Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequent side effects caused by antineoplastic agents, with a prevalence from 19% to over 85%. Clinically, CIPN is a mostly sensory neuropathy that may be accompanied by motor and autonomic changes of varying intensity and duration. Due to its high prevalence among cancer patients, CIPN constitutes a major problem for both cancer patients and survivors as well as for their health care providers, especially because, at the moment, there is no single effective method of preventing CIPN; moreover, the possibilities of treating this syndrome are very limited. There are six main substance groups that cause damage to peripheral sensory, motor and autonomic neurons, which result in the development of CIPN: platinum-based antineoplastic agents, vinca alkaloids, epothilones (ixabepilone), taxanes, proteasome inhibitors (bortezomib) and immunomodulatory drugs (thalidomide). Among them, the most neurotoxic are platinum-based agents, taxanes, ixabepilone and thalidomide; other less neurotoxic but also commonly used drugs are bortezomib and vinca alkaloids. This paper reviews the clinical picture of CIPN and the neurotoxicity mechanisms of the most common antineoplastic agents. A better understanding of the risk factors and underlying mechanisms of CIPN is needed to develop effective preventive and therapeutic strategies.

Mechanisms of Chemotherapy-Induced Peripheral Neuropathy.

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

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Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy

This review provides an update on the current clinical and preclinical understanding of chemotherapy induced peripheral neuropathy (CIPN). The overview of the clinical syndrome includes a review of its assessment, diagnosis and treatment. CIPN is caused by several widely-used chemotherapeutics including paclitaxel, oxaliplatin, bortezomib. Severe CIPN may require dose reduction, or cessation, of chemotherapy, impacting on patient survival. While CIPN often resolves after chemotherapy, around 30% of patients will have persistent problems, impacting on function and quality of life. Early assessment and diagnosis is important, and we discuss tools developed for this purpose. There are no effective strategies to prevent CIPN, with limited evidence of effective drugs for treating established CIPN. Duloxetine has moderate evidence, with extrapolation from other neuropathic pain states generally being used to direct treatment options for CIPN. The preclinical perspective includes a discussion on the development of clinically-relevant rodent models of CIPN and some of the potentially modifiable mechanisms that have been identified using these models. We focus on the role of mitochondrial dysfunction, oxidative stress, immune cells and changes in ion channels from summary of the latest literature in these areas. Many causal mechanisms of CIPN occur simultaneously and/or can reinforce each other. Thus, combination therapies may well be required for most effective management. More effective treatment of CIPN will require closer links between oncology and pain management clinical teams to ensure CIPN patients are effectively monitored. Furthermore, continued close collaboration between clinical and preclinical research will facilitate the development of novel treatments for CIPN.

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Clinical and preclinical perspectives on Chemotherapy-Induced Peripheral Neuropathy (CIPN): a narrative review

The free radical oxidants such as reactive oxygen species, reactive nitrogen species, and reactive sulfur species are produced inside cells through various metabolic processes. The body is equipped with an antioxidant defense system that guards against oxidative damage caused by these reactive oxidants and plays a major role in protecting cells from oxidative stress and damage. Antioxidants such as glutathione (GSH), thioredoxin, ascorbic acid and enzymes, for example, superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) counter the oxidative stress and protect lipids, proteins, and DNA. Antioxidants such as tocopherols, ascorbic acid, carotenoids, flavonoids, amino acids are also natural antioxidants present in foods. There is increasing demand and availability of designer foods fortified with antioxidants and probiotics that may be important in human health. The review article presents a brief overview of oxidants and antioxidant systems inside the human body including the role of probiotics and inflammation. PRACTICAL APPLICATIONS: Antioxidants such as GSH, thioredoxin, ascorbic acid, etc. and protective enzymes, for example, SOD, GPx, CAT, etc. counter oxidative stress and protect cellular biomolecules. Antioxidants such as tocopherols, ascorbic acid, carotenoids, flavonoids, amino acids, phospholipids, and sterols are natural antioxidants found in consumed foods. They play a major role in scavenging free radical and non-radical oxidants, and protect cells from oxidative stress and damage. The importance of antioxidants can be understood from the fact that oxidative damage is now associated with a variety of diseases including cancer, neurodegeneration, diabetes, etc. Several approaches to improve human health and achieve longevity use dietary antioxidants as formulation in diet and fortified foods. Antioxidants also maintain freshness and prolonging the shelf life of food products. The fortified or designer foods that are added with antioxidant nutrients and the use of microorganisms as probiotics are increasingly available in the market as health foods and supplements.

Understanding oxidants and antioxidants: Classical team with new players.

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious adverse side effect of many chemotherapeutic agents, affecting >60% of patients with cancer. Moreover, CIPN persists long into survivorship in approximately 20% to 30% of these patients. To the authors' knowledge, no drugs have been approved to date by the US Food and Drug Administration to effectively manage chemotherapy-induced neuropathic pain. The majority of the drugs tested for the management of CIPN aim at symptom relief, including pain and paresthesia, yet are not very efficacious. The authors propose that there is a need to acquire a more thorough understanding of the etiology of CIPN so that effective, mechanism-based, disease-modifying interventions can be developed. It is important to note that such interventions should not interfere with the antitumor effects of chemotherapy. Mitochondria are rod-shaped cellular organelles that represent the powerhouses of the cell, in that they convert oxygen and nutrients into the cellular energy "currency" adenosine triphosphate. In addition, mitochondria regulate cell death. Neuronal mitochondrial dysfunction and the associated nitro-oxidative stress represent crucial final common pathways of CIPN. Herein, the authors discuss the potential to prevent or reverse CIPN by protecting mitochondria and/or inhibiting nitro-oxidative stress with novel potential drugs, including the mitochondrial protectant pifithrin-μ, histone deacetylase 6 inhibitors, metformin, antioxidants, peroxynitrite decomposition catalysts, and anti-inflammatory mediators including interleukin 10. This review hopefully will contribute toward bridging the gap between preclinical research and the development of realistic novel therapeutic strategies to prevent or reverse the devastating neurotoxic effects of chemotherapy on the (peripheral) nervous system. Cancer 2018;124:2289-98. © 2018 American Cancer Society.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.31248

Olivia E McKenna

Papers

Oxidative stress in the development, maintenance and resolution of paclitaxel-induced painful neuropathy.