Prevention Of Chemotherapy-induced Peripheral Neuropathy Research Articles

Effect of gradient pressure therapy on the prevention of chemotherapy-induced peripheral neuropathy in patients with breast cancer.

To investigate the effect of gradient pressure therapy on the prevention of chemotherapy-induced peripheral neuropathy (CIPN) and improvement in activities of daily living (ADL) in patients with breast cancer. Eighty female patients with breast cancer treated at Tangshan People's Hospital between October 2022 and July 2023 were selected as research participants and divided into control and intervention, with 40 patients in each group. The control group received routine treatment and care, whereas the intervention group received gradient pressure therapy based on routine treatment and care. Incidence of peripheral neuropathy and the degree of impact on ADL between the two groups were compared after the intervention for cycles 2, 4, and 6. There was no significant difference in the general information between the two groups (P > 0.05). After two intervention cycles, there was no significant difference in the incidence of CIPN, various dimensions of Chemotherapy-Induced Peripheral Neuropathy Assessment Tool (CIPNAT), and total scores between the two groups (P > 0.05). After four intervention cycles, the two groups had a statistically significant difference in the incidence of CIPN, sensory dimension, general activity dimension, and total CIPNAT score (P < 0.05). After six intervention cycles, there was a significant difference in the incidence of CIPN, sensory dimension, fine activity dimension, general activity dimension, and total CIPNAT score between the two groups (P < 0.05), while there was no significant difference in the other dimensions (P > 0.05). Gradient pressure therapy can effectively prevent or alleviate peripheral neuropathy in patients with breast cancer undergoing chemotherapy and improve their ability to perform ADL. Thus, it is safe, effective, and worthy of clinical application. RMYY-LLKS-2022-054.

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.

Phytic Acid Maintains Peripheral Neuron Integrity and Enhances Survivability against Platinum-Induced Degeneration via Reducing Reactive Oxygen Species and Enhancing Mitochondrial Membrane Potential.

Phytic acid (PA) has been reported to possess anti-inflammatory and antioxidant properties that are critical for neuroprotection in neuronal disorders. This raises the question of whether PA can effectively protect sensory neurons against chemotherapy-induced peripheral neuropathy (CIPN). Peripheral neuropathy is a dose-limiting side effect of chemotherapy treatment often characterized by severe and abnormal pain in hands and feet resulting from peripheral nerve degeneration. Currently, there are no effective treatments available that can prevent or cure peripheral neuropathies other than symptomatic management. Herein, we aim to demonstrate the neuroprotective effects of PA against the neurodegeneration induced by the chemotherapeutics cisplatin (CDDP) and oxaliplatin. Further aims of this study are to provide the proposed mechanism of PA-mediated neuroprotection. The neuronal protection and survivability against CDDP were characterized by axon length measurements and cell body counting of the dorsal root ganglia (DRG) neurons. A cellular phenotype study was conducted microscopically. Intracellular reactive oxygen species (ROS) was estimated by fluorogenic probe dichlorofluorescein. Likewise, mitochondrial membrane potential (MMP) was assessed by fluorescent MitoTracker Orange CMTMRos. Similarly, the mitochondria-localized superoxide anion radical in response to CDDP with and without PA was evaluated. The culture of primary DRG neurons with CDDP reduced axon length and overall neuronal survival. However, cotreatment with PA demonstrated that axons were completely protected and showed increased stability up to the 45-day test duration, which is comparable to samples treated with PA alone and control. Notably, PA treatment scavenged the mitochondria-specific superoxide radicals and overall intracellular ROS that were largely induced by CDDP and simultaneously restored MMP. These results are credited to the underlying neuroprotection of PA in a platinum-treated condition. The results also exhibited that PA had a synergistic anticancer effect with CDDP in ovarian cancer in vitro models. For the first time, PA's potency against CDDP-induced PN is demonstrated systematically. The overall findings of this study suggest the application of PA in CIPN prevention and therapeutic purposes.

