Severe Chemotherapy-induced Peripheral Neuropathy Research Articles

Melatonin mitigates vincristine-induced peripheral neuropathy by inhibiting TNF-α/astrocytes/microglial cells activation in the spinal cord of rats, while preserving vincristine's chemotherapeutic efficacy in lymphoma cells

Vincristine (VCR), an anti-tubulin chemotherapy agent, is known to cause peripheral and central nerve damage, inducing severe chemotherapy-induced peripheral neuropathy (CIPN). Although melatonin has been recently recognized for its potential anti-neuropathic effects, its efficacy in countering VCR-induced neuropathy remains unclear. This study examines the neuroprotective potential of melatonin against VCR-induced neuropathy using a rat model. Neuropathic pain was induced through 10 VCR injections (0.1 mg/kg/day i.p.), administered in two five-day cycles with a two-day break. Melatonin treatment started two days before VCR administration and continued daily throughout the experiment. Rats were assigned to five groups: control, VCR, and three melatonin-treated groups receiving VCR with melatonin (5, 10, or 20 mg/kg/day i.p.). We assessed mechanical (von-Frey and Randall-Selitto tests) and thermal (hot-plate and tail-flick tests) hyperalgesia, motor coordination (rotarod test), and sciatic nerve conduction velocity (NCV). Changes in body weight, spinal cord histopathology (H&E), and proinflammatory markers (TNF-α, IL-1β, and IL-6), reactive astrocytes (GFAP) and microglial cells (IBA-1) were also assessed, as well as spinal cord degeneration (Nissl stain) and demyelination (LFB stain and MBP). Finally, the effect of melatonin on the cytotoxic activity of VCR against EL4 lymphoma cells was assessed using an MTT assay. Our results indicated that melatonin coadministration with VCR preserved spinal cord architecture, elevated nociceptive thresholds, improved motor coordination, enhanced NCV, and maintained normal body weight gain. Melatonin also reduced inflammation, decreased reactive astrocytes and microglia, and prevented neurodegeneration and demyelination in the spinal cord. Importantly, melatonin did not affect VCR's cytotoxic activity in cancer cells.

Dietary quality and chemotherapy-induced peripheral neuropathy in colon cancer.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose-limiting chemotoxicity caused by oxaliplatin. This study investigated the relationship between dietary quality and the development of moderate and/or severe CIPN in colon cancer survivors using data from the Focus on Reducing Dose-Limiting Toxicities in Colon Cancer with Resistance Exercise trial (ClinicalTrials.gov identifier NCT03291951). Diet quality was collected using a 127-item food-frequency questionnaire and was scored using the Alternative Healthy Eating Index-2010 (AHEI-2010). CIPN was assessed with the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events at each chemotherapy cycle. The association of dietary quality with time to the first moderate-to-severe (moderate-severe) or severe event of CIPN was estimated using Cox proportional hazards models. Only participants who received oxaliplatin were included in this analysis (n=132). Seventy-four participants (56.1%) reported moderate-severe CIPN. Higher dietary quality was associated with a significantly decreased risk of moderate-severe CIPN (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.93-0.99) and severe CIPN (HR, 0.91; 95% CI, 0.85-0.98). Consumption of red and processed meat (HR, 1.78; 95% CI, 1.07-2.83) and sugar-sweetened beverages (HR, 1.33; 95% CI, 1.10-1.59) was associated with an increased risk of moderate-severe CIPN. Consumption of sugar-sweetened beverages also was associated with an increased risk of severe CIPN (HR, 1.57; 95% CI, 1.14-2.18), whereas vegetable consumption was associated with a reduced risk of severe CIPN (HR, 0.29; 95% CI, 0.09-0.73). Among patients with colon cancer who received oxaliplatin-based chemotherapy, higher baseline dietary quality was associated with a reduced risk of moderate-severe CIPN.

Pre-treatment amino acids and risk of paclitaxel-induced peripheral neuropathy in SWOG S0221.

Chemotherapy-induced peripheral neuropathy (CIPN) is a treatment-limiting and debilitating neurotoxicity of many commonly used anti-cancer agents, including paclitaxel. The objective of this study was to confirm the previously found inverse association between pre-treatment blood concentrations of histidine and CIPN occurrence and examine relationships of other amino acids with CIPN severity. Pre-treatment serum concentrations of 20 amino acids were measured in the SWOG S0221 (NCT00070564) trial of patients with early-stage breast cancer receiving paclitaxel. The associations between amino acids and CIPN severity were tested in regression analysis adjusted for paclitaxel schedule, age, self-reported race, and body mass index with Bonferroni correction. The network of metabolic pathways of amino acids was analyzed using over-representation analysis. The partial correlation network of amino acids was evaluated using a debiased sparse partial correlation algorithm. In the primary analysis, histidine concentration was not associated with CIPN occurrence (odds ratio (OR) = 0.97 [0.83, 1.13], p = 0.72). In secondary analyses, higher concentrations of four amino acids, glutamate (β = 0.58 [0.23, 0.93], p = 0.001), phenylalanine (β = 0.54 [0.19, 0.89], p = 0.002), tyrosine (β = 0.57 [0.23, 0.91], p = 0.001), and valine (β = 0.58 [0.24, 0.92], p = 0.001) were associated with more severe CIPN, but none of these associations retained significance after adjustment. In the over-representation analysis, no amino acid metabolic pathways were significantly enriched (all FDR > 0.05). In the network of enriched pathways, glutamate metabolism had the highest centrality. This analysis showed that pre-treatment serum amino acid concentrations are not strongly predictive of CIPN severity. Prospectively designed studies that assess non-amino acid metabolomics predictors are encouraged.

