Severity Of Chemotherapy-induced Peripheral Neuropathy Research Articles

Exploring clinical markers of Axon degeneration processes in Chemotherapy-induced peripheral neuropathy among young adults receiving vincristine or paclitaxel.

Approximately 70% of patients receiving neurotoxic chemotherapy (e.g., paclitaxel or vincristine) will develop chemotherapy-induced peripheral neuropathy. Despite the known negative effects of CIPN on physical functioning and chemotherapy dosing, little is known about how to prevent CIPN. The development of efficacious CIPN prevention interventions is hindered by the lack of knowledge surrounding CIPN mechanisms. Nicotinamide adenine dinucleotide (NAD+) and cyclic-adenosine diphosphate ribose (cADPR) are potential markers of axon degeneration following neurotoxic chemotherapy, however, such markers have been exclusively measured in preclinical models of chemotherapy-induced peripheral neuropathy (CIPN). The overall objective of this longitudinal, observational study was to determine the association between plasma NAD+, cADPR, and ADPR with CIPN severity in young adults receiving vincristine or paclitaxel. Young adults (18-39 years old) beginning vincristine or paclitaxel were recruited from Dana-Farber Cancer Institute. Young adults completed the QLQ-CIPN20 sensory and motor subscales and provided a blood sample prior to starting chemotherapy (T1) and at increasing cumulative vincristine (T2: 3-5mg, T3: 7-9mg) and paclitaxel (T2: 300-500 mg/m2, T3: 700-900 mg/m2) dosages. NAD+, cADPR, and ADPR were quantified from plasma using mass spectrometry. Metabolite levels and QLQ-CIPN20 scores over time were compared using mixed-effects linear regression models and/or paired two-sample tests. Participants (N = 50) were mainly female (88%), white (80%), and receiving paclitaxel (78%). Sensory and motor CIPN severity increased from T1-T3 (p < 0.001). NAD+ (p = 0.28), cADPR (p = 0.62), and ADPR (p = 0.005) values decreased, while cADPR/NAD+ ratio increased from T1-T3 (p = 0.50). There were no statistically significant associations between NAD + and QLQ-CIPN20 scores over time. To our knowledge, this is the first study to measure plasma NAD+, cADPR, and ADPR among patients receiving neurotoxic chemotherapy. Although, no meaningful changes in NAD+, cADPR, or cADPR/NAD+ were observed among young adults receiving paclitaxel or vincristine. Future research in an adequately powered sample is needed to explore the clinical utility of biomarkers of axon degeneration among patients receiving neurotoxic chemotherapy to guide mechanistic research and novel CIPN treatments.

Factors affecting peripheral neuropathy induced by nanoparticle albumin-bound paclitaxel in patients with pancreatic cancer.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major toxicity limiting the use of nab-paclitaxel (Nab-P) in treating patients with pancreatic cancer. The aim of this study was to identify the factors affecting CIPN using patient-reported outcome measures and the minimally invasive volumetric absorptive microsampling (VAMS) technique. The maximum concentrations of paclitaxel (Cmax) were measured from 81 VAMS samples collected from 44 participants with pancreatic cancer. The association between CIPN development and demographic, clinical and pharmacokinetic factors was determined using univariable and multivariable logistic regression. The association between CIPN severity and the factors was evaluated using Spearman's rank correlation. The impact of Cmax and the number of treatment cycles on the severity was assessed using multivariable linear regression. The development of CIPN was significantly associated with cumulative dose (odds ratio 1.005, 95% confidence interval [CI] 1.003-1.007), treatment cycles (3.47, 2.25-5.85), alkaline phosphate (0.992, 0.985-0.998) and age (1.092, 1.020-1.179), with an area under the receiver operating characteristic curve of 0.89 (95% CI 0.83-0.95). The severity of CIPN significantly worsened with increasing cumulative dose (coefficient 0.58, 95% CI 0.44-0.69), treatment cycles (0.57, 0.44-0.68) and age (0.18, 0.00-0.35). The severity of CIPN was predictable from treatment cycles (P = .0002) and Cmax (P = .01). The higher the cumulative dose of Nab-P, treatment cycles and age, the more frequently and severely do the patients experience CIPN. In predicting the severity of CIPN using Cmax, minimally invasive VAMS is a feasible alternative to venous blood sampling.

Effectiveness of an intervention (effleurage and petrissage) on the severity of chemotherapy-induced peripheral neuropathy (CIPN) among patients: A randomized control pilot trial.

