Chemotherapy-induced Peripheral Neuropathy In Patients Research Articles

Manganese- and Platinum-Driven Oxidative and Nitrosative Stress in Oxaliplatin-Associated CIPN with Special Reference to Ca4Mn(DPDP)5, MnDPDP and DPDP

Platinum-containing chemotherapeutic drugs are efficacious in many forms of cancer but are dose-restricted by serious side effects, of which peripheral neuropathy induced by oxidative–nitrosative-stress-mediated chain reactions is most disturbing. Recently, hope has been raised regarding the catalytic antioxidants mangafodipir (MnDPDP) and calmangafodipir [Ca4Mn(DPDP)5; PledOx®], which by mimicking mitochondrial manganese superoxide dismutase (MnSOD) may be expected to overcome oxaliplatin-associated chemotherapy-induced peripheral neuropathy (CIPN). Unfortunately, two recent phase III studies (POLAR A and M trials) applying Ca4Mn(DPDP)5 in colorectal cancer (CRC) patients receiving multiple cycles of FOLFOX6 (5-FU + oxaliplatin) failed to demonstrate efficacy. Instead of an anticipated 50% reduction in the incidence of CIPN in patients co-treated with Ca4Mn(DPDP)5, a statistically significant increase of about 50% was seen. The current article deals with confusing differences between early and positive findings with MnDPDP in comparison to the recent findings with Ca4Mn(DPDP)5. The POLAR failure may also reveal important mechanisms behind oxaliplatin-associated CIPN itself. Thus, exacerbated neurotoxicity in patients receiving Ca4Mn(DPDP)5 may be explained by redox interactions between Pt2+ and Mn2+ and subtle oxidative–nitrosative chain reactions. In peripheral sensory nerves, Pt2+ presumably leads to oxidation of the Mn2+ from Ca4Mn(DPDP)5 as well as from Mn2+ in MnSOD and other endogenous sources. Thereafter, Mn3+ may be oxidized by peroxynitrite (ONOO−) into Mn4+, which drives site-specific nitration of tyrosine (Tyr) 34 in the MnSOD enzyme. Conformational changes of MnSOD then lead to the closure of the superoxide (O2•−) access channel. A similar metal-driven nitration of Tyr74 in cytochrome c will cause an irreversible disruption of electron transport. Altogether, these events may uncover important steps in the mechanism behind Pt2+-associated CIPN. There is little doubt that the efficacy of MnDPDP and its therapeutic improved counterpart Ca4Mn(DPDP)5 mainly depends on their MnSOD-mimetic activity when it comes to their potential use as rescue medicines during, e.g., acute myocardial infarction. However, pharmacokinetic considerations suggest that the efficacy of MnDPDP on Pt2+-associated neurotoxicity depends on another action of this drug. Electron paramagnetic resonance (EPR) studies have demonstrated that Pt2+ outcompetes Mn2+ and endogenous Zn2+ in binding to fodipir (DPDP), hence suggesting that the previously reported protective efficacy of MnDPDP against CIPN is a result of chelation and elimination of Pt2+ by DPDP, which in turn suggests that Mn2+ is unnecessary for efficacy when it comes to oxaliplatin-associated CIPN.

Risk factors of paclitaxel-induced peripheral neuropathy in patients with breast cancer: a prospective cohort study.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and severe adverse reaction in taxane-based chemotherapy. This study aimed to analyze the risk factors of peripheral neuropathy in patients with breast cancer receiving paclitaxel chemotherapy to provide a reference for the early prevention of CIPN. We included 350 patients with breast cancer who received chemotherapy for the first time at the Tangshan People's Hospital between August 2022 and June 2023 and were followed for at least 3 months after the end of chemotherapy. The incidence of CIPN in patients with breast cancer was calculated, and risk factors for CIPN were analyzed using logistic regression analysis. The incidence rate of CIPN was 79.1%. Multifactor logistic regression analysis indicated that age ≥45 years [odds ratio (OR)=5.119, 95% confidence interval (CI)=1.395-18.780] and ≥60 years (OR=9.366, 95% CI=1.228-71.421), history of hypertension (OR=3.475, 95% CI=1.073-11.250), cumulative dose of chemotherapy drugs >900 mg (OR=4.842, 95% CI=1.961-5.946), vitamin D deficiency (OR=6.214, 95% CI=2.308-16.729), abnormal alanine aminotransferase (OR=3.154, 95% CI=1.010-9.844), anemia before chemotherapy (OR=2.770, 95% CI=1.093-7.019), infusion duration of chemotherapy drugs >30min (OR=3.673, 95% CI=1.414-9.539), body mass index ≥24 kg/m2 (OR=8.139, 95% CI=1.157-57.240), mild depression (OR=4.546, 95% CI=1.358-15.223), and major depression (OR=4.455, 95% CI=1.237-16.037) increased the risk of CIPN. Having a regular caregiver (OR=0.223, 95% CI=0.087-0.573), high levels of physical activity (OR=0.071, 95% CI=0.008-0.647), and strong social support (OR=0.048, 95% CI=0.003-0.682) were protective factors against CIPN. Clinical attention should be paid to patients with these risk factors, and active and effective preventive measures should be taken to reduce the occurrence of CIPN and improve the quality of life.

