Prevention Of Chemotherapy-induced Peripheral Neuropathy Research Articles

Chemotherapy-induced peripheral neuropathy: where are we now?

Chemotherapy-induced peripheral neuropathy (CIPN) is a major challenge, with increasing impact as oncological treatments, using potentially neurotoxic chemotherapy, improve cancer cure and survival. Acute CIPN occurs during chemotherapy, sometimes requiring dose reduction or cessation, impacting on survival. Around 30% of patients will still have CIPN a year, or more, after finishing chemotherapy. Accurate assessment is essential to improve knowledge around prevalence and incidence of CIPN. Consensus is needed to standardize assessment and diagnosis, with use of well-validated tools, such as the EORTC-CIPN 20. Detailed phenotyping of the clinical syndrome moves toward a precision medicine approach, to individualize treatment. Understanding significant risk factors and pre-existing vulnerability may be used to improve strategies for CIPN prevention, or to use targeted treatment for established CIPN. No preventive therapies have shown significant clinical efficacy, although there are promising novel agents such as histone deacetylase 6 (HDAC6) inhibitors, currently in early phase clinical trials for cancer treatment. Drug repurposing, eg, metformin, may offer an alternative therapeutic avenue. Established treatment for painful CIPN is limited. Following recommendations for general neuropathic pain is logical, but evidence for agents such as gabapentinoids and amitriptyline is weak. The only agent currently recommended by the American Society of Clinical Oncology is duloxetine. Mechanisms are complex with changes in ion channels (sodium, potassium, and calcium), transient receptor potential channels, mitochondrial dysfunction, and immune cell interactions. Improved understanding is essential to advance CIPN management. On a positive note, there are many potential sites for modulation, with novel analgesic approaches.

Prevention of chemotherapy-induced peripheral neuropathy with classical massage in breast cancer patients receiving paclitaxel: An assessor-blinded randomized controlled trial.

This assessor-blinded, prospective, randomized controlled clinical trial aimed at investigating the effect of classical massage on chemotherapy induced peripheral neuropathy and the quality of life (QOL) in breast cancer patients receiving adjuvant paclitaxel. A total of 40 female breast cancer patients were randomly allocated to the classical massage group (CMG) or the control group (CG). Classical massage was applied to the patients in the CMG before each paclitaxel infusion. The CG received only usual care. Presence of peripheral neuropathic pain and QOL were assessed at baseline and weeks 4, 8, 12, and 16. Nerve conduction studies (NCS) findings were also recorded at baseline and week 12. The peripheral neuropathic pain was lower in the CMG compared to the CG at week 12 (p < 0.05). The sensory and motor sub-scale scores of the QOL measure showed statistically significant differences over time in favor of the CMG (p < 0.05). Sensory action potential amplitude of the median nerve was significantly higher and the tibial nerve latency was significantly shorter in the CMG compared to the CG at week 12. This study suggested that classical massage successfully prevented chemotherapy-induced peripheral neuropathic pain, improved the QOL, and showed beneficial effects on the NCS findings.

Searching for analgesic drug candidates alleviating oxaliplatin-induced cold hypersensitivity in mice.

Oxaliplatin is a third-generation, platinum-based derivative used to treat advanced colorectal cancer. Within the patient population on oxaliplatin therapy, a lower incidence of hematological adverse effects and gastrointestinal toxicity is noted, but severe neuropathic pain episodes characterized by increased cold and tactile hypersensitivity are present in ~95% of patients. This drug is also used to induce a rodent model of chemotherapy-induced peripheral neuropathy (CIPN)-related neuropathic pain which is widely used in the search for novel therapies for CIPN prevention and treatment. This paper provides a step-by-step, detailed description of the prevention and intervention protocols used in our laboratory for the assessment of oxaliplatin-induced cold allodynia in mice. To establish cold sensitivity in mice, the cold plate test was used. Latencies to pain reaction in response to cold stimulus (2.5°C) for vehicle-treated non-neuropathic mice, vehicle-treated mice injected with oxaliplatin (neuropathic control), and oxaliplatin-treated mice treated additionally with duloxetine are compared. Duloxetine is a serotonin/noradrenaline reuptake inhibitor which was found to produce significant pain relief in patients with CIPN symptoms. In our present study, duloxetine administered intraperitoneally at the dose of 30mg/kg served as a model antiallodynic drug which attenuated or partially prevented cold allodynia caused by oxaliplatin.