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-dependent, nerve-damaging adverse reaction with reported prevalence rates of 68.1% at the first month after starting chemotherapy; 60.0 % at the third month; and 30% at the sixth month. To determine the effectiveness of an intervention (effleurage and petrissage) on severity of CIPN among patients receiving platinum-based chemotherapy. Sixty patients receiving either a third or fourth cycle of platinum-based chemotherapy were randomly assigned to one of two groups with a pre- and post-test design. The interventional group received effleurage and petrissage prior to chemotherapy for a period of one month. Comparisons of CIPN levels among both groups were done at Day 7, 14, 21, and 1 month using the FACT/ GOG-Ntx subscale. Prior to intervention, the mean score (+SD) of CIPN in the intervention group was 17.17 (+4.907) and 17.10 (+ 4.421) in the control group (T = 0.055, P value 0.956). The post-test scores following intervention at 1 month, was a mean score (+SD) for CIPN in the intervention group of 10.70 (±2.855) and 16.27 (±3.039) in the control group (P value 0.000). This pilot result supports that the intervention (effleurage and petrissage) can be effective in reducing CIPN severity levels among patients receiving platinum-based chemotherapy.

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.

Validity of Patient-Reported Outcome Measures in Evaluating Nerve Damage Following Chemotherapy

Chemotherapy-induced peripheral neuropathy (CIPN) is a substantial adverse effect of anticancer treatments. As such, the assessment of CIPN remains critically important in both research and clinic settings. To compare the validity of various patient-reported outcome measures (PROMs) with neurophysiological and sensory functional measures as the optimal method of CIPN assessment. This cohort study evaluated participants treated with neurotoxic chemotherapy across 2 cohorts using a dual-study design. Participants commencing treatment were assessed prospectively at beginning of neurotoxic treatment, midtreatment, and at the end of treatment. Participants who completed treatment up to 5 years prior were assessed cross-sectionally and completed a single assessment time point. Participants were recruited from oncology centers in Australia from August 2015 to November 2022. Data analysis occurred from February to November 2023. Neurotoxic cancer treatment including taxanes, platinums, vinca-alkaloids, proteasome inhibitors, and thalidomide. CIPN was assessed via PROMs (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC-CIPN20], Functional Assessment of Cancer Therapy/Gynecological Cancer Group Neurotoxicity Questionnaire (FACT/GOG-Ntx), and the patient-reported outcomes version of the Common Terminology Criteria for Adverse Events [PRO-CTCAE]), neurological and neurophysiological assessment (Total Neuropathy Score and sural and tibial compound nerve amplitudes), and sensory measures (Grating orientation, Von Frey monofilament, and 2-point discrimination tasks). Core measurement properties of CIPN outcome measures were evaluated. Convergent and known-groups validity was assessed cross-sectionally following treatment completion, and responsiveness was evaluated prospectively during treatment. Neurological, neurophysiological, and sensory outcome measure scores were compared between those who reported high and low levels of CIPN symptoms using linear regressions. A total of 1033 participants (median [IQR] age, 61 [50-59] years; 676 female [65.4%]) were recruited to this study, incorporating 1623 assessments. PROMs demonstrated best ability to accurately assess CIPN (convergent validity), especially the PRO-CTCAE composite score (r = 0.85; P < .001) and EORTC-CIPN20 (r = 0.79; P < .001). PROMS also demonstrated the best ability to discriminate between CIPN severity (known-groups validity) and to detect changes at onset of CIPN development (responsiveness), especially for EORTC-CIPN20 (d = 0.67; 95% CI, 0.52-0.83), FACT/GOG-Ntx (d = 0.65; 95% CI, 0.49-0.81) and the PRO-CTCAE (d = 0.83; 95% CI, 0.64-1.02). Other measures did not achieve threshold for convergent validity (α < 0.7). Neurophysiological and sensory measures did not demonstrate acceptable responsiveness. In regression models, neurological, neurophysiological, and sensory outcome measures were significantly impaired in participants who reported high levels of CIPN symptoms compared with those who reported low levels of CIPN symptoms. In this cohort study of 1033 cancer patients, PROMs were the only measures to satisfy all 3 core measurement property criteria (convergent validity, known-groups validity, and responsiveness). These findings suggest that adoption of PROMs in clinical practice can equip clinicians with valuable information in assessing CIPN morbidity.

Chemotherapy-Induced Peripheral Neuropathy in Patients With Gastroesophageal Cancer.