Adhesive capsaicin 8% patch for improved control of pain caused by chemotherapy-induced peripheral neuropathy in patients with multiple myeloma: A single-centre, seven-case series.

Capsaicin is a highly selective agonist of the transient receptor potential vanilloid 1. The adhesive capsaicin patch provides a high capsaicin concentration (8%) directly in the painful area - its efficacy in benign peripheral neuropathic pain (diabetic neuropathy or postherpetic neuralgia) has recently been described in the literature. However, there is scant evidence of its efficacy in chemotherapy-induced peripheral neuropathy (CIPN). This is a concern for patients with multiple myeloma, who suffer from peripheral neuropathic pain induced by first-line treatments (bortezomib or thalidomide). To describe improved control of CIPN in patients with multiple myeloma using adhesive capsaicin 8% patch. We opted for a retrospective observational case series. Between October 2017 and October 2020, we collected clinical data from adult multiple myeloma patients affected by CIPN who were administered the capsaicin 8% patch in our palliative care outpatient clinic. We compiled Numerical Pain Rating Scale (NPRS) scores, patients' medication needs and performance status before and after patch application. Two women and five men with an average age of 62.85 years received bortezomib. Two patients (28.57% of the sample) also received thalidomide. The average NPRS score before patch application was 6.42/10. Five of the seven patients (71.42%) received a mean daily oral morphine dose of 52.85 mg/day, five (71.42%) received gabapentinoids and one (14.28%) received antidepressants. The average NPRS score decreased to 4/10 seven days after patch application, while the mean daily oral morphine dose remained stable. Performance status improved slightly in two patients (28.57%) and remained stable in the rest. One patient (14.28%) required an extra analgesic dose during patch application. Capsaicin 8% patch application appears to reduce pain intensity in patients with multiple myeloma suffering from CIPN.

Proton Pump Inhibitors Ameliorate Oxaliplatin-induced Peripheral Neuropathy: Retrospective Analysis of Two Real-world Clinical Databases.

Chemotherapy-induced peripheral neuropathy (CIPN) due to oxaliplatin (L-OHP) is a major clinical problem. Effective and safe preventive strategies for CIPN are urgently needed. Although proton pump inhibitors (PPIs) have various off-target effects, their clinical impact on L-OHP-induced CIPN remains unclear. In the present study, we investigated the effects of PPIs on L-OHP-induced CIPN in patients using two real-world clinical databases. We retrospectively analyzed the electronic medical records of Osaka University Hospital to examine the effect of PPIs on CIPN development in 217 patients who received XELOX (L-OHP plus capecitabine) therapy for colorectal cancer. In addition, the Japanese Adverse Drug Event Report (JADER) database was used to validate the effects of PPIs on L-OHP-induced CIPN. The incidences of CIPN (grade ≥2) and discontinuation of L-OHP were significantly lower in patients with PPIs than in those without PPIs. Multivariate analysis showed that concomitant PPIs use was an independent factor that significantly contributed to the prevention of grade ≥2 CIPN (odds ratio=0.054, p<0.001). Kaplan-Meier analysis showed that the time to onset of grade ≥2 CIPN was significantly prolonged in patients with PPIs without affecting the therapeutic efficacy of L-OHP (p=0.004). Moreover, JADER database analyses revealed that the reporting odds ratio of any PPI for L-OHP-induced CIPN was 0.485. Concomitant PPI use ameliorated L-OHP-induced CIPN in patients with colorectal cancer.

Platinum-based chemotherapy induces demyelination of Schwann cells in oral squamous cell carcinoma treatment

BackgroundCisplatin, carboplatin, and oxaliplatin are the only three platinum-based antineoplastic drugs that have been accepted worldwide for treating various cancers. Up to 83.6% of patients treated with platinum-based antineoplastic drugs will develop chemotherapy-induced peripheral neuropathy (CIPN), manifesting as sensory paresthesias, dysesthesias, and hypoesthesias that can cause significant adverse impact to daily activities. AimTo investigate how these three platinum-based drugs affect mitochondrial function and myelination state of Schwann cells and the signalling pathway involved. Method2 μM Cisplatin, 20 μM carboplatin, and 1 μM oxaliplatin were used to inhibit the growth of CAL-27 by 20% respectively. These drugs were then used to induce chemotherapy-induced peripheral neuropathy in Rat Schwann Cells (RSC96). The changes in cell metabolism and myelin formation in RSC96 were investigated. ResultCisplatin and carboplatin, but not oxaliplatin increased intracellular and mitochondrial reactive oxygen species in RSC96. Only Cisplatin and carboplatin decreased mitochondrial membrane potential (ΔΨm) and ATP production in RSC96. Both Cisplatin and carboplatin led to demyelination of RSC96, characterized by increased expression of p75NTR and decreased expression of myelin protein zero (MPZ). ConclusionCisplatin and carboplatin, but not oxaliplatin, caused mitochondrial dysfunction and induced demyelination in RSC96 while showing similar toxicity to head and neck cancer cells. Oxaliplatin may be a potential chemotherapy drug to prevent CIPN in patients with head and neck cancer.