(369) Cell Specific Role of HDAC6 in Chemotherapy-Induced Mechanical Allodynia and Loss of Intraepidermal Nerve Fibers

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious healthcare issue that can impair cancer treatment and reduce quality of life for cancer survivors. Currently there is no FDA-approved medication to manage CIPN, emphasizing the urgent need to identify novel mechanism-based interventions for CIPN. Histone deacetylase 6 (HDAC6) is an attractive target, given its pathogenic role in both cancer and neurodegenerative diseases. We show that cisplatin enhances HDAC6 expression and decreases acetylation of the HDAC6 substrate α-tubulin in the dorsal root ganglion (DRG). Pharmacological inhibition of HDAC6 with ACY-1215, an HDAC6 inhibitor that is currently in clinical trials as add-on cancer therapy, prevented cisplatin-induced mechanical allodynia, loss of intraepidermal nerve fibers (IENFs), and mitochondrial dysfunction in the DRG neurons and peripheral nerves in male and female mice. Genetic deletion of HDAC6 also protected against all CIPN signs. Interestingly, cell specific deletion of HDAC6 in Advilin-positive sensory neurons prevented loss of IENFs and mitochondrial deficits in the peripheral nerves, but not mechanical allodynia or DRG neuronal mitochondrial dysfunction. We previously showed that T cells are required for spontaneous resolution of mechanical allodynia in CIPN. Here we assessed the contribution of T cells to the beneficial effects of HDAC6 inhibition. HDAC6 inhibition during chemotherapy in T cell deficient Rag2−/− mice also prevented IENF loss and mitochondrial dysfunction in the peripheral nerves, but not mechanical allodynia or DRG mitochondrial deficits. Reconstitution with T cells normalized the protective effects of ACY-1215. Adoptive transfer of HDAC6 deficient T cells to Rag2−/− mice failed to protect against CIPN, indicating targeting HDAC6 in T cells alone was not sufficient. Taken together, our findings identify cell specific mechanisms for the protective effects of HDAC6 inhibition on cisplatin-induced mechanical allodynia and IENF loss. Our findings also strengthen the rationale for using HDAC6 inhibitors like ACY-1215 for CIPN prevention.

Abstract P4-16-11: A modest proposal for classical massage on chemotherapy-induced peripheral neuropathy in breast cancer patients receiving adjuvant paclitaxel: A randomized controlled trial using electromyography