A Case Study on the Integrated Rehabilitation of Chemotherapy-Induced Peripheral Neuropathy in a Patient with Stage IV Breast Cancer

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a significant complication of cancer treatments, affecting a substantial proportion of patients and severely impacting their quality of life. Current management strategies often fall short in addressing the multifaceted nature of this condition, highlighting the need for integrated approaches that encompass physical, psychological, and social elements. Objective: This study aimed to evaluate the efficacy of a multimodal rehabilitation program in improving physical function and psychological well-being in a patient with Stage IV breast cancer experiencing moderate CIPN. Methods: A 40-year-old female with Stage IV breast cancer underwent a 5-week multimodal rehabilitation program, including physical therapy, psychosocial support, and mobility therapy. Assessments of grip strength, knee and shoulder flexion, neuropathic pain (DN4), anxiety and depression (HADS), and overall quality of life were conducted pre- and post-intervention using a hand dynamometer, goniometer, and standardized psychological scales. Results: Post-treatment results demonstrated significant improvements: grip strength increased from 10 kg to 13 kg (right hand) and 9 kg to 14 kg (left hand); knee flexion improved from 120° to 129° (right) and 125° to 132° (left); shoulder flexion increased from 149° to 160° (right) and 152° to 159° (left). Psychological assessments showed a reduction in anxiety (HADS) scores from 12 to 8 and depression from 10 to 5. The DN4 score decreased from 7 to 4, indicating a reduction in neuropathic pain. Quality of life assessments also noted significant enhancements. Conclusion: The integrated rehabilitation program was effective in significantly improving both the physical and psychological parameters in a patient with severe CIPN. This case supports the potential benefits of multidisciplinary approaches in managing CIPN, suggesting wider applicability for similar comprehensive care models in oncological rehabilitation.

Abstract PO2-11-10: Can chemotherapy-induced peripheral neuropathy be predicted? Implications for future prevention and treatment of this side-effect

Abstract Background: The pain and sensory abnormalities associated with chemotherapy-induced peripheral neuropathy (CIPN) may persist for months or even years after chemotherapy. CIPN has a negative impact on routine activities, functions, and behaviors in the domestic, work, and social lives of cancer patients, adversely affecting the quality of their survivorship. CIPN is a major adverse effect of taxanes and other agents, possibly requiring dose-reduction or early termination of treatment. Taxane-based regimens are first-line treatment in both early-stage and metastatic breast cancer and therefore place numerous women at risk for developing CIPN. Regrettably, taxane-induced neurotoxicity can be arduous to predict, and there are no preventive or curative treatments currently available. Our work aims to assess a predictive tool for identification of patients at high risk of developing neuropathy and the progression of symptoms towards chronic CIPN. We hypothesized that oxidative stress might be a triggering event for the development of CIPN and that changes in glutathione recycling can identify patients at high risk for developing prolonged and severe CIPN. This hypothesis is based on reports in the literature proposing that CIPN is triggered by damage to the myelin sheath, which protects nerves from damage, by drug-induced free radicals in and around the nerves. Damage to myelin, a lipid- and protein rich sheath, by lipid peroxidation can result in loss of signal transmission, false signaling, or signal overload. Prolonged exposure to elevated levels of free radicals might result in structural changes to the nerves. Methods: Cancer patients seeking treatment at the Lankenau Medical Center Cancer center were asked to participate in our Institutional Review Board approved study of adverse effects. In this on-going study, the cohort (Ntotal =352) includes 104 breast cancer patients that are predominantly Caucasian with 14.9% African American. The median age is 56 (range 26 – 82) and 60.9% were treated with a taxane-based regimen. Nearly half the breast cancer group were diagnosed with Stage I disease. All consented patients donated a tube of blood prior to each treatment and filled out the Rotterdam Symptom Checklist (RSCL). Blood samples were analyzed for glutathione recycling using the ChemoTox assay (MNT™ Test, MYNARI Biomedical) and lipid peroxidation using a thiobarbituric acid reactive substances (TBARS) test (Cayman Chemical). All samples were analyzed in duplicate, and results analyzed using GraphPad Prism 8.4.3. Results: Preliminary results from the first 83 breast cancer patients showed African American patients reported a higher rate of NCCN grade 2 and 3 CIPN while Caucasians reported a higher rate of severe, long-lasting CIPN. Our results showed that patients who reported CIPN at later cycles had diminished glutathione recycling capacity already after the first treatment. Drop in recycling capacity had an inverse relationship with lipid peroxidation and grade of CIPN. Both decreased recycling capacity and increase in lipid oxidation were apparent already after the first treatment in patients that reported CIPN after cycle 6-8 or after completion of treatment Discussion: There are many proposed mechanisms for the development of CIPN. One mechanism that is shared by both most agents is damage induced by free radicals released following chemotherapy. We show that patients with reduced ability to neutralize free radicals have elevated and prolonged lipid peroxidation. Both processes precede the development of CIPN by several treatment cycles. Therefore, this test could identify patients that might benefit from other regimens rather than a taxane-based therapy. The test could also aid in the identification of patients for preventive therapy once such agents become available. Citation Format: Alisha Maity, Nolan Metz, Kathryn Fleck, Zonera Ali, Aarthi Shevade, Arezoo Ghaneie, Margaretha Wallon. Can chemotherapy-induced peripheral neuropathy be predicted? Implications for future prevention and treatment of this side-effect [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-11-10.