A randomized trial to evaluate the preventive effect of lafutidine on chemotherapy-induced peripheral neuropathy in patients treated with carboplatin and paclitaxel for lung cancer.

Chemotherapy-induced peripheral neuropathy (CIPN) has a significant impact on the therapeutic efficacy of chemotherapy and patients' quality of life. The aim of this study was to assess the preventive effect of lafutidine on CIPN. Patients were randomly assigned (1:1) to carboplatin and paclitaxel chemotherapy with lafutidine 10 mg twice daily (lafutidine group) or without lafutidine (control group). Peripheral neuropathy in both groups was assessed with the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and two patient-based questionnaires, the Patient Neurotoxicity Questionnaire (PNQ) and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx). The primary outcome was the incidence of grade 2 or higher peripheral neuropathy in CTCAE version 5.0. The target number of cases was set at approximately 40. In total, 18 patients were screened, and 16 patients were assigned to the lafutidine group (n=9) or control group (n=7) between January 2021 and January 2023. Due to poor recruitment, the target number of cases was not reached. Grade 2 or higher neuralgia was 22.2% in the lafutidine group and 14.3% in the control group. Grade 2 or higher peripheral sensory neuropathy was 100% in the lafutidine group and 71.4% in the control group (P=0.175). Grade 3 or higher peripheral neuropathy was not detected in either group. There was no significant difference in PNQ scores between the two groups. Median FACT/GOGNtx scores after the fourth cycle tended to be lower in the lafutidine group than in the control group. There was no statistically significant difference in progression free survival (PFS) between the two groups. There were no adverse events due to lafutidine administration. Although the preventive effect of lafutidine on CIPN could not be demonstrated statistically, lafutidine FACT/GOG-Ntx scores showed a trend toward decreased neurotoxicity as chemotherapy proceeded. More reliable studies using lafutidine on the prevention of CIPN should be conducted. Japan Registry of Clinical Trials identifier: jRCTs021200031.

Effectiveness of Nonpharmacologic Interventions for Chemotherapy-Induced Peripheral Neuropathy in Patients With Breast Cancer: A Systematic Review and Network Meta-analysis.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect in patients with breast cancer (BC) during treatment. Patients experiencing CIPN develop neuropathic symptoms, which could lead to the modification or discontinuation of chemotherapy. Nonpharmacological interventions can be simple and safe, but evidence of their effectiveness in patients with BC experiencing CIPN is currently insufficient. To compare and rank the effectiveness of nonpharmacologic interventions for CIPN in patients with BC. We conducted a systematic search of randomized controlled trials registered from database inception until October 2022 in 7 databases. We assessed studies that met the inclusion and exclusion criteria and evaluated the risk of bias. Network meta-analysis was conducted using Stata SE 17.0 (StataCorp, College Station, Texas). A total of 13 studies involving 9 nonpharmacologic interventions and comprising 571 participants were included. The results of the network meta-analysis showed that cryotherapy (standard mean difference, -1.22; 95% confidence interval, -2.26 to -0.17) exerted significant effects versus usual care. Cryotherapy (surface under the cumulative ranking area [SUCRA]: 0.74) was associated with the highest likelihood of effectively alleviating CIPN in patients with BC, followed by exercise (SUCRA: 0.62) and self-acupressure (SUCRA: 0.59). Cryotherapy was the most effective nonpharmacologic intervention for alleviating CIPN in patients with BC. Large-scale studies are required to verify the present findings. This study provides evidence regarding the effectiveness of nonpharmacologic interventions for CIPN. Physicians and nurses could incorporate cryotherapy into clinical practice to alleviate CIPN in patients with BC.

A prospective study of a novel test to quantify tactile sensation and chemotherapy-induced peripheral neuropathy in patients with gynecologic malignancies (1147)

A prospective study of a novel test to quantify tactile sensation and chemotherapy-induced peripheral neuropathy in patients with gynecologic malignancies (1147)

Effect of Exercise on Chemotherapy-Induced Peripheral Neuropathy Among Patients Treated for Ovarian Cancer