Spinal Neuronal miR-124 Inhibits Microglial Activation and Contributes to Preventive Effect of Electroacupuncture on Chemotherapy-Induced Peripheral Neuropathy in Mice.

Chemotherapy-induced peripheral neuropathy (CIPN) is a persistent and irreversible side effect of antineoplastic agents. Patients with CIPN usually show chronic pain and sensory deficits with glove-and-stocking distribution. However, whether spinal neuronal microRNA (miR)-124 is involved in cisplatin-induced peripheral neuropathy remains to be studied. In this study, miR-124 was significantly reduced in the spinal dorsal horn in CIPN mice. Overexpression of neuronal miR-124 induced by injecting adeno-associated virus with neuron-specific promoter into the spinal cord of mice prevented the development of mechanical allodynia, sensory deficits, and the loss of intraepidermal nerve fibers induced by cisplatin. Meanwhile, cisplatin-induced M1 microglia activation and the release of proinflammatory cytokines were significantly inhibited by overexpression of neuronal miR-124. Furthermore, electroacupuncture (EA) treatment upregulated miR-124 expression in the spinal dorsal horn of CIPN mice. Interestingly, downregulation of spinal neuronal miR-124 significantly inhibited the regulatory effect of EA on CIPN and microglia activity as well as spinal neuroinflammation induced by cisplatin. These results demonstrate that spinal neuronal miR-124 is involved in the prevention and treatment of EA on cisplatin-induced peripheral neuropathy in mice. Our findings suggest that spinal neuronal miR-124 might be a potential target for EA effect, and we provide, to our knowledge, a new experimental basis for EA prevention of CIPN.

Renin-angiotensin-aldosterone system inhibitors are associated with improved paclitaxel-induced peripheral neuropathy in lung cancer: a study using administrative claims data.

Chemotherapy-induced peripheral neuropathy (CIPN) has been reported to reduce patients' quality of life and impair cancer treatment by causing anticancer drug withdrawal or interruption. However, there are currently no effective methods for the prevention of CIPN. Renin-angiotensin-aldosterone system (RAAS) inhibitors may be associated with a reduced risk of developing oxaliplatin-induced peripheral neuropathy, and it would be valuable to examine whether they have the same effect on CIPN caused by other anticancer drugs. Our study explored the potential preventive effects of RAAS inhibitors on preventing paclitaxel-induced peripheral neuropathy (PIPN). An exploratory cohort study was conducted using commercially available administrative claims data on lung cancer patients treated with paclitaxel-based chemotherapy. Cumulative paclitaxel doses, RAAS inhibitor prescriptions, and incidences of PIPN were identified using patient medical records. Fine-Gray analyses with death as a competing risk were performed. A propensity score approach was applied to address the problem of confounding. Patients with lung cancer who received paclitaxel-based chemotherapy were classified into users of RAAS inhibitor (n = 1320) and non-users of RAAS inhibitor (n = 4566). The doses of RAAS inhibitors in our study were similar to those commonly used to treat hypertension. The PIPN incidence was significantly lower in users of RAAS inhibitor than in the non-users of RAAS inhibitor (sub-distribution hazard ratio, 0.842; 95% confidence interval, 0.762-0.929). The result was consistent in various sensitivity analyses and important subgroup analyses. RAAS inhibitors at doses commonly used for hypertension were associated with a reduced incidence of PIPN in patients with lung cancer.

Is Electroacupuncture Contraindicated for Preventing and Treating Chemotherapy-Induced Peripheral Neuropathy?