Abstract Background: Oncology professionals face challenges to find out a complete solution in prevention or alleviation of chemotherapy induced peripheral neuropathy (CIPN). Current pharmacological treatments used for CIPN have limited effects and pose major side effects. At this point, management of CIPN by a multidisciplinary team approach is very crucial. Therefore, this randomized controlled study aimed to examine the effect of classical massage on CIPN using objective and subjective measurements in breast cancer patients receiving adjuvant paclitaxel. Method:The study was conducted at Dr. Abdurrahman Yurtaslan Ankara Training and Research Hospital in Turkey between July 2017 and June 2018. The study was approved by a local ethical committee. Eligible patients with breast cancer included those who (a) were 18 years and older; (b) had no documented diagnosis of CIPN; (c) had receiving the first cycle of adjuvant paclitaxel. Exclusion criteria were (a) history of severe psychiatric disorder; (b) history of peripheral neuropathy due to any cause; (c) had lesion on hands or feet; (d) had bleeding or coagulation disorders. Simple randomization method was utilized to allocate patients to an intervention group (n=18) and a control group (n=19). Patients in the intervention group (IG) received totally 12 sessions classical massage, on the days of chemotherapy cycles. The duration of each massage was 30 min, with 20 min for the feet and 10 min for the hands. The CG received only routine care. After completion of paclitaxel regimen no intervention was applied to neither the IG nor the CG, and patients were followed at week 16. Subjective measurement tools included the Self-Leeds Assessment of Neuropathic Symptoms and Sign (S-LANSS); and the European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy (EORTC QLQ-CIPN20). Electromyography (EMG) was applied as an objective measurement at baseline and week 12 for all patients by the same neurologist. The data were collected at five time points including baseline (T1), week 4 (T2) week 8 (T3), week 12 (T4) and week 16 (T5). To analyze data repeated measures ANOVA and Mann Whitney U tests were used. Results: The S-LANSS scores were significantly lower in the IG when compared the CG (p&amp;lt;.05). Motor sub-dimension scores of EORTC QLQ-CIPN20 were significantly lower in favor of the IG compared to the CG. As for sensorial and autonomic sub-dimensions of the EORTC QLQ CIPN20 showed no significant difference. Regarding EMG outcomes, compound muscle action potentials of ulnar nerve and posterior tibial nerve in the IG were significantly higher than the CG at week 12. Conclusion: In this study, classical massage initiated concurrently with adjuvant paclitaxel regimen decreased neuropathic pain severity and prevented motor axonal neuropathy in the IG when compared to the CG. Accordingly, classical massage had promising effects on prevention and alleviation of CIPN. Based on the results, classical massage can be recommended as a preventive complementary option for breast cancer patients receiving adjuvant paclitaxel. Citation Format: Demirci U, Izgu N, Gok Metin Z, Karadas C, Ozdemir L, Çetin N. A modest proposal for classical massage on chemotherapy-induced peripheral neuropathy in breast cancer patients receiving adjuvant paclitaxel: A randomized controlled trial using electromyography [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-16-11.

The National Cancer Institute Clinical Trials Planning Meeting for Prevention and Treatment of Chemotherapy-Induced Peripheral Neuropathy.

Although recent scientific advances have improved our understanding of basic biological mechanisms underlying chemotherapy-induced peripheral neuropathy (CIPN), few interventions are available to prevent or treat CIPN. Although some biological targets from preclinical studies show promise in nonhuman animal models, few targets have been translated to successful clinical trials. To address this problem, the National Cancer Institute's Symptom Management and Health-Related Quality of Life Steering Committee convened a meeting of experts in the CIPN and oncology symptom management fields to participate in a Clinical Trials Planning Meeting (CTPM). Investigators presented data from preclinical and translational studies for possible CIPN interventions; these were evaluated for readiness of randomized clinical trial testing by experts, and recommendations were provided. Breakout sessions were convened to discuss and develop future studies. The CTPM experts concluded that there is compelling evidence to move forward with selected pharmacological and nonpharmacological clinical trials for the prevention and treatment of CIPN. Several key feasibility issues need to be addressed, however. These include identification of optimal outcome measures to define the CIPN phenotype, establishment of parameters that guide the evaluation of clinically meaningful effects, and adoption of approaches for inclusion of translational and biomarker and/or genetic measures. The results of the CTPM provide support for conducting clinical trials that include both pharmacological and nonpharmacological approaches, alone or in combination, with biomarkers, genetics, or other measures designed to inform underlying CIPN mechanisms. Several working groups were formed to design rigorous CIPN clinical trials, the results of which are ongoing.