Chemotherapy-induced peripheral neuropathy (CIPN), one of the most common and severe adverse effects of chemotherapy, is associated with worse quality of life among survivors of ovarian cancer. Currently, there is no effective treatment for CIPN. To evaluate the effect of a 6-month aerobic exercise intervention vs attention-control on CIPN among women treated for ovarian cancer in the Women's Activity and Lifestyle Study in Connecticut (WALC) to provide evidence to inform the guidelines and recommendations for prevention or treatment of CIPN. This prespecified secondary analysis evaluated the Women's Activity and Lifestyle Study in Connecticut (WALC), a multicentered, open-label, population-based, phase 3 randomized clinical trial of an aerobic exercise intervention vs attention control for CIPN in patients who were diagnosed with ovarian cancer. Only WALC participants who received chemotherapy were included in this analysis. Participants were randomized 1:1 to either a 6-month aerobic exercise intervention or to attention control. All analyses were conducted between September 2022 and January 2023. The exercise intervention consisted of home-based moderate-intensity aerobic exercise facilitated by weekly telephone counseling from an American College of Sports Medicine/American Cancer Society-certified cancer exercise trainer. Attention control involved weekly health education telephone calls from a WALC staff member. Change in CIPN was the primary outcome in this secondary analysis. This outcome was represented by CIPN severity, which was self-measured by participants at baseline and 6 months using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity scale, with a score range of 0 to 44. A mixed-effects model was used to assess the 6-month change in CIPN between the exercise intervention and attention control arms. Of the 134 participants (all females; mean [SD] age, 57.5 [8.3] years) included in the analysis, 69 were in the exercise intervention arm and 65 were in the attention control arm. The mean (SD) time since diagnosis was 1.7 (1.0) years. The mean (SD) baseline CIPN scores were 8.1 (5.6) in the exercise intervention arm and 8.8 (7.9) in the attention control arm (P = .56). At 6 months, the self-reported CIPN score was reduced by 1.3 (95% CI, -2.3 to -0.2) points in the exercise intervention arm compared with an increase of 0.4 (95% CI, -0.8 to 1.5) points in the attention control arm. The between-group difference was -1.6 (95% CI, -3.1 to -0.2) points. The point estimate was larger among the 127 patients with CIPN symptoms at enrollment (-2.0; 95% CI, -3.6 to -0.5 points). Findings of this secondary analysis of the WALC trial indicate that a 6-month aerobic exercise intervention vs attention control significantly improved self-reported CIPN among patients who were treated for ovarian cancer. While replication of the findings in other studies is warranted, incorporating referrals to exercise programs into standard oncology care could reduce CIPN symptoms and increase quality of life in patients with ovarian cancer. ClinicalTrials.gov Identifier: NCT02107066.

Efficacy of cryotherapy on chemotherapy-induced peripheral neuropathy in patients with breast cancer: a propensity score-matched study.

This study investigated the effectiveness of cryotherapy in preventing CIPN and its effect on the quality of life (QoL) during chemotherapy. Eligible participants are cancer patients who began therapy with carboplatin, docetaxel, or paclitaxel in the Breast Oncology Unit between May 2022 and October 2022. Patients were distributed into intervention groups that utilized cryotherapy with ice gloves and ice boots and control groups that did not receive cryotherapy. Patient self-report questionnaires were used to quantify patients' symptoms and QoL after treatment. The intervention group exhibited significantly less cold sensitivity, hand and foot numbness, and hand tingling than the control group. Daily CIPN symptoms were substantially milder in the intervention group. Before and after treatment, nerve pain, balance, and muscle and joint discomfort were similar. Intervention and control groups have varied neurotoxicity adverse reaction scores. 2.4% of controls had grade 4 motor neurotoxicity impairment. Physical function and QoL improved in the intervention group. Cryotherapy relieves CIPN symptoms in breast cancer patients receiving carboplatin and paclitaxel chemotherapy. More thorough trials should be carried out to determine the best time limit and duration of cryotherapy.

Can Endoplasmic Reticulum Stress Responses Predict the Development of CIPN in Patients Receiving Paclitaxel-based Therapy? (P12-13.001)