The impact of scrambler therapy on pain and quality of life for chemotherapy-induced peripheral neuropathy: A pilot study.

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating disturbance among patients who received chemotherapy, with no effective treatment available. Scrambler therapy (ST) is a noninvasive treatment capable of improving multiple quality-of-life symptoms beyond pain. We aimed to evaluate the efficacy of ST for pain and nonpain symptoms related to CIPN. Ten patients with moderate to severe CIPN symptoms for >3 months were enrolled in a single-arm trial of ST for 10 daily sessions. CIPN-related symptoms were measured throughout the treatment period and up to 6 months thereafter. The worst pain was reduced by 6 months (p = 0.0039). QST demonstrated the greatest improvement in pressure of 60 g (p = 0.308, Cohen's d = 0.42) and cold temperature threshold of 2.5°C (p = 0.9375, Cohen's d = 0.51) in the gastrocnemius area. Symptoms of numbness, tingling, trouble walking, and disturbed sleep had significant improvements at 6 months. Pain medication use decreased by 70% at the end of treatment and by 42% at 6 months. Patient satisfaction was high (82%) and no adverse events with ST treatment were reported. The results of this pilot trial support the use of ST by demonstrating improvement in multiple domains of quality of life for CIPN patients during an extended follow-up of 6 months. However, further large-scale studies are needed to confirm our findings.

Patient perceptions of altering chemotherapy treatment due to peripheral neuropathy.

Clinical practice guidelines recommend altering neurotoxic chemotherapy treatment in patients experiencing intolerable chemotherapy-induced peripheral neuropathy (CIPN). The primary objective of this survey was to understand patient's perspectives on altering neurotoxic chemotherapy treatment, including their perceptions of the benefits of preventing irreversible CIPN and the risks of reducing treatment efficacy. A cross-sectional online survey was distributed via social networks to patients who were currently receiving or had previously received neurotoxic chemotherapy for cancer. Survey results were analyzed using descriptive statistics and qualitative analysis. Following data cleaning, 447 participants were included in the analysis. The median age was 57 years, 93% were white, and most were from the UK (53%) or USA (38%). Most participants who were currently or recently treated expected some CIPN symptom resolution (86%), but 45% of those who had completed treatment more than a year ago reported experiencing no symptom resolution. Participants reported that they would discontinue chemotherapy treatment for less severe CIPN if they knew their symptoms would be permanent than if symptoms would disappear after treatment. Most patients stated that the decision to alter chemotherapy or not was usually made collaboratively between the patient and their treating clinician (61%). The most common reason participants were reluctant to talk with their clinician about CIPN was fear that treatment would be altered. Participants noted a need for improved understanding of CIPN symptoms and their permanence, better patient education relating to CIPN prior to and after treatment, and greater clinician understanding and empathy around CIPN. This survey highlights the importance of shared decision-making, including a consideration of both the long-term benefits and risks of altering neurotoxic chemotherapy treatment due to CIPN. Additional work is needed to develop decision aids and other communication tools that can be used to improve shared decision making and help patients with cancer achieve their treatment goals.

Plasma lipidomic profiling of chemotherapy-induced peripheral neuropathy.

3031 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of cytotoxic cancer treatment. This may result in dose reduction (DR) or chemotherapy discontinuation (CD) and ultimately decrease the efficacy of therapy. There is a lack of studies examining the role of lipids in relation to CIPN, despite the association of obesity with worse CIPN, and hyperlipidaemia with diabetic neuropathy. The aim of this study is to determine if circulating lipids are associated with CIPN severity. Methods: Pre-chemotherapy plasma samples from 137 patients with CIPN from docetaxel or paclitaxel-based treatment underwent lipidomic analysis (788 lipids). CIPN severity was measured using the neurological grading scale Total Neuropathy Score-clinical version (TNSc score; John Hopkins University) and patient-reported outcome measure EORTC QLQ-CIPN20. The association of baseline lipid levels with severe CIPN, as defined by high TNSc and CIPN20 scores, was performed using linear modelling (LIMMA). Baseline lipids associated with shorter time to dose reduction (DR) or chemotherapy discontinuation (CD) due to CIPN was determined by Cox regression, with adjustment for body mass index (BMI), age and diabetes. Lipid profiles were identified using latent class analysis (LCA) of significant lipids from the Cox regression. Results: Higher TNSc or CIPN20 scores were associated with 107 and 43 lipid species respectively (LIMMA p<0.05), of which only 3 species were in common. Triacylglycerols (TG) represented a significant proportion of lipids with elevated levels associated with higher TNSc (32.5%) or CIPN20 (9.1%) scores (Fisher’s exact test p<0.001). 70 lipid species were associated with shorter time to DR/CD (Cox regression p<0.05), which included 15 TG with higher levels associated with shorter time to DR/CD. Unsupervised LCA identified a specific lipid profile associated with worse CIPN [Hazard ratio 2.61 (95% CI 1.40 – 4.84, p=0.002)]. This lipid profile also had higher levels of TG (t-test p<0.05). The high risk CIPN lipid profile was independently associated with shorter time to DR/CD when modelled with clinical factors (diabetes, age, BMI or prior numbness/tingling; Cox regression p<0.006); however, these clinical factors were not associated with time to DR/CD in the multivariable models (p>0.08). Conclusions: Higher levels of baseline plasma TG are associated with increased CIPN severity and shorter time to DR/CD in taxane-treated patients. These findings are consistent with other reports regarding the association of hyperlipidaemia with neuropathy. Further research is required to determine if TG-lowering medication can reduce the risk of CIPN development.

