Pathophysiology Of Chemotherapy-induced Peripheral Neuropathy Research Articles

Chemotherapy-Induced Peripheral Neuropathy: A Recent Update on Pathophysiology and Treatment.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major long-lasting side effect of some chemotherapy drugs, which threatens cancer survival rate. CIPN mostly affects sensory neurons and occasionally motor neurons, causing numbness, tingling, discomfort, and burning pain in the upper and lower extremities. The pathophysiology of CIPN is not completely understood; however, it is believed that chemotherapies induce peripheral neuropathy via directly damaging mitochondria, impairing the function of ion channels, triggering immunological mechanisms, and disrupting microtubules. The treatment of CIPN is a medical challenge, and there are no approved pharmacological options. Currently, duloxetine and other antidepressants, antioxidant, anti-inflammatory, and ion-channel targeted therapies are commonly used in clinics to relieve the symptoms of CIPN. Several other types of drugs, such as cannabinoids, sigma-1 receptor antagonists, and nicotinamides ribose, are being evaluated in preclinical and clinical studies. This paper summarizes the information related to the physiology of CIPN and medicines that could be used for treating this condition.

Review of the Role of the Brain in Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating, and dose-limiting side effect of many chemotherapy regimens yet has limited treatments due to incomplete knowledge of its pathophysiology. Research on the pathophysiology of CIPN has focused on peripheral nerves because CIPN symptoms are felt in the hands and feet. However, better understanding the role of the brain in CIPN may accelerate understanding, diagnosing, and treating CIPN. The goals of this review are to (1) investigate the role of the brain in CIPN, and (2) use this knowledge to inform future research and treatment of CIPN. We identified 16 papers using brain interventions in animal models of CIPN and five papers using brain imaging in humans or monkeys with CIPN. These studies suggest that CIPN is partly caused by (1) brain hyperactivity, (2) reduced GABAergic inhibition, (3) neuroinflammation, and (4) overactivation of GPCR/MAPK pathways. These four features were observed in several brain regions including the thalamus, periaqueductal gray, anterior cingulate cortex, somatosensory cortex, and insula. We discuss how to leverage this knowledge for future preclinical research, clinical research, and brain-based treatments for CIPN.

Physiotherapy management of chemotherapy-induced peripheral neuropathy in Pretoria, South Africa.

BackgroundThe increase in newly diagnosed patients with cancer in South Africa and globally, may contribute to the increase in patients living with chemotherapy-induced peripheral neuropathy (CIPN). Chemotherapy-induced peripheral neuropathy negatively impacts on quality of life (QoL) during and post chemotherapy treatment. Physiotherapy management of CIPN helps patients to manage symptoms and improves function in activity- and participation-levels to ultimately improve QoL. However, little evidence exists regarding the type or combination of physiotherapy management strategies in South Africa.ObjectivesThe purpose of our study was to determine how the symptoms of CIPN were managed by physiotherapists in Pretoria, South Africa.MethodA quantitative, descriptive study design was used. Electronic questionnaires were distributed to physiotherapists who worked with cancer patients and who treated patients with CIPN.ResultsPhysiotherapists used massage, proprioceptive neuromuscular facilitation, sensory integration, activities of daily living training, postural drainage, lifestyle modifications; Bobath-, breathing-, stability-, stretching-, strengthening- and endurance-exercises; electrical stimulation, thermal modalities, transcutaneous electrical nerve stimulation, soft tissue mobilisation; muscle energy-, positional- and Mulligan-techniques in the management of CIPN.ConclusionCardiopulmonary therapy, therapeutic exercises, manual therapy and neuro-developmental techniques were used by physiotherapists in the management of CIPN. Almost half of the participants did not use electrotherapy techniques. Physiotherapy management strategies that are used in Pretoria are similar to published research.Clinical implicationsPhysiotherapists in Pretoria are managing CIPN according to international practices. However, studies to determine the effectiveness of the management strategies in a South African context should be conducted. Alternative management strategies, based on the pathophysiology of CIPN, should be explored.Keywordsphysiotherapy; chemotherapy-induced peripheral neuropathy; intervention; management; cancer.