Prevention and Treatment for Chemotherapy-Induced Peripheral Neuropathy: Therapies Based on CIPN Mechanisms.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a progressive, enduring, and often irre-versible adverse effect of many antineoplastic agents, among which sensory abnormities are common and the most suffering issues. The pathogenesis of CIPN has not been completely understood, and strategies for CIPN prevention and treatment are still open problems for medicine.Objectives: The objective of this paper is to review the mechanism-based therapies against sensory abnormities in CIPN.Methods: This is a literature review to describe the uncovered mechanisms underlying CIPN and to provide a summary of mechanism-based therapies for CIPN based on the evidence from both animal and clinical studies.Results: An abundance of compounds has been developed to prevent or treat CIPN by blocking ion channels, targeting in-flammatory cytokines and combating oxidative stress. Agents such as glutathione, mangafodipir and duloxetine are expected to be effective for CIPN intervention, while Ca/Mg infusion and venlafaxine, tricyclic antidepressants, and gabapentin dis-play limited efficacy for preventing and alleviating CIPN. And the utilization of erythropoietin, menthol and amifostine needs to be cautious regarding to their side effects.Conclusions: Multiple drugs have been used and studied for decades, their effect against CIPN are still controversial ac-cording to different antineoplastic agents due to the diverse manifestations among different antineoplastic agents and complex drug-drug interactions. In addition, novel therapies or drugs that have proven to be effective in animals require further inves-tigation, and it will take time to confirm their efficacy and safety.

HMGB1 as a target for prevention of chemotherapy-induced peripheral neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) considerably impairs cancer patients' QOL, and may lead to discontinuation of drug treatment of cancer. Currently, there is no effective strategy against CIPN. Therefore, it is an urgent issue to develop clinically available drugs that prevent or treat CIPN. We have shown that high mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) molecule, plays an essential role in the development of CIPN. Most interestingly, thrombomodulin α, approved as a medicine for treatment of disseminated intravascular coagulation (DIC) in Japan, causes thrombin-dependent degradation of extracellular HMGB1 that is released in response to chemotherapeutics, and prevents CIPN. Thus, we expect that targeting HMGB1 or its receptors would lead to prevention of CIPN in cancer patients in near future.

Prevention of chemotherapy-induced peripheral neuropathy by targeting HMGB1

Prevention of chemotherapy-induced peripheral neuropathy by targeting HMGB1

Wen-Luo-Tong Decoction Attenuates Paclitaxel-Induced Peripheral Neuropathy by Regulating Linoleic Acid and Glycerophospholipid Metabolism Pathways

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious dose-limiting toxicity of many anti-neoplastic agents, especially paclitaxel, and oxaliplatin. Up to 62% of patients receiving paclitaxel regimens turn out to develop CIPN. Unfortunately, there are so few agents proved effective for prevention or management of CIPN. The reason for the current situation is that the mechanisms of CIPN are still not explicit. Traditional Chinese Medicine (TCM) has unique advantages for dealing with complex diseases. Wen-Luo-Tong (WLT) is a TCM ointment for topical application. It has been applied for prevention and management of CIPN clinically for more than 10 years. Previous animal experiments and clinical studies had manifested the availability of WLT. However, due to the unclear mechanisms of WLT, further transformation has been restricted. To investigate the therapeutic mechanisms of WLT, a metabolomic method on the basis of UPLC- MS was developed in this study. Multivariate analysis techniques, such as principal component analysis (PCA) and partial least squares discriminate analysis (PLS-DA), were applied to observe the disturbance in the metabolic state of the paclitaxel-induced peripheral neuropathy (PIPN) rat model, as well as the recovering tendency of WLT treatment. A total of 19 significant variations associated with PIPN were identified as biomarkers. Results of pathway analysis indicated that the metabolic disturbance of pathways of linoleic acid (LA) metabolism and glycerophospholipid metabolism. WLT attenuated mechanical allodynia and rebalanced the metabolic disturbances of PIPN by primarily regulating LA and glycerophospholipid metabolism pathway. Further molecular docking analysis showed some ingredients of WLT, such as hydroxysafflor yellow A (HSYA), icariin, epimedin B and 4-dihydroxybenzoic acid (DHBA), had high affinity to plenty of proteins within these two pathways.