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side-effect of several drugs used to combat cancer. Thus, researchers have sought better treatments for and prevention of CIPN, such as electroacupuncture (EA). Some trials show EA worsens or prolongs CIPN pain and recommend against further studies on this. This narrative review explores EA for preventing or treating CIPN, comparing positive and negative outcomes. PubMed, ScienceDirect, and Google Scholar were searched for electroacupuncture, CIPN, and peripheral neuropathy. A snowballing method was used to find systematic reviews and studies in systematic reviews. Seven English-language trials were found on using EA for preventing or treating CIPN. In 3 prevention studies, 1 had significant benefits, 1 had modest benefits, and 1 had worse pain in an EA group at follow-up, compared to sham controls. In 4 treatment studies, 2 had significant benefits, 1 had no difference from 3 controls, and 1 had sham control was superior to verum EA. Most of the studies were limited by small sample sizes, and some studies used EA protocols and treatment doses (frequency and total number of sessions) that were potentially suboptimal. The quantity and quality of the studies are insufficient to draw firm conclusions on effectiveness and safety. More studies must test optimal EA protocols and treatment dosages. It is inappropriate to say that EA is not recommended for CIPN prevention or treatment, because there is no robust evidence to justify this. Generally, research has found benefits and no harms.

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.

2074P Oral cannabidiol for prevention of chemotherapy-induced peripheral neuropathy

2074P Oral cannabidiol for prevention of chemotherapy-induced peripheral neuropathy

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.

The motivation of breast cancer patients to participate in a national randomized control trial

PurposeClinical trials are essential for development of better cancer care. Therefore, patient willingness to participate in these trials is important. The aim of this study was to assess motivation and thoughts of breast cancer patients concerning participation in a clinical trial.MethodsTwenty-one patients participated in two semi-structed interviews about participating in a clinical trial testing the efficacy of cryotherapy for the prevention of chemotherapy-induced peripheral neuropathy in breast cancer patients treated with paclitaxel. The interviews took place before and after the intervention and were coded and categorized following the steps in Braun & Clarke’s thematic analysis to identify motivational factors and experiential themes.ResultsFour overarching themes were identified: (1) reasons to participate in the trial, (2) personal resources, (3) safety, and (4) experience of the randomization. The most frequent reason for participating in the trial was to support research and help others, but many also participated hoping to receive the intervention treatment. The study showed that a surplus of personal resources played an important role when the patients decided to participate in the trial. Differences were found between patients belonging to the intervention and the control group in relation to these themes. Finally, both groups experienced the extra examinations received during the trial as an additional source of safety.ConclusionThis qualitative study found different factors influencing the experience of participating in a clinical trial, e.g., intervention-status, personal resources, and safety. This knowledge can be valuable when planning future clinical trials involving breast cancer patients.

Whole genome sequencing across clinical trials identifies rare coding variants in GPR68 associated with chemotherapy-induced peripheral neuropathy

BackgroundDose-limiting toxicities significantly impact the benefit/risk profile of many drugs. Whole genome sequencing (WGS) in patients receiving drugs with dose-limiting toxicities can identify therapeutic hypotheses to prevent these toxicities. Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting neurological toxicity of chemotherapies with no effective approach for prevention.MethodsWe conducted a genetic study of time-to-first peripheral neuropathy event using 30× germline WGS data from whole blood samples from 4900 European-ancestry cancer patients in 14 randomized controlled trials. A substantial number of patients in these trials received taxane and platinum-based chemotherapies as part of their treatment regimen, either standard of care or in combination with the PD-L1 inhibitor atezolizumab. The trials spanned several cancers including renal cell carcinoma, triple negative breast cancer, non-small cell lung cancer, small cell lung cancer, bladder cancer, ovarian cancer, and melanoma.ResultsWe identified a locus consisting of low-frequency variants in intron 13 of GRID2 associated with time-to-onset of first peripheral neuropathy (PN) indexed by rs17020773 (p = 2.03 × 10−8, all patients, p = 6.36 × 10−9, taxane treated). Gene-level burden analysis identified rare coding variants associated with increased PN risk in the C-terminus of GPR68 (p = 1.59 × 10−6, all patients, p = 3.47 × 10−8, taxane treated), a pH-sensitive G-protein coupled receptor (GPCR). The variants driving this signal were found to alter predicted arrestin binding motifs in the C-terminus of GPR68. Analysis of snRNA-seq from human dorsal root ganglia (DRG) indicated that expression of GPR68 was highest in mechano-thermo-sensitive nociceptors.ConclusionsOur genetic study provides insight into the impact of low-frequency and rare coding genetic variation on PN risk and suggests that further study of GPR68 in sensory neurons may yield a therapeutic hypothesis for prevention of CIPN.

