Taxane and epothilone‐induced peripheral neurotoxicity: From pathogenesis to treatment

Abstract

Taxane-induced peripheral neurotoxicity (TIPN) is the most common nonhematological side effect of taxane-based chemotherapy, and may result in dose reductions and discontinuations, having as such a detrimental effect on patients' overall survival. Epothilones share similar mechanism of action with taxanes. The typical TIPN clinical presentation is mainly comprised of numbness and paresthesia, in a stocking-and-glove distribution and may progress more proximally over time, with paclitaxel being more neurotoxic than docetaxel. Motor and autonomic involvement is less common, whereas an acute taxane-induced acute pain syndrome is frequent. Patient reported outcomes questionnaires, clinical evaluation, and instrumental tools offer complementary information in TIPN. Its electrodiagnostic features include reduced/abolished sensory action potentials, and less prominent motor involvement, in keeping with a length-dependent, axonal dying back predominately sensory neuropathy. TIPN is dose-dependent and may be reversible within months after the end of chemotherapy. The single and cumulative delivered dose of taxanes is considered the main risk factor of TIPN development. Apart from the cumulative dose, other risk factors for TIPN include demographic, clinical, and pharmacogenetic features with several single-nucleotide polymorphisms potentially linked with increased susceptibility of TIPN. There are currently no neuroprotective strategies to reduce the risk of TIPN, and symptomatic treatments are very limited. This review critically examines the pathogenesis, incidence, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of TIPN. K E Y W O R D S assessment, chemotherapy, docetaxel, ixabepilone, neurotoxicity, paclitaxel, prevention 1 | INTRODUCTION Taxanes (paclitaxel, docetaxel, cabazitaxel) were among the most important new chemotherapy agents in the late 20th century. 1 Paclitaxel is a natural compound with potent anticancer properties, which was originally isolated from the bark of the Pacific yew tree (Taxus brevifolia) in 1967, but low natural availability and insolubility in water hindered its diffusion since the 1980s. 2 Paclitaxel and docetaxel are currently obtained through a semisynthetic process from a precursor contained in the needles of the European yew tree (Taxus baccata),which is more widely available worldwide. 2 Nanoparticle albuminbound paclitaxel (nab-paclitaxel) is a novel formulation containing human serum albumin to encapsulate hydrophobic paclitaxel molecules to increase tumor uptake and reduce hypersensitivity

Chemotherapy-Induced Peripheral Neuropathy: Epidemiology, Pathomechanisms and Treatment

“…Ab fibres and to a lesser extent Ad and C-fibres are affected in a glove-and-stocking distribution [31,76,77]. Patients report tingling, numbness, paraesthesia, neuropathic pain, cold-induced dysaesthesia and muscle cramps [26,78], which typically worsen with treatment and gradually improve with cessation [26], although 31 factor kappa B (NF-kB), initiating inflammatory and cytokine cascades [94]. TLR4, MyD88 and ERK1/2 expression is increased in IB4and CGRP ?…”

“…TIPN primarily causes an acute, length-dependent distal sensory neuropathy, accompanied by neuropathic pain, which may progress proximally in more severe cases. Aβ fibres and to a lesser extent Aδ and C-fibres are affected in a glove-and-stocking distribution [ 31 , 76 , 77 ]. Patients report tingling, numbness, paraesthesia, neuropathic pain, cold-induced dysaesthesia and muscle cramps [ 26 , 78 ], which typically worsen with treatment and gradually improve with cessation [ 26 ], although 31–44% of patients treated with docetaxel or paclitaxel report symptoms after up to 6 years of follow-up [ 79 – 81 ].…”

“…Chemotherapeutic agents result in neurotoxicity through a variety of mechanisms, culminating in a predominantly symmetrical sensory or sensorimotor, length-dependent neuropathy and autonomic dysfunction [23][24][25][26][27][28]. Neuropathic syndromes specific to chemotherapeutic agents can be observed, each with their own presentation and natural history [29][30][31][32][33] (Table 2). CIPN can develop, or continue to worsen, several months after treatment has stopped, in a phenomenon termed ''coasting''.…”

Integrated Medicine for Chemotherapy-Induced Peripheral Neuropathy

“…Bortezomib-induced CIPN can be reduced using subcutaneous administration [22]. Genetic variations may also set a role in the gene-environment interaction, which may act as predictive CIPN biomarkers [30][31][32][33][34][35][36][37][38][39][40][41][42][43], and are one of the risk factors for developing CIPN. It is recognized that the PNS damage triggers the migration of macrophages and Schwann cells into the lesions to clean up debris, followed by the release of neurotrophic factors by Schwann cells to promote neuroregeneration.…”

Mechanisms of Axon Elongation Following CNS Injury: What Is Happening at the Axon Tip?

“…Regardless of the multiple cellular sites of action, these studies determined that drugs that impact microtubule stability and dynamics may have therapeutic value in promoting axon regeneration. However, these drugs can lead to peripheral neuropathy, a potential major therapeutic caveat (Landowski et al, 2016 ; Tamburin et al, 2019 ). Furthermore, in contrast to the beneficial effects of taxol on CNS regeneration, treatment with taxol adversely affected regeneration in peripheral nerves (Hsu et al, 2017 ).…”