Emerging trends in understanding chemotherapy-induced peripheral neuropathy (original) (raw)
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Mechanisms of Chemotherapy-Induced Peripheral Neuropathy
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 commonlyused 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.
Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy
Frontiers in Molecular Neuroscience
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.
Considerations for a Reliable In Vitro Model of Chemotherapy-Induced Peripheral Neuropathy
Toxics, 2021
Chemotherapy-induced peripheral neuropathy (CIPN) is widely recognized as a potentially severe toxicity that often leads to dose reduction or discontinuation of cancer treatment. Symptoms may persist despite discontinuation of chemotherapy and quality of life can be severely compromised. The clinical symptoms of CIPN, and the cellular and molecular targets involved in CIPN, are just as diverse as the wide variety of anticancer agents that cause peripheral neurotoxicity. There is an urgent need for extensive molecular and functional investigations aimed at understanding the mechanisms of CIPN. Furthermore, a reliable human cell culture system that recapitulates the diversity of neuronal modalities found in vivo and the pathophysiological changes that underlie CIPN would serve to advance the understanding of the pathogenesis of CIPN. The demonstration of experimental reproducibility in a human peripheral neuronal cell system will increase confidence that such an in vitro model is clin...
Expert Opinion on Drug Safety, 2015
Chemotherapy-induced peripheral neuropathies (CIPN) are a dose-limiting adverse effect of certain anticancer drugs (platinum salts, vinca alkaloids, taxanes, bortezomib, thalidomide, epothilones, eribulin). CIPN are mainly responsible for sensory disturbances and are associated with a decrease in quality of life. After the end of chemotherapy, CIPN can last for several months and even years. Unfortunately, recent meta-analyses of clinical trials have demonstrated that there is no univocal gold standard for the prevention and treatment of CIPN. Areas covered: Using animal models of CIPN, several new strategies to prevent or treat CIPN are under development. These new strategies involve several pathways, including ion channels, neuroprotectants, glutamatergic neurotransmission, oxidative stress, cannabinoid system, inflammation, and mitochondrial functions. Expert opinion: To date, based on meta-analyses of clinical trials, no drug can be proposed as a gold standard to prevent or treat CIPN. Consequently, there is a strong discrepancy between the optimistic results of animal studies and the poor outcomes of clinical trials. Pain assessment in preclinical and clinical studies is probably not the best outcome measurement tool and all these studies should include composite outcomes including the full complexity of CIPN symptoms, such as positive symptoms (pain, paresthesia, and dysesthesia) and negative ones (numbness).
Mechanisms in cancer-chemotherapeutic drugs-induced peripheral neuropathy
Toxicology, 2012
Anti-cancer drugs such as vincristine, paclitaxel, oxaliplatin, cisplatin and bortezomib are well reported to exert direct and indirect effects on sensory nerves to alter the amplitude of action potential, conduction velocity and induce pain. It results in patient suffering and also limits the treatment with potentially useful anticancer drugs. The different scientists have worked in this area to explore the mechanisms responsible for its pathogenesis. Anti-cancer agents activate plasma membrane localized ion channels on dorsal root ganglia and dorsal horn neurons including sodium, calcium, potassium, glutamate activated NMDA receptors to alter cytosolic ionic mileu particularly intracellular calcium that trigger secondary changes to induce neuropathic pain. These may include opening of mPTP pore on mitochondria to induce intracellular calcium release; activation of protein kinase C; phosphorylation of TRPV; activation of calpases/calpains; generation of nitric oxide and free radicals to induce cytotoxicity to axons and neuronal cell bodies. Furthermore, the inflammatory process initiated in glial cells and macrophages also trigger changes in the sensory neurons to alter nociceptive processing. The present review elaborates the role of all these individual targets in the pathogenesis of anticancer agents-induced neuropathic pain to develop effective therapeutic modalities for pain management.
Chemotherapy-Induced Neuropathy
Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the most severe and unpredictable side effects of modern anticancer treatment. In recent years, a clear understanding of the importance of an integrated approach to CIPN has become evident, and efforts are increasing to better characterize its features and to identify more accurate methods to report and grade its occurrence. The clinically relevant impact of CIPN on cancer patients has been known for a long time, but knowledge of its pathogenetic aspects is still very limited. This incomplete knowledge is one of the major limitations in identifying targets for evidence-based neuroprotective strategies. Nevertheless, several studies have been devoted to the prevention or at least the effective treatment of symptoms secondary to peripheral nerve damage and to the early identification of patients at high risk of developing severe CIPN. Unfortunately, none of these studies has been successful and the optimal management of CIPN patients is still an unmet clinical need. Therefore, the modification of chemotherapy is currently the only available approach to limit the severity of neuropathy in the vast majority of patients. The indications for treatment modification are not universally accepted and they can differ among the various drugs. Generally, treatment modification should be considered as soon as symptoms and signs impair the daily life activities of the patient, but the possibility of a delayed worsening of CIPN after treatment withdrawal ("coasting") should always be considered, and delay of modification decisions should be avoided.
