Emerging pharmacological strategies for the management of chemotherapy-induced peripheral neurotoxicity (CIPN), based on novel CIPN mechanisms

ABSTRACT

Introduction

Based on results of available clinical trials, the treatment and prevention of chemotherapy-induced peripheral neurotoxicity (CIPN) largely remains an unmet clinical need. However, new approaches have emerged in the last few years, attempting to modify the natural history of acute and late CIPN effects through a better knowledge of the pathogenic process on the molecular level.

Areas covered

Clinical results of recently published (last 5 years) or ongoing emerging therapeutic/preventive pharmacological approaches based on novel CIPN mechanisms have been identified from Pubmed and ClinicalTrials.gov. Results are reviewed and discussed, in order to assess the trend of new clinical studies but also to infer the role novel approaches may have in the future.

Expert opinion

The large heterogeneity of disease-causing mechanisms prevents researchers from identifying a reliable approach to effectively and safely treat or prevent CIPN. Understanding of novel pathophysiologic processes is leading the way to novel therapies, which, through targeting the sphingosine 1-phosphate receptor or pharmacologically inhibiting axonal degeneration might achieve in the future both treatment and prevention of CIPN. Toward this end, a multi-targeting approach, combining drugs to target different CIPN pathomechanisms seems to be a rational approach that warrants testing.

KEYWORDS:

• Chemotherapy
• neurotoxicity
• peripheral neuropathy
• molecular mechanisms
• treatment
• prevention

Article highlights

• Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common dose-limiting side effect of several anticancer medications.

• There are no agents recommended for the prevention of CIPN.

• The best available data support a modest recommendation for the symptomatic treatment of CIPN with duloxetine.

• The large heterogeneity of disease-causing mechanisms has limited of the development of a reliable approach to treat or prevent CIPN.

• Enhanced mechanistic approaches to identify potential druggable therapeutic targets are now available.

• Targeting sphingosine 1-phosphate receptor (S1PR1) and axonal degeneration appear to be the most attractive and promising options to treat and prevent CIPN, from the mechanistic point of view.

• A multi-targeting approach, combining drugs to target different CIPN pathomechanisms may provide a rational future approach.

Acknowledgments

This review paper was produced by members of the Clinical Working Group of the Toxic Neuropathy Consortium (TNC), representing the core TNC of the Peripheral Nerve Society (PNS). However, the members of the core TNC not quoted in the authors’ list are not qualified to be named as authors, contributors, collaborators, or co-investigators of this manuscript.

Declaration of interest

A Argyriou received fees for participation in a CIPN trial, sponsored by Laboratorios del Doctor Esteve, S.A., Spain (reference 26). He is a Board Member of the Toxic Neuropathy Consortium. J Bruna received fees from Laboratorios del Doctor Esteve, S.A. and Mundipharma Research GmbH as consultant and for trial design (reference 26). SB Park is a Board Member of the Toxic Neuropathy Consortium. G Cavaletti serves as a Consultant to PledPharma AB, Helsinn, Disarm, Rottapharm, and Toray. He is a non-voting member of the Board of Directors of The Peripheral Nerve Society and Chair of the Toxic Neuropathy Consortium. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.