Trial designs for chemotherapy-induced peripheral neuropathy prevention

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially dose-limiting side effect of neurotoxic chemotherapies. No therapies are available to prevent CIPN. The small number of positive randomized clinical trials (RCTs) evaluating preventive therapies for CIPN provide little guidance to inform the design of future trials. Moreover, the lack of consensus regarding major design features in this area poses challenges to development of new therapies. An Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities and Networks (ACTTION)-Consortium on Clinical Endpoints and Procedures for Peripheral Neuropathy Trials (CONCEPPT) meeting attended by neurologists, oncologists, pharmacists, clinical trialists, statisticians, and regulatory experts was convened to discuss design considerations and provide recommendations for CIPN prevention trials. This article outlines considerations related to design of RCTs that evaluate preventive therapies for CIPN including (1) selection of eligibility criteria (e.g., cancer types, chemotherapy types, inclusion of preexisting neuropathy); (2) selection of outcome measures and endpoints, including those that incorporate alterations in chemotherapy dosing, which may affect the rate of CIPN development and its severity; (3) potential effects of the investigational therapy on the efficacy of chemotherapy; and (4) sample size estimation. Our hope is that attention to the design considerations and recommendations outlined in this article will improve the quality and assay sensitivity of CIPN prevention trials and thereby accelerate the identification of efficacious therapies.

Abstract 602: The α7 nicotinic acetylcholine receptor silent agonist R-47 prevents and reverses paclitaxel-induced peripheral neuropathy without enhancing the proliferation of lung cancer cells or interfering with paclitaxel-induced antitumor activity

Abstract While cancer chemotherapy continues to significantly contribute to the number of cancer survivors, exposure to these drugs can often result in chemotherapy-induced peripheral neuropathy (CIPN), a consequence of peripheral nerve fiber dysfunction or degeneration. CIPN is characterized by sensory symptoms such as numbness, burning, and allodynia, resulting in an overall decrease in quality of life. Paclitaxel (Taxol), a microtubule poison that is commonly used to treat breast, lung, and ovarian cancers, has been found to cause CIPN in 59-78% of cancer patients. There is currently no effective preventative or therapeutic treatment for this side effect, which can be a dose-limiting factor for chemotherapy or delay treatment. Our laboratories have previously shown that nicotine, the prototypical nicotinic acetylcholine receptor (nAChR) agonist, can prevent and reverse paclitaxel-induced peripheral neuropathy without increasing lung tumor growth in mice. Our current studies have demonstrated that the α7 nAChR silent agonist R-47 may be a promising preventative and therapeutic treatment for CIPN as well. R-47 (10 mg/kg, p.o.) was administered to male C57BL/6J mice treated with paclitaxel (8 mg/kg, i.p., every other day for a total of four injections). Von Frey filament testing revealed that R-47 can both prevent and reverse paclitaxel-induced mechanical allodynia; the latter effect can be inhibited by the α7 nAChR antagonist methyllycaconitine. In support of these findings, R-47 also prevents the reduction of intra-epidermal nerve fibers in the hind paws of paclitaxel-treated mice. In addition, α7 nAChR knockout mice exhibit a greater and sustained increase in mechanical allodynia after paclitaxel administration when compared to wild-type mice, suggesting the involvement of this receptor subtype in hindering CIPN development and/or maintenance. With regard to cancer, R-47 fails to increase A549 and H460 non-small cell lung cancer cell viability, colony formation, or proliferation alone, and does not interfere with paclitaxel-induced growth arrest, apoptosis, or DNA fragmentation. Most importantly, R-47 does not increase the growth of A549 tumors or interfere with the antitumor activity of paclitaxel in tumor-bearing mice. These data suggest that the use of an α7 nAChR silent agonist may be a safe and efficacious approach for the prevention and treatment of CIPN. Citation Format: S Lauren Kyte, Wisam Toma, Ganeshsingh Thakur, M Imad Damaj, David A. Gewirtz. The α7 nicotinic acetylcholine receptor silent agonist R-47 prevents and reverses paclitaxel-induced peripheral neuropathy without enhancing the proliferation of lung cancer cells or interfering with paclitaxel-induced antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 602.