Taxane-Induced Neuropathy and Its Ocular Effects-A Longitudinal Follow-up Study in Breast Cancer Patients.

A common severe neurotoxic side effect of breast cancer (BC) therapy is chemotherapy-induced peripheral neuropathy (CIPN) and intervention is highly needed for the detection, prevention, and treatment of CIPN at an early stage. As the eye is susceptible to neurotoxic stimuli, the present study aims to determine whether CIPN signs in paclitaxel-treated BC patients correlate with ocular changes by applying advanced non-invasive biophotonic in vivo imaging. Patients (n = 14, 10 controls) underwent monitoring sessions after diagnosis, during, and after therapy (T0-T3). Monitoring sessions included general anamnesis, assessment of their quality of life, neurological scores, ophthalmological status, macular optical coherence tomography (OCT), and imaging of their subbasal nerve plexus (SNP) by large-area confocal laser-scanning microscopy (CLSM). At T0, no significant differences were detected between patients and controls. During treatment, patients' scores significantly changed while the greatest differences were found between T0 and T3. None of the patients developed severe CIPN but retinal thickenings could be detected. CLSM revealed large SNP mosaics with identical areas while corneal nerves remained stable. The study represents the first longitudinal study combining oncological examinations with advanced biophotonic imaging techniques, demonstrating a powerful tool for the objective assessment of the severity of neurotoxic events with ocular structures acting as potential biomarkers.

46P Long-term residual chemotherapy-induced peripheral neuropathy (CIPN) and relationship with single nucleotide polymorphisms (SNPs) in ovarian cancer patients free of disease in the GINECO Vivrovaire study

Paclitaxel and carboplatin remains a backbone treatment of ovarian cancer (OC) inducing peripheral neuropathy in a significant proportion of patients. Meanwhile, long term survival of OC has dramatically increased with the recent therapeutic progress. Predictive factors for long-term CIPN are needed considering the impact on quality of life (Qol) of patients. We investigated the link between the incidence of CIPN and selected genetic polymorphisms in a cohort of ovarian cancer survivors. Vivrovaire is a French multi-center long-standing cohort of ovarian cancer patients free of disease 3 years after the end of the primary treatment. Long-term analysis of Qol in linked with neuropathy was performed including peripheral neuropathy assessed by the FACT/GOG-Ntx4 self-questionnaire. CIPN scores were correlated with SNPs in the selected CYP2C8, CYP3A4, ERCC1 and XPC genes. 130 patients were included with a median time from the end of chemotherapy of 63 months [35-180]. Median CIPN score was 37 [18-44] with 35 patients (27 %) having a severe score (< 33). SNPs (homozygotous/heterozygotous) were identified as follows: CYP2C8 [n=32 (24.6%)/ n=99 (76%)]; CYP3A4 [n=0 (0%)/ n=8 (6.1%)], ERCC1 [n=21 (16.1%)/ n=57 (43.8%)] and XPC [n=45 (34.6%)/ n=66 (50.8%)]. In univariate analysis, homozygous SNP (ho SNP) in any of the selected genes was associated with CIPN score as a continuous variable (p=0.045) but not with severe score (< 33) (OR: 1.66; 95% CI [0.74-3.88], p=0.22). Patients with CYP2C8_rs1934951 SNP tend to have CIPN score <33, (OR: 2.22; 95% CI [0.98-5.02], p=0.057). In multivariate analyses including age, interval from the end of chemotherapy, type and number of chemotherapy courses, identification of homozygotous or heterozygotous CYP2C8_rs1934951 SNP was associated with a severe CIPN score (OR: 2.41; 95% CI [1.02-5.70], p=0.043). Our study shows that residual CIPN is a frequent concern for ovarian cancer survivors. CYP2C8_rs1934951 SNP may be associated with severe residual CIPN in long-term survivors of ovarian cancer.