<h3>Objective:</h3> To determine if XBP1s correlates with the onset and severity of chemotherapy-induced peripheral neuropathy (CIPN) in patients receiving paclitaxel (PTX) therapy for their cancer. <h3>Background:</h3> Neuroinflammation is one proposed mechanism for the development of CIPN. X-box binding protein 1 (XBP1s), a prominent molecule in the IRE1α–XBP1 signaling pathway (which regulates the production of enzymes that mediate inflammation-induced pain), shows promise as a potential biomarker to predict the onset of CIPN. <h3>Design/Methods:</h3> Patients newly diagnosed with gynecologic malignancy receiving PTX-based first-line therapy were recruited before treatment initiation. Once consented, blood samples were drawn before treatment and at each scheduled PTX infusion. Determination of serum PTX levels using mass spectrometry and XBP1s mRNA levels in peripheral blood mononuclear cells (PBMCs) by qPCR were performed. In addition, at every infusion time point, each patient’s level of peripheral neuropathy was graded by a physician or advanced provider based on CTCAE (Common Terminology Criteria for Adverse Events) grading criteria (scored 0–5, with 0 being asymptomatic and higher numbers indicating worse neuropathy). Cellular XBP1s, serum PTX, and neuropathy CTCAE scores were statistically associated. <h3>Results:</h3> The study cohort consisted of 8 patients; all female; mean age 55±17 years. All 8 received PTX/carboplatin. Of these, 7 developed symptomatic CIPN (physician assessment). Median peak neuropathy CTCAE grade was 1 (range 0–2). Mean XBP1s peak value was 0.049±0.032; mean baseline XBP1s value was 0.027±0.015. There was a significant association between rise of XBP1s from baseline to peak and neuropathy CTCAE grade (r=0.830, R₂=0.725, p=0.018). Patients with higher serum PTX also had higher PBMC XBP1s expression relative to baseline (p=0.022). Patients with longer days to peak of XBP1s also had longer days to onset of CIPN (r=0.757, R₂=0.573, p=0.049). <h3>Conclusions:</h3> A greater rise from baseline in XBP1s, a marker of ER stress, correlated with the timing and severity of PTX-induced CIPN. <b>Disclosure:</b> Mr. Limia has nothing to disclose. Dr. Foneca has nothing to disclose. Dr. Gelblung has nothing to disclose. Dr. Shalowitz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Nimble, LLC. The institution of Dr. Shalowitz has received research support from Foundation for Women’s Cancers. The institution of Dr. Shalowitz has received research support from National Cancer Institute. Dr. Kelly has nothing to disclose. Fang-Chi Hsu has nothing to disclose. Dr. Furdui has stock in Xoder Technologies. Dr. Furdui has received intellectual property interests from a discovery or technology relating to health care. Dr. Cubillos-Ruiz has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for NextRNA Therapeutics. The institution of Dr. Cubillos-Ruiz has received research support from Department of Defense. The institution of Dr. Cubillos-Ruiz has received research support from National Institutes of Health. The institution of Dr. Cubillos-Ruiz has received research support from The Mark Foundation for Cancer Research. Edgar Alfonso Romero-Sandoval has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Journal of Pain Research. The institution of Edgar Alfonso Romero-Sandoval has received research support from NINDS. The institution of Edgar Alfonso Romero-Sandoval has received research support from NIDA. The institution of Edgar Alfonso Romero-Sandoval has received research support from NIGMS. Dr. Strowd has received personal compensation for serving as an employee of Kaplan. Dr. Strowd has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Monteris Medical, Inc. Dr. Strowd has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novocure. Dr. Strowd has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Academy of Neurology. The institution of Dr. Strowd has received research support from Southeastern Brain Tumor Foundation. The institution of Dr. Strowd has received research support from Jazz Pharmaceuticals. The institution of Dr. Strowd has received research support from National Institutes of Health. The institution of Dr. Strowd has received research support from Alpha Omega Alpha. The institution of Dr. Strowd has received research support from American Board of Psychiatry and Neurology. Dr. Strowd has received publishing royalties from a publication relating to health care. Dr. Strowd has received publishing royalties from a publication relating to health care.

An evaluation of the effect of lithium on taxane-induced neuropathy.

No medications are known to protect against chemotherapy-induced peripheral neuropathy (CIPN). Pre-clinical models suggest that lithium may lessen taxane-induced neuropathy. Our aim was to use clinical data to assess whether concurrent lithium usage decreased the frequency or severity of CIPN in patients receiving taxane chemotherapy. A retrospective analysis was performed using the electronic health record at Mayo Clinic to identify all patients prescribed concurrent lithium and paclitaxel. Four controls were matched to each case based on clinical variables. Neuropathy severity was graded from available patient and clinician reports. Rates of any neuropathy, dose reduction for CIPN, and treatment discontinuation for CIPN were compared. Conditional regression analysis was performed with propensity score matching. Six patients, receiving concurrent lithium and paclitaxel, were included in the analysis, and compared to 24 control cases. A similar number of paclitaxel cycles were administered to both groups. Any neuropathy was experienced by 33% (2/6) of patients receiving lithium and 38% (9/24) patients who did not receive lithium (p = 1.000). There was no difference in neuropathy severity (p = 0.8565), rate of chemotherapy dose reduction (17% vs. 17%, p = 1.000), or treatment discontinuation (17% vs 4%, p = 0.3655) for CIPN. In the propensity score analysis, the odds ratio for developing any neuropathy was 0.63 (95% confidence interval, 0.06 to 6.96, p = 0.7079). Lithium does not appear to significantly lessen the risk of neuropathy for patients receiving paclitaxel. Targeted approaches for preventing CIPN are desperately needed. Despite sound scientific rationale, the current study did not identify neuroprotective properties of lithium.