A pilot study of intraneural facilitation versus standard physical therapy for prevention of chemotherapy-induced peripheral neuropathy.

12068 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect necessitating chemotherapy (CT) dose adjustments or early termination. Intraneural Facilitation (INF) is a novel form of manual physical therapy (PT) developed to mitigate CIPN-related symptoms and improve patients’ functional outcome. We conducted a randomized pilot study evaluating the efficacy of INF vs. standard PT in the prevention of CIPN (NCT 03272919). Methods: Eligible participants were patients with newly diagnosed breast cancer (stages I-III) and gynecologic cancer without preexisting peripheral neuropathy planning to receive platinum-based and/or taxane-based CT. Participants were randomly assigned to either INF or PT arm and received two 45-minute treatments twice a week for six weeks during their CT course. Outcomes reported here are a) assessment of pain between the 2 arms using the Pain Quality Assessment Scale (PQAS), and b) measurement of vascular patterns using ultrasound (US), evaluating pulsatility index, volume flow and peak systolic velocity between the 2 arms. Participants were evaluated at baseline, week 3 (W3), week 6 (W6), and month 3 (M3). PQAS scores ranged from 0 to 10 with subscale evaluations of paroxysmal, surface, and deep pain. Pain scores on a scale from 0 to 10 were grouped into none (0), mild (1-3), moderate (4-6) and severe (7-10). The use of neuropathy medications, CT dose reductions, premature CT discontinuation and participant satisfaction surveys between the two groups were previously reported at SABCS 2022. Results: Of 104 screened participants, 44 met the eligibility criteria, with 38 eligible for analysis (n=20 INF arm and n=18 PT arm). Participants reporting moderate or severe pain in either arm were combined (Table). Pain symptoms peaked at W6 coinciding with cumulative CT effects. At M3, none in the INF arm reported moderate or severe paroxysmal pain compared to two participants in the PT arm. One participant in each arm reported moderate or severe surface or deep pain at M3. The US results showed physiologic impact in both arms at W3 and W6, suggesting their role in preserving neural tissue blood flow and reducing vascular damage. Conclusions: Our study shows fewer number of participants on both intervention arms reporting pain, with numerically lower scores on PQAS in INF arm compared to PT arm, especially during ongoing CT. The US results suggest that INF has a unique pathophysiological impact on the microvasculature compared to standard PT; further studies are needed to validate these findings and potentially address their clinical significance as a combined modality. Clinical trial information: NCT03272919 . [Table: see text]

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.

Abstract P4-04-01: Safety and efficacy of cryotherapy in the prevention and treatment of chemotherapy-induced peripheral neuropathy in breast cancer patients