Association of Taxane Type With Patient-Reported Chemotherapy-Induced Peripheral Neuropathy Among Patients With Breast Cancer

Understanding the detailed symptom spectrum of chemotherapy-induced peripheral neuropathy (CIPN) could facilitate shared decision-making and promote early intervention. To compare the symptom spectrum of patient-reported CIPN associated with nab-paclitaxel, paclitaxel, and docetaxel treatments among patients with breast cancer. This prospective cohort study was conducted at 9 medical centers across China from 2019 to 2021. Participants included hospitalized women diagnosed with invasive breast cancer, assessed with overlap propensity score weighting. Data were analyzed from from December 2021 to May 2022. Treatment with nab-paclitaxel-, paclitaxel-, or docetaxel-based regimens. Patient-reported CIPN on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire: CIPN 20-item instruments, consisting of sensory, motor, and autonomic scales. Multiple regression models were adjusted for baseline patient, tumor, and treatment characteristics. Of 1234 participants, the mean (SD) age was 50.9 (10.4) years, and 295 patients (23.9%) received nab-paclitaxel, 514 patients (41.7%) received paclitaxel, and 425 patients (34.4%) received docetaxel. The nab-paclitaxel group mostly reported numbness in hands or feet related to sensory symptoms (83 patients [81.4%]), while the paclitaxel and docetaxel groups reported mainly motor (eg, weakness in legs: 60 patients [47.2%] in the paclitaxel group; 52 patients [44.4%] in the docetaxel group) and autonomic (eg, blurred vision: 58 patients [45.7%] in the paclitaxel group; 51 patients [43.6%] in the docetaxel group) symptoms. Patients reported motor symptoms earlier than sensory abnormalities, with a median of 0.4 (95% CI, 0.4-2.3) weeks in the nab-paclitaxel group, 2.7 (95% CI, 1.7-3.4) weeks in the paclitaxel group, and 5.6 (95% CI, 3.1-6.1) weeks in the docetaxel group. After overlap propensity score weighting and compared with the nab-paclitaxel group, the risks of patient-reported CIPN were lower in the paclitaxel (hazard ratio [HR], 0.59 [95% CI, 0.41-0.87]; P = .008) and the docetaxel (HR, 0.65 [95% CI, 0.45-0.94]; P = .02) groups. Similarly, patients who received paclitaxel (HR, 0.44 [95% CI, 0.30-0.64]; P < .001) or docetaxel (HR, 0.52 [95% CI, 0.36-0.75]; P < .001) reported less sensory discomfort compared with those who received nab-paclitaxel. However, the risk of patients in the paclitaxel or docetaxel groups reporting motor (paclitaxel: HR, 0.76 [95% CI, 0.52-1.11]; P = .15; docetaxel: HR, 0.69 [95% CI, 0.47-1.01]; P = .05) and/or autonomic (paclitaxel: HR, 1.00 [95% CI, 0.68-1.49]; P = .98; docetaxel: HR, 0.88 [95% CI, 0.59-1.30]; P = .52) symptoms was not lower than that in the nab-paclitaxel group. In this cohort study of women with invasive breast cancer, nab-paclitaxel was associated with more severe CIPN than either paclitaxel or docetaxel. In addition to sensory symptoms, the risk of motor and autonomic abnormalities was not low among these 3 taxanes, and patients-reported motor symptoms even earlier than sensory symptoms. These findings may facilitate early detection and intervention for CIPN in taxane treatments for breast cancer.

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.

Predictive Assay for Chemotherapy-Induced Peripheral Neuropathy Associated with Vinca Alkaloids in Lymphoid Malignancies

Introduction: Vinca alkaloids, such as vincristine, are important anticancer agents mainly employed in the treatment of hematological cancers. The principal mechanism for the antineoplastic activity is microtubule disruption. However, these agents also cause damage to mitochondria which leads to oxidative stress and production of reactive oxygen species (ROS). Other chemotherapeutic drugs that are suggested to cause peripheral neuropathy by this mechanism, i.e., increased oxidative stress, include taxanes and platinum compounds. Oxidative damage to peripheral neurons can cause damage to myelin sheath, mitochondrial proteins, and other antioxidant enzymes, resulting in hyperexcitability of peripheral neurons. This nerve damage results in the commonly seen dose-limiting neurological side effect chemotherapy-induced peripheral neuropathy (CIPN). Hence, assessment of biomarkers for peroxidation, myelin repair/maintenance, and red-ox balance (glutathione recycling) can be helpful in monitoring the on-set and course of peripheral neuropathy. We hypothesize that chemotherapeutic agents with similar effects on mitochondria (vinca alkaloids, taxanes and platinum compounds) will produce a specific pattern of glutathione recycling in patients prone to CIPN.Methods: Patients who had given written consent to participate in this exploratory single-centered, prospective IRB approved study contributed a blood sample prior to each treatment cycle. At each visit, the Rotterdam Symptoms Check-List (RSCL) was filled out and reported symptoms confirmed by comparison to notes in medical records.Whole blood was analyzed for glutathione recycling capacity using the bioactive probe hydroxyethyldisulfide (HEDS) and incubated at room temperature for 2 hours with gentle mixing. Prior to spectrophotometric determination, blood cells and proteinaceous thiols will be removed from the sample by acid precipitation and centrifugation. The final spectrophotometric reading will be converted into ME produced using the conversion factor provided in the assay kit Rockland Inc). Recycling capacity was compared to self-reported grade of CIPN.Results: Thus far we have enrolled 276 patients with an average age of 63.69 years (±12.85 STDEV; Range; 25-91). Patients are predominantly of Caucasian heritage (80.8%) along with 18.1 % African American and 1.1% Asian heritage. Females constitute 53.26 % of the cohort. To date we have 150 patients with more than 24 months of follow-up and among these patients, 5.5% had no reported symptoms of CIPN. Of those with severe CIPN (NCCN grade 3) neuropathy, 71% had a reduction in GSH recycling of greater than or equal to 40% from pre-treatment level. The reduced glutathione recycling capacity preceded on-set of symptoms by approximately 4 weeks. The majority of patients demonstrating this pattern of glutathione recycling had persistence CIPN that lasted for 6-18 months before an improvement was noted in medical records. We are currently assessing the value of adding biomarkers for lipid peroxidation and/or myelin formation/maintenance to further improve the likelihood ratio and AUROC values for the test.Conclusions: This data suggests the importance of GSH recycling in the ability to predict risk of CIPIN. Patients whose pre-treatment baseline was less than 1 or progressively dropped by at least 40%, seem to be at most risk for CIPN. Further, this may predict persistence of CIPN even after cessation of chemotherapy. Most patients in this cohort received taxanes or platinum therapy. However, given the similarity in mechanism and results from an early assessment of lymphoma patients treated with vinca alkaloids that resulted in similar outcomes with reduced glutathione recycling capacity suggest the possible use of this test to predict CIPN among lymphoma patients. DisclosuresNo relevant conflicts of interest to declare.