Blockade of IL-6 signaling prevents paclitaxel-induced neuropathy in C57Bl/6 mice

The microtubule-stabilizing agent paclitaxel frequently leads to chemotherapy-induced peripheral neuropathy (CIN), which further increases the burden of disease and often necessitates treatment limitations. The pathophysiology of CIN appears to involve both “upstream” effects including altered intracellular calcium signaling and activation of calcium dependent proteases such as calpain as well as subsequent “downstream” neuro-inflammatory reactions with cytokine release and macrophage infiltration of dorsal root ganglia. In this study, we aimed to investigate whether these processes are linked by the pro-inflammatory cytokine interleukin-6 (IL-6). We observed that paclitaxel exposure induced IL-6 synthesis in cultured sensory neurons from postnatal Wistar rats, which could be prevented by co-treatment with a calpain inhibitor. This suggests a calcium dependent process. We demonstrate that adult C57BL/6 mice deficient in IL-6 are protected from developing functional and histological changes of paclitaxel-induced neuropathy. Furthermore, pretreatment with an IL-6-neutralizing antibody resulted in the prevention of paclitaxel-induced neuropathy in C57BL/6 mice. Electrophysiological data from our preclinical model was adequately reflected by measurements of patients undergoing paclitaxel therapy for ovarian cancer. In this cohort, measured Il-6 levels correlated with the severity of neuropathy. Our findings demonstrate that IL-6 plays a pivotal role in the pathophysiology of paclitaxel-induced neuropathy per se and that pharmacological or genetic interference with this signaling pathway prevents the development of this potentially debilitating adverse effect. These findings provide a rationale for a clinical trial with IL-6 neutralizing antibodies to prevent dose-limiting neurotoxic adverse effects of paclitaxel chemotherapy.

Associations between self-reported diet during treatment and chemotherapy-induced peripheral neuropathy in a cooperative group trial (S0221)

BackgroundThe pathophysiology of chemotherapy-induced peripheral neuropathy (CIPN) is not well understood. Currently, dose reduction is the only recommendation for alleviating symptoms, often leading to premature treatment cessation. The primary aim of this analysis was to determine the association between components of diet during taxane treatment for breast cancer and change in CIPN symptoms over treatment.MethodsWomen with stage II or III invasive breast cancer were enrolled into an ancillary study to the North American Breast Cancer Intergroup phase III trial (S0221) led by the Southwest Oncology Group (SWOG). Questionnaires including a food frequency questionnaire and the Functional Assessment of Cancer Treatment Gynecologic Oncology Group—Neurotoxicity were administered to assess diet and neuropathic conditions at baseline and during chemotherapy. Ordinal regression was used to estimate odds ratios (ORs) for associations between various food groups and change in neuropathy score (< 10%, 10–30%, > 30%) (n = 900).ResultsThe odds of worse neuropathy decreased by 21% for each increase in tertile of grain consumption (OR = 0.79, 95% CI 0.66–0.94, p = 0.009). We also observed a nominal 19% increase with higher consumption of citrus fruits (OR = 1.19, 95% CI 1.01–1.40, p = 0.05).ConclusionsDistinguishing between those who experienced a moderate and a severe change in neuropathy, we found that citrus fruit and grain consumption may play a role in the severity of symptoms. Since there are no existing dietary recommendations for the management of CIPN, further research is needed to investigate whether there may be certain foods that could worsen or alleviate neuropathy symptoms associated with treatment for breast cancer.Trial registrationClinicalTrials.gov, NCT03413761. Registered retrospectively on 29 January 2018.

Role of Mitochondrial Mechanism in Chemotherapy-Induced Peripheral Neuropathy.

Even though chemotherapeutic regimens show considerable importance, it may cause progressive, continuing and sometimes irreversible peripheral neuropathy. Chemotherapy induced peripheral neuropathy (CIPN) is comprised of sensory abnormalities that are most distressing issues. The mechanism associated with CIPN pathogenesis is not completely revealed and its treatment is still questionable. The purpose of this review was to investigate the role of mitochondria in CIPN. This review is literature based that describes the mitochondrial mechanism underlying CIPN and the neuropathic complications associated with different antineoplastic agents. For severe pain, a modification towards less efficient chemotherapeutic drugs could possibly be needed and/or patients perhaps prefer to withdrawal therapeutic regimen. The epidemiology of CIPN is still debatable. The major recurrent molecules causing CIPN are platinum based drugs including cisplatin and oxaliplatin, thalidomide, bortezomib, vinka alkaloids and taxanes. Neuropathic pain is one of the symptoms of CIPN. Various neuropathic disorders as well as CIPN are due to mitochondrial impairment, relevant impairment of Ca2+ signalling pathways and reactive oxygen species (ROS) that ultimately leads to apoptosis. The pathophysiology of CIPN is complicated as chemotherapeutic medications often involve combination of drugs. With these combinatorial therapies cancer survivors develop continuing effects of CIPN which require rehabilitation strategies for the recovery of patient's condition and quality of life.