Randomized double-blind, placebo-controlled study of oral gabapentin for prevention of neuropathy in patients receiving paclitaxel

BackgroundPeripheral neuropathy is a common dose-limiting side effect of paclitaxel. To date, there is no effective strategy to prevent paclitaxel-induced peripheral neuropathy. A recent small phase II study demonstrated the potential role of oral gabapentin in this setting. This phase III study is aimed to assess the efficacy of oral gabapentin in preventing paclitaxel-induced neuropathy.ObjectiveTo compare the efficacy of oral gabapentin with placebo in preventing clinically significant peripheral neuropathy (NCI CTCAEv5.0 grade 2 or higher) in patients receiving paclitaxel.MethodsThis is a randomized, placebo-controlled, double-blind, parallel-group superiority trial. The primary outcome is the development of grade 2 or higher chemotherapy-induced peripheral neuropathy. Secondary outcomes include any grade neuropathy, the percentage change in sensory nerve conduction velocities in peripheral nerves, time to development of any grade neuropathy, paclitaxel dose reductions and delays due to peripheral neuropathy, patient-reported outcomes, adverse events, and adherence to oral therapy. A total of 136 patients receiving paclitaxel will be randomly allocated (stratified by weekly vs. non-weekly administration) to receive either oral gabapentin or placebo till three weeks after the last dose of chemotherapy or occurrence of the primary outcome.ConclusionThis study aims to find if oral gabapentin reduces the incidence of grade 2 or higher chemotherapy-induced peripheral neuropathy in patients receiving paclitaxel.Trial registrationThe trial is registered prospectively with the Clinical Trials Registry of India (CTRI/2022/02/040030) on April 4, 2022.

Mitigation of paclitaxel-induced peripheral neuropathy in breast cancer patients using limb-cooling apparatus: a study protocol for a randomized controlled trial.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common adverse events that can significantly impair the quality of life of patients. Although limb cooling may be beneficial for preventing CIPN, logistical challenges exist in ensuring consistent efficacy and safety. The purpose of this randomized controlled trial is to validate whether limb cooling with strict temperature control can reduce CIPN in patients with breast cancer receiving weekly paclitaxel as a perioperative treatment. This study is a multicenter, double-blinded, randomized controlled trial. We plan to enroll patients with breast cancer who are scheduled to receive 12 weekly doses of paclitaxel (60 min 80 mg/m2 intravenous infusion) as perioperative chemotherapy. Patients will be randomly divided into the intervention or control groups and undergo limb cooling therapy maintained at a constant temperature of 13°C and 25°C, respectively. The primary endpoint is the proportion of patients who report Patient Neurotoxicity Questionnaire (PNQ) ≥ D in their limbs by the end of the study treatment or at the time of discontinuation. The results of this trial will contribute to the establishment of new evidence for limb cooling therapy in the mitigation of CIPN and present a safe and stable cooling device that may be suitable for use in the clinic. https://jrct.niph.go.jp/en-latest-detail/jRCT2032210115, identifier jRCT2032210115.

Patterns of Neuropathy in ALL Patients Treated with Vincristine Based Regimens with and without Tyrosine Kinase Inhibitors

Introduction: Acute lymphoblastic leukemia (ALL) is the most common acute leukemia in pediatric patients, but accounts for only 20% of acute leukemia diagnoses in adults. Vincristine (VCR) is a cornerstone chemotherapy agent in the management of ALL, but is known to cause high rates of chemotherapy induced peripheral neuropathy (CIPN). Tyrosine kinase inhibitors (TKIs) are routinely incorporated into the treatment of Philadelphia chromosome positive (Ph+) ALL, and have been shown to have potential neuroprotective effects in the prevention of CIPN. Pre-clinical work using animal models has suggested the attenuation of VCR CIPN with the TKI nilotinib. Based on these pre-clinical results, we sought to evaluate whether TKIs had a protective effect on the development of CIPN in patients with ALL treated with VCR containing regimens. Methods: We performed a retrospective study on adult ALL patients who were treated with VCR-based regimens from 1/1/11 to 12/31/20 at the Ohio State University James Cancer Hospital. Demographics including age, gender, race/ethnicity, relationship status, and drug and alcohol use were collected. Clinical information was also collected including performance status, height/weight, subtype of ALL and date of diagnosis, chemotherapy regimen, comorbidities, falls, date of last follow-up, and information on CIPN. Descriptive statistics were generated on all patients, stratified by those who received a TKI and those who did not. Chi-squared tests were performed to assess for an association between presence and severity of CIPN and TKI use and to evaluate other significant factors associated with the development of CIPN. Given that the majority of TKI patients received hyper-CVAD (cyclophosphamide, VCR, doxorubicin hydrochloride, and dexamethasone), a sub-analysis was performed for all patients treated with hyper-CVAD. Results: A total of 220 patients were included in the analysis, with a summary of key patient characteristics shown in Table 1. Median age at diagnosis was 42 (range 17-80) and 57.7% of patients were male. The majority of patients had B-cell ALL (75%), with 18.6% T-cell ALL and 6.4% other. The most common treatment regimen was hyper-CVAD (50.5%), followed by the CALGB 10403 (Stock Blood 2019) regimen (29.5%). Approximately one quarter (26.8%) of patients received TKIs, with the large majority (96.6%) receiving dasatinib and 1.7% receiving either nilotinib or ponatinib. The presence of baseline peripheral neuropathy and lower body mass index (BMI) were the only statistically significant variables between the no CIPN group (grp) and the CIPN grp (P=0.0092, 0.0359). Median BMI was 30 (range 18.9-54.7) in the no CIPN grp as compared to 27.2 (range 17.2-52.9) in the CIPN grp. Cumulative dosing and total doses of VCR was not significant between the no CIPN and CIPN grps (P=0.2675, 0.0630). When comparing those patients who received TKI (TKI grp) to those who did not (no TKI grp), there was a trend toward lower rates of CIPN in the TKI as compared to the no TKI grp at 71.2% compared to 81.4%, but no significant difference was seen (P=0.1027, Table 2). In the sub-analysis of patients who received hyper-CVAD (n=111), 66% of pts in the TKI grp developed CIPN as compared to 71.9% in the no TKI grp, with no significant difference seen (P=0.504, Table 2). For both the entire cohort and hyper-CVAD sub-analysis, there was no significant difference in max dose reduction, holds or cessation due to neuropathy, or grade at worst seen between the grps (Table 2). For both analyses, the no TKI grp also received significantly higher cumulative doses and total doses of VCR (Table 2). Conclusions: Overall, we found no significant differences in the development of neuropathy in patients with ALL treated with VCR-based regimens with or without TKI, despite higher doses of VCR utilized in patients treated without TKIs. However, the majority of our patients received dasatinib rather than nilotinib, which has been the focus of recent pre-clinical studies. Our findings may suggest a potential mechanistic difference in the effects of dasatanib and nilotinib on the neuronal transport of VCR. While our findings should be confirmed in a larger analysis, they suggest that dasatinib lacks a protective effect against neuropathy for ALL patients treated with VCR-based regimens. Based on promising preclinical data, future studies should focus on the impact of nilotinib for neuroprotection in the prevention of CIPN. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Sigma Antagonists for Treatment of Neuropathic Pain Syndromes in Cancer Patients: A Narrative Review