Improvement In Neuropathic Pain,Proprioception, And Gait Stability After Spinal Cord Stimulator Implantation For Chemotherapy-Induced Peripheral Neuropathy

BACKGROUND: We present a patient with gait instability and pain due to chemotherapy-induced peripheral neuropathy (CIPN) who experienced marked improvement in motor function, proprioception, and pain following placement of a spinal cord stimulator (SCS). CASE REPORT: A 62-year-old woman underwent placement of a permanent SCS after failing conservative therapy to manage her severe CIPN. Preoperatively, she reported significant gait instability in addition to her pain, typically suffering 10 falls per month. Postoperatively, she experienced a pronounced reduction in her pain level from 8 of 10 to 2 of 10 and in her number of falls from 10 to 0 per month. Furthermore, we formally assessed gait speed and function, Timed Up and Go (TUG) testing, postural control, and lower extremity function before and after SCS placement, and we found a profound improvement in all measurements. CONCLUSIONS: For patients with CIPN, SCS devices represent an increasingly viable treatment option. Our patient demonstrated significant improvements in not only pain, but also surprisingly in her motor function and gait stability with SCS therapy. This case highlights a potential additional benefit of neuromodulation in patients suffering from CIPN. KEY WORDS: Balance, cancer pain, chemotherapy-induced peripheral neuropathy, gait speed, neuromodulation, neuropathic pain, paresthesia, proprioception, spinal cord stimulation

Yoga for cancer survivors with chemotherapy-induced peripheral neuropathy: Health-related quality of life outcomes.

BackgroundYoga is a meditative movement therapy focused on mind‐body awareness. The impact of yoga on health‐related quality of life (HRQOL) outcomes in patients with chemotherapy‐induced peripheral neuropathy (CIPN) is unclear.MethodsWe conducted a pilot randomized wait‐list controlled trial of 8 weeks of yoga (n = 21) versus wait‐list control (n = 20) for CIPN in 41 breast and gynecological cancer survivors with persistent moderate to severe CIPN. HRQOL endpoints were Hospital Anxiety and Depression Scale (HADS), Brief Fatigue Inventory (BFI), and Insomnia Severity Index (ISI). The Treatment Expectancy Scale (TES) was administered at baseline. We estimated mean changes and 95% confidence intervals (CIs) from baseline to weeks 8 and 12 and compared arms using constrained linear mixed models.ResultsAt week 8, HADS anxiety scores decreased −1.61 (−2.75, −0.46) in the yoga arm and −0.32 (−1.38, 0.75) points in the wait‐list control arm (p = 0.099). At week 12, HADS anxiety scores decreased −1.42 (−2.57, −0.28) in yoga compared to an increase of 0.46 (−0.60, 1.53) in wait‐list control (p = 0.017). There were no significant differences in HADS depression, BFI, or ISI scores between yoga and wait‐list control. Baseline TES was significantly higher in yoga than in wait‐list control (14.9 vs. 12.7, p = 0.019). TES was not associated with HADS anxiety reduction and HADS anxiety reduction was not associated with CIPN pain reduction.ConclusionsYoga may reduce anxiety in patients with CIPN. Future studies are needed to confirm these findings.Clinical Trial Registration Number: ClinicalTrials.gov Identifier: NCT03292328.

Spinal Cord Stimulator for Treating Chemotherapy-induced Peripheral Neuropathy

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is not only one of the most common adverse experiences of cancer survivors, but it is also one which has the greatest effect on quality of life. Ultimately, CIPN can lead to unwanted modification of treatment such as chemotherapy dose reductions or termination of treatment altogether. CASE REPORT: We present a case of a 47-year-old man with severe bilateral CIPN resistant to conservative management, who was successfully treated with spinal cord stimulation. CONCLUSION: Spinal cord stimulation can be an effective treatment for CIPN resistant to conservative management. KEY WORDS: Spinal cord stimulator, chemotherapy induced neuropathy, peripheral neuropathy

Screening for Chemotherapy-induced Peripheral Neuropathy and Utilization of Physical Therapy in Pediatric Patients Receiving Treatment for Hematologic Malignancies.