Abstract Introduction Chemotherapy-induced peripheral neuropathy (CIPN) is a serious clinical problem that can be caused by some cytotoxic agents used in breast cancer (BC) treatment, most commonly seen following taxane-based therapy[1,2]. Several strategies have been studied for CIPN prevention and treatment, but, still, there is no standard recommendation, options are limited and results unsatisfactory [1]. Cryotherapy is a technique that consists of reducing the blood flow in a certain area of the body by cold temperatures, in order to limit the cytotoxic reach. A few studies have been conducted to analyze the safety and efficacy of this strategy in CIPN prevention and treatment, and results are controversial [3,4,5]. More data is needed to clarify cryotherapy role in this clinical context. Methods This is a retrospective analysis of 40 BC patients treated at a single Brazilian institution between December 2019 and June 2022, aiming at efficacy and safety of cryotherapy in the prevention and treatment of CIPN. Cryotherapy was administered by the Hilotherm Clinic Chemo HT02 device (Hilotherm GmbH - Oberwil bei Zug, Switzerland [6]). The procedure consisted of patients using glove and sock-like devices on hands and feet throughout the chemotherapy infusion. The devices were pre-cooled to 10oC and then put on patients 30 minutes before starting, till one hour after the end of chemotherapy infusion. A questionnaire, as proposed by Leonard et al [7], was administered to patients every cycle to assess the development and severity of CIPN symptoms. Statistical analyses were performed by using a Cox regression model. Results Of the 40 patients analysed, 33 (83.5%) underwent a taxane-based regimen. The median number of cryotherapy sessions was three (ranging from 1 to 12), and, when excluded patients who underwent only one session of cryotherapy, the median was 4 (range 2 to 12). 75% of the 40 patients underwent cryotherapy in all chemotherapy sessions, or were still receiving chemo with cryotherapy by the time of our analysis. 80% of those who left treatment did so after the first session (HR 40.44 (CI95: 8.34 – 196.1; p&amp;lt; 0.0001). CIPN was stable or better than the baseline status for 26 (87%) of the 30 patients that underwent more than 1 session of cryotherapy; only 1 (25%) of the four patients who developed CIPN worse than the baseline status had grade 2 symptoms. Conclusion Cryotherapy is a safe and tolerable strategy that can be used during chemotherapy for breast cancer. Our data suggests that this is an efficient approach to prevent and treat CIPN, but the retrospective nature of the study and the small sample size must be considered when interpreting the results. Finally, strategies must be developed to further improve adherence and tolerability, and prospective randomized trials are needed to confirm the efficacy of cryotherapy in this context. 1. Loprinzi et al. Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: ASCO Guideline Update. J Clin Oncol 38:3325-3348. 2020 2. Rivera et al. Chemotherapy-Associated Peripheral Neuropathy in Patients With Early-Stage Breast Cancer: A Systematic Review. JNCI J Natl Cancer Inst, 2018, Vol. 110, No. 2 3. Rosenbaek et al. Effect of cryotherapy on dose of adjuvant paclitaxel in early-stage breast cancer. Supportive Care in Cancer (2020) 28:3763–3769 4. Ruddy et al. Randomized controlled trial of cryotherapy to prevent paclitaxel-induced peripheral neuropathy (RU221511I); an ACCRU trial. The Breast Volume 48, December 2019 5. Shigematsu et al. Cryotherapy for the prevention of weekly paclitaxel-induced peripheral adverse events in breast cancer patients. Support Care Cancer. 2020 6. https://www.hilotherm.com/en/about-hilotherm/ accessed on July 15 2022 at 23:03 7. Leonard et al. Survey of oxaliplatin-associated neurotoxicity using an interview-based questionnaire in patients with metastatic colorectal cancer. BMC Cancer 2005, 5:116 Citation Format: Rafael B. Costa, Angélica Nogueira-Rodrigues, Claynner Paccely Oliveira Bessa, Rafaela Cristina Adalberto Menezes, Fernanda Coelho de Miranda Jorge Oliveira, Matheus Costa e Silva, Flávia Rocha Paes, Bruno L. Ferrari. Safety and efficacy of cryotherapy in the prevention and treatment of chemotherapy-induced peripheral neuropathy in breast cancer patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-04-01.

Abstract OT1-17-01: Protocol Description of Genetics and Inflammatory Markers to predict Chemotherapy-Induced Peripheral Neuropathy among Early Stage Breast Cancer Patients Receiving Taxane Therapy – GENIE Study