Pathophysiology 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.

Post-chemotherapy neuropathy

BACKGROUND AND OBJECTIVES: Anticancer chemotherapeutics can induce painful peripheral neuropathy. Symptoms range widely and can involve sensory, motor, and autonomic systems. However, chemotherapy-induced peripheral neuropathy is under-assessed and undertreated and its diagnosis is somewhat complicated by the lack of consensus on its pathophysiology and presentation. The objective of this study was to review medical publications in English, Spanish and Portuguese, in the last ten years, about painful peripheral neuropathy. CONTENTS: Systematic literature review on painful peripheral neuropathy associated with systemic anticancer chemotherapy. CONCLUSION: Although limited reliable evidence regarding the appropriate treatment for this condition exists, it is based on current neuropathic pain guidelines. Further studies on differences between the pathophysiology of chemotherapy-induced peripheral neuropathy and those of other neuropathic pain conditions may lead to the development of more effective treatment modalities. Additionally, therapeutic strategies for the management of chemotherapy-induced peripheral neuropathy must be validated by large-scale randomized clinical trials to meet the demands of evidenced-based medicine.

The search for treatments to reduce chemotherapy-induced peripheral neuropathy

Oxaliplatin, a commonly used chemotherapeutic agent, is associated with both acute and chronic neurotoxicity. Chronic sensory neuropathy can be dose limiting and may have detrimental effects on patients' quality of life. Preclinical studies provide an understanding of the pathophysiology of chemotherapy-induced peripheral neuropathy (CIPN) and may be important for developing effective preventative interventions. In this issue of the JCI, Coriat and colleagues used an animal model and a human pilot trial to evaluate the use of mangafodipir to reduce CIPN. Although many pilot clinical studies have reported promising data, larger clinical trials have repeatedly been unable to confirm these preliminary results. Thus, no agents are currently clinically recommended for the prevention of CIPN.

Chemotherapy‐induced peripheral neurotoxicity: A critical analysis

With a 3-fold increase in the number of cancer survivors noted since the 1970s, there are now over 28 million cancer survivors worldwide. Accordingly, there is a heightened awareness of long-term toxicities and the impact on quality of life following treatment in cancer survivors. This review will address the increasing importance and challenge of chemotherapy-induced neurotoxicity, with a focus on neuropathy associated with the treatment of breast cancer, colorectal cancer, testicular cancer, and hematological cancers. An overview of the diagnosis, symptomatology, and pathophysiology of chemotherapy-induced peripheral neuropathy will be provided, with a critical analysis of assessment strategies, neuroprotective approaches, and potential treatments. The review will concentrate on neuropathy associated with taxanes, platinum compounds, vinca alkaloids, thalidomide, and bortezomib, providing clinical information specific to these chemotherapies.

Diagnosis, Management, and Evaluation of Chemotherapy-Induced Peripheral Neuropathy

Peripheral neuropathy induced by cancer chemotherapy represents a large unmet need for patients due to the absence of treatment that can prevent or mitigate this common clinical problem. Chemotherapy-induced peripheral neuropathy (CIPN) diagnosis and management is further compounded by the lack of reliable and standardized means to diagnose and monitor patients who are at risk for, or who are symptomatic from, this complication of treatment. The pathogenesis and pathophysiology of CIPN are not fully elucidated, but there is increasing evidence of damage or interference with tubulin function. The diagnosis of CIPN may present a diagnostic dilemma due to the large number of potential toxic etiologies and conditions, which may mimic some of the clinical features; the diagnosis must be approached with care in such patients. The incidence and severity of CIPN is commonly under-reported by physicians as compared with patients. The development of new and reliable methods for the assessment of CIPN as well as safe and effective treatments to prevent this complication of treatment would represent important medical advancements for cancer patients.