Physical therapy (PT) has been shown to be a helpful intervention in the treatment of chemotherapy-induced peripheral neuropathy (CIPN). Our aim was to screen for CIPN in patients with hematologic malignancies receiving vincristine chemotherapy and obtain a baseline assessment on the percentage of patients utilizing PT in the treatment of CIPN. A retrospective review of surveys administered to parents and patients regarding the severity of peripheral neuropathy symptoms from October 2016 through March 2018 was conducted. Of 116 patients, a total of 102 patients (67 male and 35 female; 4 to 10 y of age, N=63; 11 to 15 y of age, N=19; 16 to 20 y of age, N=20) were eligible for the study, with 67.6% (N=69) reporting symptoms of CIPN. Of these patients, 16.7% scored 4 or greater on the surveys, suggesting clinically severe CIPN. Common parental concerns included decreased strength, difficulty walking up stairs, tripping, and foot drops. Approximately 55.1% of the 69 patients who reported CIPN symptoms were referred to outpatient PT, while 44.9% were not referred. A simple survey consisting of 4 questions that only took several minutes to administer was capable of identifying CIPN in 67.6% of patients receiving vincristine chemotherapy.

Vitamin E for the Prevention of Chemotherapy-Induced Peripheral Neuropathy: A meta-Analysis.

Background: Vitamin E has been increasingly used to prevent chemotherapy-induced peripheral neuropathy (CIPN) in recent years. However, it is still unclear whether vitamin E can effectively prevent CIPN. Methods: We searched all clinical studies in the Embase, Cochrane Library, Clinicaltrials.gov, and PubMed databases from inception to December 2020. We performed a meta-analysis of 9 randomized controlled trials (RCTs) with 486 patients that compared the vitamin E group with the control group. Outcomes of the study were incidence of all-grade CIPN, incidence of severe CIPN, and the total neuropathy scores (TNS). Random effect models were used to make the meta-analysis results more cautious. Results: Notably, vitamin E significantly reduced the incidence of all-grade CIPN (overall risk ratio (RR) = 0.55, 95% CI: 0.36, 0.85, I2 = 77.3%, p = 0.007), and TNS (overall standard mean difference (SMD) = −0.64, 95% CI: −1.03, −0.25, I2 = 42.7%, p = 0.001). However, the results of the subgroup analysis, which included only double-blind RCTs, suggested that vitamin E did not significantly reduce the incidence of all-grade CIPN (overall RR = 0.52, 95% CI: 0.07, 4.06, I2 = 77.5%, p = 0.531). Moreover, there was no significant difference in the incidence of severe CIPN between these two arms (p = 0.440). Conclusion: The results of our meta-analysis suggests that vitamin E has a beneficial effect on the incidence and symptoms of CIPN. However, routine prophylactic use of vitamin E is still not recommended. Moreover, more high-quality double-blind RCTs are needed to further validate the effects of vitamin E in prevention of CIPN.

Abstract PS9-51: Secondary outcomes in a randomized controlled trial of acupuncture versus sham acupuncture and usual care in solid tumor survivors with chemotherapy-induced peripheral neuropathy