Abstract Background Chemotherapy induced peripheral neuropathy (CIPN) is one of the most common dose-limiting side effects seen among patients with early stage breast cancer and received taxane-containing regimens. The primary clinical manifestation of CIPN is sensory neuropathy such as numbness, tingling and pain in hands and feet, which negatively affect the patient’s quality of life (QoL). Although in most patients, CIPN improves over time, in a subset of patients, it remains a substantial debilitating problem, significantly affecting QoL. To date, there are no effective prevention strategies- or sufficient treatment due to the limited understanding of CIPN pre-disposing factors or pathophysiology. We hypothesize that a multimodal integration of biomarkers with CIPN progression analysis will be required to understand the pathophysiology and to consistently predict patient susceptibility. Further, we hypothesize that this multimodal approach may be leveraged to identify targets for CIPN treatment and/or prevention. This abstract describes the study protocol used to explore this hypothesis. Objective This study is designed to 1) identify genetic, transcriptional, epigenetic, metabolic, inflammatory biomarkers predictive of CIPN development among patients with early stage breast cancer receiving a taxane containing therapy; 2) With these biomarkers, develop an algorithm to identify patients who are at risk of developing CIPN before or during taxane therapy. Methods This is a longitudinal, multicenter, observational study. Patients with early-stage breast cancer who are receiving a taxane-containing (paclitaxel, docetaxel or nab-paclitaxel) treatment regimen, without preexisting peripheral neuropathy are eligible. Estimated enrollment is 400 patients. Demographic and clinical data are collected after patients consent to participate. Molecular data and patient reported outcomes (PRO) are collected prior to initiation of taxane therapy, the 4th, 8th, and 12th week of taxane therapy, and at 3, 6, and 9 months after completion of taxane therapy. Blood samples are collected for molecular data which include genetic, transcriptional, epigenetic (DNA-methylation), and metabolic data. PRO are assessed using (i) the European Organization for Research and Treatment of Cancer CIPN20 questionnaire, (ii) the Brief Pain Inventory, (iii) the Pain Catastrophizing Scale, and (iv) the PRO Measurement System for anxiety, depression and pain interference. Initial data analysis will characterize the association of biomarkers in each modality (e.g., genetic, epigenetic, etc.) with the presence or absence of CIPN, and machine learning will be used to build candidate biomarker signatures to predict CIPN before and during taxane treatment. Two distinct multi-modal prediction models will be constructed: 1) a pre-treatment model to predict risk of developing CIPN, and 2) an on-treatment model to predict the onset of CIPN. The goal is to develop a parsimonious, clinically translatable model for robust and accurate predictions of taxane-induced CIPN. Trial Status: Active, 135 subjects enrolled. Trial Centers: 1) Cleveland Clinic Foundation (8 regional sites in Ohio and 1 in Florida); 2) Huntsman Cancer Institute, University of Utah Research Funding: National Institute of Neurological Disorder and Stroke. Grant No.: 1R61NS113258-01A1 Citation Format: Mei Wei, Anukriti Sharma, Ken Johnson, Bihua Bie, courtney hershberger, Alper Sen, Emily E. Rhoades, Chi-Fan Hocking, George Budd, N. Lynn Henry, Charis Eng, Joseph Foss, daniel rotroff. Protocol Description of Genetics and Inflammatory Markers to predict Chemotherapy-Induced Peripheral Neuropathy among Early Stage Breast Cancer Patients Receiving Taxane Therapy – GENIE Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-17-01.

Abstract P5-07-14: A pilot study of novel approach of intraneural facilitation versus standard physical therapy for prevention of chemotherapy induced peripheral neuropathy