Identifying chemotherapy-induced peripheral neuropathy (CIPN) and its treatment using claims data: A URCC NCORP and NIH Collaboratory study.

e18707Background: Investigating CIPN prevention and treatment strategies is a high priority that could be pursued with claims data. However, no studies have investigated the feasibility of identify...

Protective Effect of a Mitochondria-Targeted Peptide against the Development of Chemotherapy-Induced Peripheral Neuropathy in Mice.

Several chemotherapeutic agents used for cancer treatment induce dose-limiting peripheral neuropathy that compromises patients' quality of life and limits cancer treatment. Recently, mitochondrial dysfunction has been shown to be involved in the mechanism of chemotherapy-induced peripheral neuropathy. SS-20 is a mitochondria-targeted peptide that promotes mitochondrial respiration and restores mitochondrial bioenergetics. In the present study, we examined the protective effect of SS-20 against the development of chemotherapy-induced peripheral neuropathy utilizing a murine model of peripheral neuropathy induced by oxaliplatin, a first-line chemotherapy agent for colon cancer. Weekly administrations of oxaliplatin induced peripheral neuropathy as demonstrated by the development of neuropathic pain and loss of intraepidermal nerve fibers in the hind paw. Continuous administration of SS-20 protected against the development of oxaliplatin-induced neuropathic pain and mitigated the loss of intraepidermal nerve fibers to normal levels. Our findings suggest that SS-20 may be a drug candidate for the prevention of chemotherapy-induced peripheral neuropathy.

Abstract P3-14-06: The prevention and management of chemotherapy-induced peripheral neuropathy in breast cancer patients: A systematic review

Abstract Background: Chemotherapy induced peripheral neuropathy (CIPN) remains a common treatment related adverse event for breast cancer (BC) patients. CIPN interferes with the ability to complete chemotherapy &amp; therefore potentially compromises survival outcomes. CIPN can worsen health-related quality of life and also add to the ongoing morbidity experienced by BC survivors. Previously, systematic reviews &amp; ASCO guidelines have examined CIPN across many cancer types &amp; different chemotherapies, which may lead to the introduction of confounding factors not relevant to BC patients. A recent prospective cohort also identified other specific lifestyle factors associated with CIPN in BC patients (1). From our search, a systematic review specifically looking at CIPN in BC patients has not previously been undertaken. Methods: We conducted a systematic search in PubMed, EMBASE, CINAHL and CENTRAL. Clinical trials and observational studies for all potential pharmacological and non-pharmacological interventions were included. Risk of bias for full-text papers was assessed using the Cochrane Risk of Bias Assessment or the modified Newcastle Ottawa score. Results: Of 706 records being identified, 601 unique citations were screened with 21 full text papers retrieved for assessment, and 16 studies included in the qualitative assessment. We identified 10 randomised controlled trials (RCTs), one observational cohort study, and five controlled before-and-after studies (CBA). Pharmacological interventions which were investigated included calcium/magnesium infusion, glutamine, amifostine, goshajinkigan, omega 3 fatty acids, acetyl-L-carnitine, pregabalin, alpha-lipoic acid and minocycline. Non-pharmacological interventions included body mass index &amp; lifestyle factors, electroacupuncture, exercise, limb hypothermia, carbon dioxide limb bathing and limb compression therapy. All trials identified were investigating primary prevention of CIPN in the setting of taxane chemotherapy. Improvements in the incidence of CIPN were reported with omega 3 fatty acids, glutamine and alpha-lipoic acid, but only one of these studies is a published RCT. In two of the studies, the benefit was identified only on physical examination, but no significant benefit with nerve conduction (NCS) testing. On subgroup analysis of trials investigating exercise, there was a benefit in the use of high intensity exercise versus low intensity exercise, particularly in patients &amp;lt;50 years old within a healthy weight range. Mixed results were seen with goshajinkigan. An increase in CIPN was seen with antioxidant use, electroacupuncture and acetyl L carnitine. Majority of the RCTs were associated with a high overall risk of bias. Conclusions: There has been a paucity of research on CIPN in BC patients. There were no interventions identified in this systematic review which show a clear clinical benefit in the prevention of CIPN in BC patients. BC patients may have specific lifestyle and hormonal factors which influence CIPN and this should prompt ongoing specific patient focussed research within this subgroup with large, blinded, randomised controlled trials. Greenlee, et al. Natl Cancer Inst 2017; 109(2). Citation Format: Roberts KE, Feng S, Adsett I, Rickett K, Woodward N. The prevention and management of chemotherapy-induced peripheral neuropathy in breast cancer patients: A systematic review [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-14-06.