Almost 40% of cancer patients have neuropathic pain or mixed pain with a neuropathic component, which can be intense, debilitating, and challenging to treat. New studies on sigma receptors show these enigmatic ligand-binding protein chaperones may be helpful drug targets for new pharmacologic options to reduce many types of neuropathies, including chemotherapy-induced peripheral neuropathy (CIPN) and other cancer-related neuropathic pain syndromes. Our objective was to review the literature, including preclinical findings, in support of sigma-1 receptor (S1R) antagonists in reducing neuropathic pain and sigma-2 receptor (S2R) agonists for neuroprotection. The mechanisms behind these effects are not yet fully elucidated. The role of S1R antagonists in treating CIPN appears promising. In some cases, combination therapy of an opioid—which is a true analgesic—with a S1R antagonist, which is an anti-hyperalgesic and anti-allodynic agent, has been proposed. Of interest, but not well studied is whether or not S1R antagonists might be effective in treating CIPN in patients with pre-existing peripheral diabetic neuropathy. While neuropathic syndromes may occur with hematologic cancers, the role of S1R agonists may be effective. Sigma receptors are being actively studied now for a variety of conditions ranging from Alzheimer’s disease to Parkinson’s disease as well as neuropathic pain.

Preventive effect of goshajinkigan against peripheral neuropathy induced by paclitaxel-containing chemotherapy: An open-label, randomized, phase II study.

TPS12141 Background: Paclitaxel is a taxane agent that has been used as a standard treatment for various malignancies. However, taxanes, such as paclitaxel, unfortunately cause a high frequency of chemotherapy-induced peripheral neuropathy (CIPN) as a result of axonal damage (All grade; 70%) (Clin Cancer Res.1996), CIPN worsens patients’ QOL and then lead to poor treatment compliance. Furthermore, there is no evidence for the prevention of CIPN. Goshajinkigan (GJG) is one of the Kampo medicine and it is approved in Japan for the treatment of numbness and has been commonly used for diabetic peripheral neuropathy. In addition, a non-clinical study has also shown the preventive effect of GJG against CIPN induced by paclitaxel (Molecular pain. 2014). To investigate if GJG indeed has a preventive effect for severe CIPN in patients receiving chemotherapy including paclitaxel, we started a two-arm randomized trial of GJG vs physician’s choice of treatment for patients. Methods: Patients have to meet the followings: pathologically diagnosed with malignant tumor (regardless of cancer type) and scheduled to receive ≥4 courses of chemotherapy including carboplatin and paclitaxel (paclitaxel ≥150mg/m2 every 3-4 weeks) as initial chemotherapy; age ≥20yrs; Performance Status of 0 or 1. The primary endpoint is set as a proportion of ≥G2 CIPN by CTCAE ver.5.0 by the end of 4 courses of chemotherapy. With stratification by cancer type and age, patients will be randomized centrally to receive GJG at the same time as chemotherapy (A), or to receive the physician’s choice of treatment for pts if ≥G2 CIPN occurs without prophylaxis (B). Assuming that the incidence of ≥G2 CIPN would be 50% without prophylaxis and 20% with GJG prophylaxis, and assuming an 80% completion rate of four paclitaxel courses, the required sample size is 66 patients (1-β: 0.75, α: 0.1). The secondary endpoint includes time to the onset of CIPN G2, incidence rate and severity of CIPN at the end of each course, relative dose intensity of paclitaxel, adverse events other than CIPN. Enrollment began in 2022, and will be complete by 2025. Clinical trial information: 061210047.