Abstract Background Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent side effect of commonly used chemotherapy (CT) regimens and often results in dose reduction or cessation of treatment which can adversely affect cancer outcomes. Treatment options for CIPN are limited and no standard approaches exist to prevent CIPN. A novel therapy, Intraneural Facilitation (INF) has been developed by physical therapists at our institution’s neuropathy treatment center as a preventative and treatment modality for CIPN. INF therapy involves physical maneuvers and systematic application of pressure to improve peripheral microvascular circulation to the endoneurial capillaries of the extremities. We conducted a randomized pilot study evaluating INF versus standard physical therapy (PT) maneuvers as a non-invasive treatment modality for preventing CIPN during participants’ ongoing chemotherapy. This study was supported by an intramural (GRASP) grant and registered on clinicaltrials.gov (NCT0327919). Methods Newly diagnosed patients with breast cancer stages I to III and CT naive gynecologic cancers without preexisting peripheral neuropathy planning to receive treatment with platinum-based compounds and/or taxanes were eligible for this study. Participants were randomized into two treatment groups. Group one received INF and group two received a standardized program of PT including muscle stretching and strengthening exercises. Each group received two (45-minute) treatments twice a week for six weeks under the supervision of trained physical therapists. Participants were evaluated at baseline, week 3, week 6, and 3 months after the date of initiation of chemotherapy. The use of neuropathy medications, CT dose reductions, and treatment discontinuation was compared between the two treatment groups. Vascular perfusion was also evaluated at the same intervals using ultrasound to measure volume flow and pulsatility of the popliteal and posterior tibial arteries. Participants completed a survey at the end of treatment evaluating the effectiveness and satisfaction of the intervention. Results 44 out of 104 patients screened met the eligibility criteria and were randomized to either of the two therapy modalities from July 2017 to June 2022. A total of 38 participants received the allocated intervention and were included in the analysis (n=20 in the INF arm and n=18 in the PT arm). CT dose reduction due to CIPN grade 2 or higher occurred in 6/18 (33%) and 4/20 (20%) participants who received standard PT and INF, respectively. 2/18 (11%) participants required discontinuation of CT prematurely due to CIPN in the standard PT arm when compared to 1/20 (5.0%) in the INF arm. Pharmacologic interventions were required to manage CIPN in 4/18 (22%) participants in the standard PT arm vs 2/20 (10%) in the INF arm at the end of CT. Participants reported more control over their health (95.2% INF arm vs. 83.3% PT arm) and decreased nerve discomfort (75% in the INF arm vs. 61.1% in the PT arm). Participants reported high levels of satisfaction overall at the end of each intervention (95% in the INF arm vs. 83% in the PT arm). Conclusion Our pilot study evaluated the feasibility and potential for INF therapy compared to standard PT for the prevention of CIPN during ongoing chemotherapy. Based on the patient satisfaction survey, the burden and satisfaction with the assigned therapy modality between the two arms were favorable overall. Our results showed that CT dose reduction and early cessation in addition to pharmacologic interventions for CIPN were numerically less prevalent in the INF arm compared to the standard PT arm; however, further studies are needed to validate these findings. Citation Format: Dani Ran Castillo, Won Jin Jeon, Carvy Floyd Luceno, Mark Bussell, Ron Coleman, Karla Pieters, Jamie Hankins, Annette Boggs, Lorena Garcia, Salem Dehom, Ellen D’Errico, Gayathri Nagaraj. A pilot study of novel approach of intraneural facilitation versus standard physical therapy for prevention of chemotherapy induced peripheral neuropathy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-07-14.

Prevention of Chemotherapy-Induced Peripheral Neuropathy by Inhibiting C-X-C Motif Chemokine Receptor 2.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major drawback in the use of chemotherapeutic agents for patients with cancer. Although studies have investigated a broad number of molecules that might be related to CIPN, the differences in the chemokine pathways between various chemotherapeutic agents, such as vincristine and oxaliplatin, which are some of the most widely used treatments, have not been fully elucidated. We confirmed that the administration (intraperitoneal injections for seven days) of vincristine (0.1 mg/kg) and oxaliplatin (3 mg/kg) induced pain by using the von Frey behavioral test. Subsequent applications with vincristine and oxaliplatin led to mechanical allodynia that lasted more than one week from the fifth day. After the induction of mechanical allodynia, the mRNA expression of CXCR2, CXCL1, CXCL3, and CXCL5 was examined in the dorsal root ganglia (DRG) and spinal cord of the CIPN models. As a result, the mRNA expression of CXCR2 robustly increased in the lumbar spinal cord in the oxaliplatin-treated mice. Next, to evaluate the involvement of CXCR2 in CIPN, reparixin, a CXCR1/2 inhibitor, was administered intrathecally or intraperitoneally with vincristine or oxaliplatin and was further verified by treatment with ruxolitinib, which inhibits Janus kinase 2 downstream of the CXCR1/2 pathway. Reparixin and ruxolitinib blocked oxaliplatin-induced allodynia but not vincristine-induced allodynia, which suggests that CXCR2-related pathways are associated with the development of oxaliplatin-induced neuropathy. Together with the above results, this suggests that the prevention of oxaliplatin-induced neuropathy by CXCR2 inhibition can lead to successful chemotherapy, and it is important to provide appropriate countermeasures against CIPN development for each specific chemotherapeutic agent.