Abstract Background: Chemotherapy-induced peripheral neuropathy (CIPN) is the most common and debilitating long-term adverse effect of neurotoxic chemotherapy and it significantly worsens cancer survivors’ quality of life. In a previously reported randomized controlled trial, we showed that real acupuncture is more effective in reducing persistent CIPN symptoms compared to usual care, with a trend of greater CIPN pain reduction compared to sham acupuncture (Bao et al, JAMA Netw Open, 2020). Here, we report secondary outcomes in this trial. Patients and Methods: Solid tumor survivors with persistent moderate to severe CIPN (symptoms of numbness, tingling, or pain rated ≥4 on a numeric rating scale [NRS]) were randomized to three arms: 1) Eight weeks of real acupuncture (RA); 2) eight weeks of sham acupuncture (SA); and 3) usual care (UC). The secondary endpoints were Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx), Hospital Anxiety and Depression Score (HADS), and Insomnia Severity Index (ISI). For each endpoint, the mean changes from baseline and 95% confidence intervals (CI) were estimated within each arm and compared between arms using linear mixed models.Results: We enrolled and randomized 75 solid tumor survivors (53% breast cancer) with moderate to severe CIPN to the study. Compared to baseline, at week 8, FACT/GOG-Ntx, HADS anxiety, and ISI scores significantly improved in both RA and SA arms, but not in the UC arm (Table 1). At week 8, FACT/GOG-Ntx scores significantly increased in both RA and SA arms when compared with UC (p=0.001 and 0.007), indicating improved CIPN related symptoms and quality of life. There was no statistically significant difference between RA and SA arms, p=0.498. When comparing RA and SA with UC, we found no statistically significant difference in changes from baseline in HADS anxiety and ISI. Conclusions: Our study showed acupuncture may be effective in improving CIPN symptoms and reducing anxiety and insomnia in cancer survivors with persistent CIPN. Further large sample size studies are needed to delineate possible placebo effects from SA. Table 1. Secondary Outcomes in RA, SA, and UC Arms and Changes From BaselineReal Acupuncture(n=27)Sham Acupuncture (n=24)Usual Care (n=24)OutcomeWeekMean (95% CI)Change from Baseline,Mean (95% CI)Mean (95% CI)Change from Baseline,Mean (95% CI)Mean (95% CI)Change from Baseline,Mean (95% CI)FACT/GOG-Ntx024.41 (21.38, 27.44)NA25.13 (21.91, 28.34)NA27.01 (23.80, 30.22)NA828.60 (25.52, 31.67)4.19 (2.39, 5.99)***28.42 (25.19, 31.66)3.30 (1.45, 5.15)***26.61 (23.32, 29.89)-0.40 (-2.35, 1.54)HADS Anxiety06.61 (4.98, 8.25)NA7.66 (5.93, 9.39)NA6.52 (4.79, 8.25)NA85.61 (3.95, 7.27)-1.00 (-1.99, -0.01)*6.64 (4.89, 8.38)-1.02 (-2.03, -0.01)*6.76 (4.99, 8.53)0.24 (-0.81, 1.29)ISI012.93 (10.24, 15.61)NA12.46 (9.61, 15.31)NA10.17 (7.32, 13.02)NA810.63 (7.88, 13.37)-2.30 (-3.99, -0.61)**10.20 (7.33, 13.07)-2.26 (-3.99, -0.53)*8.96 (6.05, 11.87)-1.21 (-3.01, 0.60)Table Symbols: *, p &amp;lt; 0.05; **, p &amp;lt; 0.01; ***, p &amp;lt; 0.001 Citation Format: Ting Bao, Ray Baser, Crystal Lin, Qing Li, Lauren Piulson, Iris Zhi. Secondary outcomes in a randomized controlled trial of acupuncture versus sham acupuncture and usual care in solid tumor survivors with chemotherapy-induced peripheral neuropathy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-51.

Abstract PS9-19: Health-related quality of life (HRQOL) outcomes in arandomized controlled trial of yoga in breast and gynecological cancer survivors with chemotherapy-induced peripheral neuropathy

Abstract Background: Yoga is a meditative movement therapy that improves body conditioning, flexibility, and balance through mind-body awareness. We conducted a two-armed pilot randomized wait-list controlled trial in breast and gynecological (GYN) cancer survivors with persistent moderate to severe chemotherapy-induced peripheral neuropathy (CIPN) and found that yoga significantly reduced CIPN pain. Here we report on the HRQOL results. Patients and Methods: We randomized breast and GYN cancer survivors with persistent moderate to severe CIPN to eight weeks of yoga or usual care (UC). The HRQOL endpoints were Hospital Anxiety and Depression Score (HADS), Treatment Expectancy Scale (TES), Brief Fatigue Inventory (BFI), and Insomnia Severity Index (ISI). We estimated and compared the mean changes from baseline to weeks 8 and 12 along with 95% confidence intervals (CIs) between arms using linear mixed models. Results: From February 2018 to May 2019, we enrolled and randomized 41 female cancer survivors (93% breast, 7% GYN; mean (SD) age 61.7 (10.2) years; 56% white/non-Hispanic, 20% African American, 12% Asian, 12% other) to yoga (N=21) and UC (N=20) arms. The HADS anxiety score significantly reduced in the yoga arm compared to usual care at weeks 8 and 12. At baseline, the mean (95% CI) HADS anxiety score was 9.23 (7.42, 11.04) in the yoga arm, and 5.05 (3.19, 6.91) in the UC arm (p=0.002). At week 8, the mean (95% CI) HADS anxiety score decreased by -1.91 (-3.07, -0.76) points in the yoga arm, and by -0.02 (-1.10, 1.06) points in the UC arm (p=0.019). At week 12, in the yoga arm, the mean HADS anxiety score was 7.50 (5.62, 9.39), and a decrease of 1.73 (-2.88, -0.57) points; in the UC arm, the mean was 5.81 (3.94, 7.69) with an increase of 0.76 (-0.32, 1.84) points (p=0.002). There was no difference in HADS depression, BFI, and ISI scores between yoga and UC arms at baseline, week 8, and week 12. The TES at baseline was 14.9 (3.27) in the yoga arm, which was significantly higher than in the UC arm 14.9 (SD 3.27) vs. 12.7 (SD: 2.58), p= 0.019. The TES was not associated with HADS anxiety reduction, and HADS anxiety reduction was not associated with CIPN pain reduction. Conclusions: Our trial showed that a yoga intervention may be useful to reduce anxiety in patients with CIPN. We previously found that a yoga intervention reduced CIPN pain. CIPN pain reduction was not associated with anxiety reduction or TES. Future studies are needed to confirm our findings and to explore the mechanism of yoga in CIPN pain reduction. Citation Format: Wanqing Iris Zhi, Raymond Baser, Lillian Zhi, Lauren Piulson, Qing Li, Ting Bao. Health-related quality of life (HRQOL) outcomes in arandomized controlled trial of yoga in breast and gynecological cancer survivors with chemotherapy-induced peripheral neuropathy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-19.