Management of chemotherapy-induced peripheral neuropathy
Current Pain and Headache Reports, 2006
Recent advances in the development and administration of chemotherapy for malignant diseases have been rewarded with prolonged survival rates. The cost of progress has come at a price and the nervous system is frequently the target of chemotherapy-induced neurotoxicity. Unlike more immediate toxicities that effect the gastrointestinal tract and bone marrow, chemotherapy-induced neurotoxicity is frequently delayed in onset and may progress over time. In the peripheral nervous system, the major brunt of the toxicity is directed against the peripheral nerve, resulting in chemotherapy-induced peripheral neuropathy (CIPN). Chemotherapeutic agents used to treat hematologic and solid tumors target a variety of structures and functions in the peripheral nervous system, including the neuronal cell body, the axonal transport system, the myelin sheath, and glial support structures. Each agent exhibits a spectrum of toxic effects unique to its mechanism of toxic injury, and recent study in this field has yielded clearer ideas on how to mitigate injury. Combined with the call for a greater recognition of the potentially devastating ramifications of CIPN on quality of life, basic and clinical researchers have begun to investigate therapy to prevent neurotoxic injury. Preliminary studies have shown promise for some agents including glutamine, glutathione, vitamin E, acetyl-L-carnitine, calcium, and magnesium infusions, but final recommendations await prospective confirmatory studies.
Chemotherapy-induced peripheral neuropathy — diagnosis, evolution and treatment
Ginekologia Polska, 2016
Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequent neurologic complications experienced by patients receiving antineoplastic drugs. Involvement of the peripheral nerves may have an important impact on daily activities and lead to severe impairment of the patient's quality of life (QoL). It seems to be of crucial importance to make a correct and early diagnosis of polyneuropathy and, if possible, spare the patient unnecessary suffering or loss of function. In the preceding article we have presented epidemiology, grading and pathogenesis of the toxic CIPN. The purpose of this article is to review current knowledge of diagnostic techniques, prevention and management strategies in the context of CIPN.
Chemotherapy Induced Peripheral Neuropathy and Therapeutic Options: A Review
Texila International Journal of Basic Medical Sciences, 2018
Background: Peripheral neuropathy is characterized by distal damage to neurons along PNS which consists of loss of function. This would result from various factors. Chemotherapy Induced Peripheral Neuropathy (CIPN), a side effect of chemotherapy decreasing quality of life. There are various mechanisms by which these cause CIPN are neuronal structural and functional alterations. Method: Background searches into peripheral neuropathy and the chemotherapeutic agents that induce CIPN and their mechanisms were done from a series of journal databases. Treatment options were sought from the same databases dating between 2003 and 2019. From this the therapeutic options that have been explored and tried and the updates to these have been enumerated a discussed. Discussion: CIPN manifests from a heterogenous group of aetiologies. One standardized treatment option is not available for proper treatment of CIPN. Research over the years has produced methods of prevention and treatment for CIPN patients, including the use of preventative therapy, polypharmacy and some specific first line drugs. Nonpharmacological methods of treating CIPN comprises of the recent use of medicinal plants and complementary therapies for severe pain relief and better quality of life for these patients. Future Scope of Studies: Over the past decade, despite many efforts to develop a standardized treatment for CIPN, there has been little success. As a result, many more future studies are strongly indicated.
Frontiers in Immunology
Peripheral neuropathies are characterized by nerves damage and axonal loss, and they could be classified in hereditary or acquired forms. Acquired peripheral neuropathies are associated with several causes, including toxic agent exposure, among which the antineoplastic compounds are responsible for the so called Chemotherapy-Induced Peripheral Neuropathy (CIPN). Several clinical features are related to the use of anticancer drugs which exert their action by affecting different mechanisms and structures of the peripheral nervous system: the axons (axonopathy) or the dorsal root ganglia (DRG) neurons cell body (neuronopathy/ganglionopathy). In addition, antineoplastic treatments may affect the blood brain barrier integrity, leading to cognitive impairment that may be severe and long-lasting. CIPN may affect patient quality of life leading to modification or discontinuation of the anticancer therapy. Although the mechanisms of the damage are not completely understood, several hypothese...