Taxane-Induced Neuropathic Pain: Current Evidence and Treating Strategies

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling adverse event of most of commonly used antineoplastic agents. Previous studies have focused on several chemotherapeutic agents and reported that CIPN incidence varies from 19% to >85%. The mechanisms underlying CIPN are currently unknown. However, different theories have been proposed including microtubules dysfunction, mitochondrial dysfunction and mitochondrial toxicity, Glial pathway, substance P pathway, adenosine receptor pathway. CIPN is not simply to treat, and most randomized controlled trials failed to identify an effective therapy. Recent evidence supports the efficacy of serotonin (5-HT) and norepinephrine (NE) dual reuptake inhibitors (SNRI) in the treatment of neuropathy-related pain. Based on current evidence, we can speculate that duloxetine and topical menthol would improve CIPN pain as symptomatic treatment while, based on preclinical data, pifithrin-μ could be considered in future for the prevention of CIPN.

Goshajinkigan for prevention of chemotherapy-induced peripheral neuropathy: a systematic review and meta-analysis.

Chemotherapy-induced peripheral neuropathy (CIPN) limits the dose of chemotherapy and reduces patients' quality of life. Goshajinkigan is a Japanese herbal medicine used to alleviate neuropathy and general pain. A clinical guideline for prevention and management of CIPN stated that the prophylactic efficacy of goshajinkigan against CIPN was inconclusive. We conducted a systematic review to examine whether goshajinkigan prevents CIPN in patients receiving neurotoxic chemotherapy. We searched PubMed, EMBASE, Ichushi, and the Cochrane Central Register of Controlled Trials for eligible trials. Randomized controlled trials that examined the efficacy and safety of goshajinkigan for prevention of CIPN were included. Our primary outcomes were incidence of CIPN, response to chemotherapy, and adverse effects. We pooled data using a random effects model. We analyzed five trials involving a total of 397 patients. When evaluated with Neurotoxicity Criteria of Debiopharm, goshajinkigan was associated with reduced incidence of CIPN of grade ≥ 1 (risk ratio [RR] 0.43; 95% CI, 0.27 to 0.66) and grade 3 (RR 0.42; 95% CI, 0.25 to 0.71), but this beneficial association was not found for grade ≥ 2 of CIPN. Goshajinkigan was not associated with reduced incidence of CIPN when assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events, or improved response to chemotherapy. Goshajinkigan was well tolerated based on one trial. Goshajinkigan is unlikely to prevent CIPN in patients undergoing neurotoxic chemotherapy. Given the low quality and insufficient amount of the evidence, use of goshajinkigan as standard of care is not currently recommended.

Goshajinkigan for reducing chemotherapy-induced peripheral neuropathy: a systematic review and meta-analysis.

