Peripheral Neuropathy Induced by Microtubule-Targeted Chemotherapies: Insights into Acute Injury and Long-term Recovery

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of disability in cancer survivors. CIPN investigations in preclinical model systems have focused on either behaviors or acute changes in nerve conduction velocity (NCV) and amplitude, but greater understanding of the underlying nature of axonal injury and its long-term processes is needed as cancer patients live longer. In this study, we used multiple independent endpoints to systematically characterize CIPN recovery in mice exposed to the antitubulin cancer drugs eribulin, ixabepilone, paclitaxel, or vinorelbine at MTDs. All of the drugs ablated intraepidermal nerve fibers and produced axonopathy, with a secondary disruption in myelin structure within 2 weeks of drug administration. In addition, all of the drugs reduced sensory NCV and amplitude, with greater deficits after paclitaxel and lesser deficits after ixabepilone. These effects correlated with degeneration in dorsal root ganglia (DRG) and sciatic nerve and abundance of Schwann cells. Although most injuries were fully reversible after 3-6 months after administration of eribulin, vinorelbine, and ixabepilone, we observed delayed recovery after paclitaxel that produced a more severe, pervasive, and prolonged neurotoxicity. Compared with other agents, paclitaxel also displayed a unique prolonged exposure in sciatic nerve and DRG. The most sensitive indicator of toxicity was axonopathy and secondary myelin changes accompanied by a reduction in intraepidermal nerve fiber density. Taken together, our findings suggest that intraepidermal nerve fiber density and changes in NCV and amplitude might provide measures of axonal injury to guide clinical practice. This detailed preclinical study of the long-term effects of widely used antitubulin cancer drugs on the peripheral nervous system may help guide clinical evaluations to improve personalized care in limiting neurotoxicity in cancer survivors. .

Vinca alkaloids, thalidomide and eribulin‐induced peripheral neurotoxicity: From pathogenesis to treatment

“…This is an analogue of halichondrin B (toxin from the sponge Halichondria okadai ), is a newer chemotherapeutic agent that also binds to tubulin and affects microtubule dynamics . Likewise, the effect of eribulin is primarily microtubule depolymerization, which also has been shown to disrupt axonal transport leading to neuropathy in animal models …”

Integrins protect nociceptive neurons in models of paclitaxel-mediated peripheral sensory neuropathy

“…It is a commonly used chemotherapeutic drug for treatment of solid cancers such as breast, ovarian and lung cancers by virtue of its ability to inhibit cell division. Paclitaxel is more likely than other chemotherapeutics to cause chronic sensory neuropathy in patients and animal models (Gornstein and Schwarz, 2014;Hershman et al, 2011;Majithia et al, 2016;Shah et al, 2018;Wozniak et al, 2018;Xiao et al, 2011).…”

Wanna Get Away? Maintenance Treatments and Chemotherapy Holidays in Gynecologic Cancers

“…Both schedules are associated with cumulative toxicity, including neurotoxicity, which is the main cause of cancer disability. 77 As a result, treatment holidays or treatment-free periods have been introduced; however, preclinical data suggest that longer taxane-free intervals might be associated with treatment resistance. 78,79 Ovarian cancer xenograft models have shown that continuous administration of taxanes is associated with less treatment resistance, including drug resistance-related genes and drug efflux transporter expression, as well as reduced tumor growth and proliferation.…”

“…Given the risk of cumulative toxicity of cisplatin and paclitaxel chemotherapy, including renal impairment and neuropathy, clinicians often must stop the chemotherapy treatment or stop one of the drugs soon after six cycles have been delivered. 77,94,95 The role of bevacizumab as a single-agent maintenance treatment has not yet been explored as part of the GOG-240 clinical trial, and this has led to concerns for regulatory agencies when only single-agent bevacizumab is administered as maintenance treatment.…”