Risk factors for interstitial lung disease induced by gemcitabine plus albumin-bound paclitaxel therapy in pancreatic ductal adenocarcinoma patients

BackgroundGemcitabine plus nab-paclitaxel (GnP) therapy is used for unresectable pancreatic ductal adenocarcinoma, but may cause interstitial lung disease (ILD) as a serious side effect. However, the risk factors for ILD in patients receiving GnP therapy are not well established. Here, we retrospectively investigated the incidence of GnP-induced ILD in pancreatic ductal adenocarcinoma patients, and the risk factors.MethodsWe investigated the patients’ background, laboratory data, previous treatment history, concomitant medications, number of doses of GnP, cumulative dosage and administration period, and occurrence of side effects.ResultsOf the 105 patients included in this study, ILD occurred in 10 (9.5%). Patients with ILD had a significantly higher frequency of concomitant treatment with Kampo medicines, especially goshajinkigan, which is considered to help prevent chemotherapy-induced peripheral neuropathy (CIPN) (odds ratio: 11.5, 95% confidence interval: 2.67–49.38). No significant differences were observed in other clinical characteristics. Notably, the severity of CIPN in patients who used goshajinkigan for prevention was not significantly different from that in patients who did not use goshajinkigan in this study.ConclusionsThese results suggest that administration of goshajinkigan to patients receiving GnP therapy for prevention of CIPN may need to be reconsidered.

Morning Chronotype Decreases the Risk of Chemotherapy-Induced Peripheral Neuropathy in Women With Breast Cancer

BackgroundThe purpose of this longitudinal prospective cohort study was to investigate the role of chronotype in the incidence of chemotherapy-induced peripheral neuropathy (CIPN) among women with breast cancer.MethodsWe recruited women with breast cancer awaiting adjuvant chemotherapy, including four cycles of docetaxel. Participants reported peripheral neuropathy symptoms of numbness/tingling at the baseline, and at 4weeks after completion of chemotherapy. Candidate psychiatric factors associated with CIPN were assessed at the baseline, using the Composite Scale of Morningness, the Pittsburgh Sleep Quality Index, and the Hospital Anxiety and Depression Scale. To examine the association between chronotype and CIPN, we built logistic regression models, adjusting for demographic, clinical, and other psychiatric variables.ResultsAmong 48 participants, 29 participants developed CIPN. The morning chronotype was inversely associated with CIPN (odds ratio, 0.06; confidence interval, 0.01–0.74; P = 0.028) after adjusting for age, BMI, education, type of operation, alcohol use, smoking, sleep quality, depression, and anxiety.ConclusionOur results suggest that the morning chronotype is a protective factor against the development of CIPN in patients with breast cancer who were treated with docetaxel.Trial RegistrationClinicalTrials.gov Identifier: NCT01887925

Investigating the Effect of Zinc on the Prevention of Acute Peripheral Neuropathy in Cancer Patients Treated with Taxanes.

Background:Chemotherapy-induced peripheral neuropathy (CIPN) is a major complication of many chemotherapeutic agents, including taxanes. Here, we aimed to investigate the effect of zinc on CIPN.Materials and Methods:This is a double-blinded controlled clinical trial that was performed in 2020–2021 in Isfahan on 55 cancer patients. We collected the data regarding CIPN, its severity, presence of abnormal deep-tendon reflexes, paresthesia, restriction in daily activities, and restriction in self-care and pain. Patients were divided into two groups: Patients in the first group were treated with capsules of zinc sulfate 25 mg daily and the control group received placebo. The duration of treatments was 3 months. Patients were visited 6, 9, and 12 weeks after study initiation.Results:There was a statistically significant decrease in the frequency of CIPN in the intervention group (37.03% vs. 14.8%, P < 0.001). The evaluation of the severity of neuropathy and presence of abnormal deep-tendon reflexes also demonstrated significant decrease in the intervention group during the study (P < 0.001 for both), but no significant changes were observed in the placebo group (P > 0.05). The activity limitations and pain severity improved significantly both in the intervention and placebo groups (P < 0.001 for both groups and items). The intervention group, however, had significantly lower frequencies of activity limitation and lower pain severity within compared to the control group during the study (P < 0.001).Conclusion:Zinc supplement therapy resulted in reduced frequency and intensity of CIPN in patients undergoing chemotherapy with taxanes.