Chemotherapy-induced peripheral neuropathy (CIPN) is common and presents with persistent and challenging symptoms for which there is no effective means of prevention. This systematic review assessed the efficacy and safety of Goshajinkigan in the prevention of CIPN. A comprehensive literature search was conducted using Scopus, Ovid MEDLINE, the Cochrane Central Register of Controlled Trials, and ICHUSHI. Randomised controlled trials comparing Goshajinkigan with an alternative strategy for preventing CIPN were selected. Of five studies included in the review, Goshajinkigan did not reduce the risk of CIPN when the common terminology criteria for adverse events was used [risk ratio (RR) 0.94, 95% confidence interval (CI) 0.57-1.57 for grade≥2 CIPN and RR 1.08, 95% CI 0.59-2.00 for grade≥3 CIPN]. When the neurotoxicity criteria of Debiopharm was used, Goshajinkigan tended to decrease the risk of CIPN, but not significantly (RR 0.74, 95% CI 0.33-1.64 for grade≥2 CIPN and RR 0.65, 95% CI 0.28-1.52 for grade≥3 CIPN). Goshajinkigan tended to prevent persistence but not severity of CIPN. Higher quality trials using multiple measures are needed in the future to clarify the preventive effect of Goshajinkigan and to assess the various aspects of CIPN.

Nicotine Prevents and Reverses Paclitaxel-Induced Mechanical Allodynia in a Mouse Model of CIPN.

Chemotherapy-induced peripheral neuropathy (CIPN), a consequence of peripheral nerve fiber dysfunction or degeneration, continues to be a dose-limiting and debilitating side effect during and/or after cancer chemotherapy. Paclitaxel, a taxane commonly used to treat breast, lung, and ovarian cancers, causes CIPN in 59-78% of cancer patients. Novel interventions are needed due to the current lack of effective CIPN treatments. Our studies were designed to investigate whether nicotine can prevent and/or reverse paclitaxel-induced peripheral neuropathy in a mouse model of CIPN, while ensuring that nicotine will not stimulate lung tumor cell proliferation or interfere with the antitumor properties of paclitaxel. Male C57BL/6J mice received paclitaxel every other day for a total of four injections (8 mg/kg, i.p.). Acute (0.3-0.9 mg/kg, i.p.) and chronic (24 mg/kg per day, s.c.) administration of nicotine respectively reversed and prevented paclitaxel-induced mechanical allodynia. Blockade of the antinociceptive effect of nicotine with mecamylamine and methyllycaconitine suggests that the reversal of paclitaxel-induced mechanical allodynia is primarily mediated by the α7 nicotinic acetylcholine receptor subtype. Chronic nicotine treatment also prevented paclitaxel-induced intraepidermal nerve fiber loss. Notably, nicotine neither promoted proliferation of A549 and H460 non-small cell lung cancer cells nor interfered with paclitaxel-induced antitumor effects, including apoptosis. Most importantly, chronic nicotine administration did not enhance Lewis lung carcinoma tumor growth in C57BL/6J mice. These data suggest that the nicotinic acetylcholine receptor-mediated pathways may be promising drug targets for the prevention and treatment of CIPN.

B Vitamin Complex and Chemotherapy-Induced Peripheral Neuropathy.

The purpose of this mini review is to evaluate the literature on B vitamins and chemotherapy-induced peripheral neuropathy. One hundred and five journal articles were evaluated and nine manuscripts were included. There was one in vitro, one was an animal and seven were human studies. The in vitro study was a safety study on vitamin B6 and oxaliplatin which was not directly related to CIPN. The animal study evaluated vitamin B3 on paclitaxel administration with positive results. The human studies varied using a vitamin B complex, vitamin B12 only and vitamin B6. Chemotherapy-induced peripheral neuropathy (CIPN) continues to plague patients and the medical fraternity. Currently, there are still no conclusive protective or treatment options. B vitamins have been found to play a role in CIPN prevention, but further studies are required to ascertain possible protection and treatment options.