PGC1α: an emerging therapeutic target for chemotherapy-induced peripheral neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN)-mediated paresthesias are a common complication in cancer patients undergoing chemotherapy. There are currently no treatments available to prevent or reverse CIPN. Therefore, new therapeutic targets are urgently needed to develop more effective analgesics. However, the pathogenesis of CIPN remains unclear, and the prevention and treatment strategies of CIPN are still unresolved issues in medicine. More and more studies have demonstrated that mitochondrial dysfunction has become a major factor in promoting the development and maintenance of CIPN, and peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1α (PGC1α) plays a significant role in maintaining the mitochondrial function, protecting peripheral nerves, and alleviating CIPN. In this review, we highlight the core role of PGC1α in regulating oxidative stress and maintaining normal mitochondrial function and summarize recent advances in its therapeutic effects and mechanisms in CIPN and other forms of peripheral neuropathy. Emerging studies suggest that PGC1α activation may positively impact CIPN mitigation by modulating oxidative stress, mitochondrial dysfunction, and inflammation. Therefore, novel therapeutic strategies targeting PGC1α could be a potential therapeutic target in CIPN.

Comprehensive Assessment of the Effectiveness of the Use of Alpha-lipoic Acid and Ipidacrine Hydrochloride for the Prevention of Paclitaxel-indused Peripheral Neuropathy in Breast Cancer Patients

Abstract. Almost 97% of women undergoing chemotherapy with paclitaxel for breast cancer suffer from symptoms of peripheral neuropathy, the severity of which directly depends on the single, cumulative dose and duration of infusion of the agent. Neurological manifestations of paclitaxel-induced peripheral neuropathy, such as bilateral numbness, neuropathic pain and paresthesias in the distal parts of the limbs, often lead to the need to reduce doses, up to the refusal of taxanes, which negatively affects the immediate and long-term results of treatment. Despite numerous scientific studies, there are no known means for prevention of chemotherapy-induced peripheral neuropathy. Of the more than 20 drugs studied so far for the prevention of chemotherapy-induced peripheral neuropathy, none has shown sustained and systemic clinically significant results.&#x0D; The aim of the study: to assess the effectiveness of the combination of alpha-lipoic acid and acetylcholinesterase inhibitor ipidacrine hydrochloride for the prevention of paclitaxel-induced peripheral neuropathy in breast cancer patients.&#x0D; Materials and methods of the study: a comprehensive assessment of clinical (survey regarding subjective symptoms and quality of life, neurological examination), neurophysiological (electroneuromyography) and morphological indices of paclitaxel-induced peripheral neuropathy in breast cancer patients who received polychemotherapy in neoadjuvant, adjuvant or palliative settings carried out according to the schemes of AT (paclitaxel, doxorubicin) or ET (paclitaxel, epirubicin) regimens with or without preventive treatment of neuropathy, has been performed.&#x0D; Results of the study. The use of the studied scheme for the prevention of paclitaxel-induced peripheral neuropathy led to a significant improvement in neurological manifestations, neurophysiological and morphometric parameters of peripheral nerves, as well as quality of life and the severity of subjective symptoms and their impact on daily life activities in comparison with patients who received chemotherapy without treatment for the prevention of neuropathy.&#x0D; Conclusions. The combination of alpha-lipoic acid and the acetylcholinesterase inhibitor - ipidacrine hydrochloride, could be recommended for prophylaxis of paclitaxel-induced peripheral neuropathy.&#x0D; Key words: breast cancer, chemotherapy, polyneuropathy, prevention, questionnaires, electroneuromyography, morphometric analysis.

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