPN can progress from acute to chronic, may deteriorate even after treatment cessation (a phenomenon known as coasting) or only partially attenuate. Different chemotherapeutic agents share both similarities and key differences in pathophysiology and clinical presentation. The diagnosis of CIPN relies heavily on identifying symptoms, with limited objective diagnostic approaches targeting the class of affected nerve fibres. Studies have consistently failed to identify at-risk cohorts, and there are no proven strategies or interventions to prevent or limit the development of CIPN. Furthermore, multiple treatments developed to relieve symptoms and to modify the underlying disease in CIPN have failed.

Implications: The increasing prevalence of CIPN demands an objective approach to identify at-risk patients in order to prevent or limit progression and effectively alleviate the symptoms associated with CIPN. An evidence base for novel targets and both pharmacological and non-pharmacological treatments is beginning to emerge and has been recognised recently in publications by the American Society of Clinical Oncology and analgesic trial design expert groups such as ACTTION.

Keywords: Chemotherapy; Epidemiology; Mechanism of action; Neuropathy; Neurotoxicity; Oxaliplatin; Paclitaxel; Pain; Peripheral neuropathy; Prevalence.

Fig. 1

The current hypothesis for the pathogenesis of OIPN. Accumulation of oxaliplatin occurs in dorsal root ganglion neurons, where it interferes with DNA and mtDNA cross-linking. This results in a direct dose-dependent toxicity of DRG neurons and neuronal mitochondria. There is a subsequent decrease in mitochondrial respiration and ATP. The resultant oxidative stress contributes to disruption in DNA and mtDNA replication and transcription, leading to diminished energy status and increased neuronal apoptosis. Increased production of ROS together with activation of astrocytes causes the release of pro-inflammatory mediators TNF-α and IL-1β and decreased expression of cytokines IL-10 and IL-4 with a neuroprotective function. Subsequently, leucocytes are activated and travel down a chemotactic gradient to the dorsal root ganglion and peripheral nerves, leading to neuroinflammation. Neuroinflammation and ROS cause damage to dorsal root ganglion neurons, leading to apoptosis, which contributes to calcium dysregulation, axonal energy depletion and damage to neuronal organelles. Both ROS and neuroinflammation are implicated in nociceptor sensitisation, mechanical hyperalgesia and cold allodynia in preclinical models. Oxaliplatin interacts directly with VGKC, NaV channel, TRPM isoforms in sensory neurons contributing to cold hyperalgesia/allodynia and hyperexcitability of peripheral neurons. Further, a metabolite of oxaliplatin, oxalate chelates Ca²⁺ ions in the acute phase, contributing to neuronal excitability and increasing spontaneous activity of neurons. ATP: adenosine triphosphate, Ca²⁺: calcium, DNA: deoxyribonucleic acid, DRG: dorsal root ganglion, NaV: voltage-gated sodium, OIPN: oxaliplatin-induced peripheral neuropathy, mtDNA: mitochondrial DNA, ROS: reactive oxygen species, IL-1B: interleukin 1B, IL-4: interleukin 4, IL-10: interleukin 10, TRPM: transient receptor potential melastatin, TNF-α: tumour necrosis factor-α, VGKC: voltage-gated potassium channel

Fig. 2

The current hypothesis for the pathogenesis of TIPN. Taxanes such as paclitaxel directly interact with TLR-4 on macrophages. This interaction upregulates the expression of TLR-4 and activates macrophages leading to the release of NF-kB, leading to further downstream pro-inflammatory cascades. Activated Langerhans cells release IL-6, IL-8, IL-10 and MCP-1. Subsequently, there is activation and migration of macrophages, cytotoxic T-cells, monocytes and neutrophils towards the DRG and peripheral nerves. DRG neurons and IB4-/GCRP+ peripheral fibres increase expression of inflammatory associated markers such as TLR4, MyD88 and ERK1/2. Similarly, inflammatory signalling is increased in Schwann cells, microglia and DRG neurons together with markers of cellular stress. Oxidative stress and the generation of ROS further impacts upon mitochondrial performance, limits intracellular energy stores of peripheral neurons and contributes to inflammation and intracellular damage. Further, taxanes such as paclitaxel interact with the MPTP, which culminates in a reduction in ATP generation and mitochondrial generation. Taxanes disrupt microtubule polymerisation and impair the function of the axonal microtubule network. The expression of CaV 3.2 and NaV 1.7 are upregulated after treatment with taxanes, resulting in changes to the excitability threshold of peripheral neurons. The sensitisation of peripheral neurons and subsequent changes in neuronal excitability result in mechanical hypersensitivity and ectopic spontaneous activity which contribute to the development of TIPN. ATP: adenosine triphosphate, CaV: low voltage-activated T-type calcium channel, CGRP: calcitonin gene-related peptide, DAMP: damage-associated molecular pattern, DRG: dorsal root ganglion, ERK1/2: extracellular signal-regulated kinase, IB4: isolectin B4-binding glycoprotein, IL-6: interleukin 6, IL-8: interleukin 8, IL-10: interleukin 10, NaV: voltage-gated sodium, NF-kB: nuclear factor kappa B, MCP-1: monocyte chemoattractant protein-1, MEK: mitogen-activated protein kinase kinase, ROS: reactive oxygen species, TIPN: taxane-induced peripheral neuropathy, TLR-4: toll-like receptor 4

Fig. 3

The current hypothesis for the pathogenesis of VIPN (A), ThiPN (B) and BIPN (C). A Vinca alkaloids such as vincristine activate leucocytes and microglia, causing the attraction and activation of downstream pro-inflammatory cytokines, leading to neuroinflammation. Vinca alkaloids inhibit the polymerisation of microtubules and therefore the formation of mitotic spindles causing disruption to axonal transport. This, together with mitotoxicity, causes net energy loss by impairing the electron transport chain. These mechanisms culminate in a distal sensorimotor axonal neuropathy. B Thalidomide inhibits VEGF, b-FGF, NF-kB and TNF-a, leading to dysregulation of neurotrophins. This impedes signalling responsible for the survival and proliferation of neurons. Further, antiangiogenic properties of thalidomide cause secondary ischaemia and hypoxia of small nerve fibres, leading to damage to sensory nerve fibres. C Bortezomib causes the release of intracellular calcium from the endoplasmic reticulum in sensory neurons, leading to caspase activation and subsequent cellular apoptosis. Pro-inflammatory mediators are upregulated after treatment with bortezomib, leading to further cytokine signalling cascades and neuroinflammation. Bortezomib is mitotoxic, leading to damage to neuronal mitochondria, diminished respiration and reduced ATP production, culminating in neuronal energy failure. Further, oxidative stress and ROS contribute to intracellular damage to neuronal organelles (including mitochondria) and apoptotic mechanisms. Ultrastructural changes are seen in the myelin sheath of neurons, although the contribution of these changes warrants further investigation. AT: adenosine triphosphate, b-FGF: basic fibroblast growth factor, Ca²⁺ calcium, CCL21 -CXCL-9-C-X-C motif chemokine 9, CXCL-10-C-X-C motif chemokine 10, C-X-C motif chemokine 21, IL-1B: interleukin 1B, NF-kB: nuclear factor kappa B, SARM1: sterile alpha and TIR motif-containing 1, SFRP2: frizzled-related protein 2, TNF-α: tumour necrosis factor α, VEGF: vascular endothelial growth factor