Chemotherapy for various stages of gastroesophageal cancer (GEC) is often neurotoxic. Chemotherapy-induced peripheral neuropathy (CIPN) impairs health-related quality of life (HRQoL). This study investigates the incidence and severity of CIPN and its association with HRQoL in patients with GEC. Patients who received chemoradiotherapy or chemotherapy for GEC were identified from the Netherlands Cancer Registry. Patient-reported data (measured using the EORTC QLQ-CIPN20 and EORTC QLQ-C30) were collected through the Prospective Observational Cohort Study of Esophageal-Gastric Cancer Patients (POCOP) at baseline and at 3, 6, 9, 12, 18, and 24 months after treatment initiation. Linear mixed effects models were constructed to assess CIPN and the correlation between CIPN and HRQoL was analyzed using Spearman's correlation. A total of 2,135 patients were included (chemoradiotherapy: 1,593; chemotherapy with curative intent: 295; palliative chemotherapy: 247). In all 3 treatment groups, CIPN significantly increased during treatment (adjusted mean score of CIPN at 6 months: chemoradiotherapy, 8.3 [baseline: 5.5]; chemotherapy with curative intent, 16.0 [baseline: 5.6]; palliative therapy, 25.4 [baseline: 10.7]). For chemoradiotherapy, the adjusted mean score continued to increase after treatment (24 months: 11.2). For chemotherapy with curative intent and palliative therapy, the adjusted mean score of CIPN decreased after treatment but did not return to baseline values. CIPN was negatively correlated with HRQoL in all treatment groups, although significance and strength of the correlation differed over time. Because of the poor prognosis of GEC, it is essential to consider side effects of (neurotoxic) treatment. The high prevalence and association with HRQoL indicate the need for early recognition of CIPN.

Impact of chemotherapy-induced peripheral neuropathy permanence on patients' preference to discontinue chemotherapy.

12046 Background: Chemotherapy-induced peripheral neuropathy (CIPN) diminishes patients’ functional ability and quality of life; approximately 40% of patients experience CIPN symptoms 3 years after treatment. Due to the absence of effective CIPN treatments, ASCO guidelines recommend discontinuing chemotherapy in patients experiencing intolerable CIPN symptoms. Little is known about patient’s preference to continue or discontinue chemotherapy when experiencing CIPN, and whether the potential permanence of CIPN symptoms affects this decision. The objective of this prospective observational study was to determine the effect of CIPN symptom permanence on patients’ preference to discontinue chemotherapy. Methods: Patients receiving taxane and/or platinum chemotherapy for breast or colorectal cancer were enrolled in a prospective observational clinical study. Patients reported their CIPN severity using the EORTC CIPN20 patient-reported outcome questionnaire at the start of each treatment cycle. At the same time, patients were asked if they would prefer to continue or discontinue chemotherapy treatment under the hypothetical scenario that their current CIPN symptoms would be temporary or permanent. A generalized linear mixed effects model was used to determine the effect of CIPN severity, permanence, and other clinical variables on a patient’s decision to discontinue (vs. continue) chemotherapy treatment. Results: A total of 66 patients completed data collection at least one time, of whom 55 (83%) had breast cancer, 12 (18%) had metastatic disease, and 52 (79%) received a taxane. The odds a patient would prefer to discontinue chemotherapy treatment if their CIPN symptoms would be permanent (vs. temporary) were nearly 30 times greater (odds ratio (OR)=30.15, 95% confidence interval (CI): 15.73-57.79, p&lt;0.001, Table). There was a statistical trend toward preferring to discontinue chemotherapy treatment as CIPN symptom severity increased (OR=1.09, 95% CI: 1.00-1.19, p=0.063). Conclusions: The potential for CIPN symptoms to be permanent has a huge effect on whether patients want to continue or discontinue chemotherapy treatment. Additional data is needed on the incidence and predictors of permanent CIPN. More importantly, shared decision-making tools that convey the risk of permanent CIPN, and the potential risk of discontinuing chemotherapy treatment, are needed to facilitate patient-centered treatment decisions so that each patient with cancer achieves their personal treatment goals. [Table: see text]

Preventing chemotherapy-induced peripheral neuropathy with acupuncture, a multinational parallel randomized controlled trials project (PACT).

TPS12156 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a significant challenge for patients (pts) with breast cancer treated with taxanes and platinum compounds. CIPN severely affects quality of life, leading to paresthesia and pain, and often results in dose modifications and discontinuation of treatment. Although preliminary trials suggest the effectiveness of acupuncture in managing existing symptoms of CIPN, the use of acupuncture to prevent CIPN is not well studied. Prior studies provide inconclusive results, underscoring the need for more rigorous investigation. We designed an international study, PACT, to evaluate the impact of acupuncture on the prevention of CIPN in breast cancer pts who undergo adjuvant or neoadjuvant taxane-based chemotherapy. Methods: PACT is a coordinated multi-national study consisting of three parallel randomized trials in USA, China, and South Korea, using the same inclusion/exclusion criteria, randomization, interventions, and validated measures. PACT is designed to evaluate the effectiveness of acupuncture in preventing CIPN in pts undergoing taxane-based chemotherapy for early-stage breast cancer. Participants include pts with newly diagnosed stage I-III breast cancer without preexisting neuropathy, scheduled for adjuvant or neoadjuvant taxane-based chemotherapy. Target enrollment is 140 pts from three sites: Dana-Farber Cancer Institute (USA) (n=100), Jiangsu Province Hospital of Chinese Medicine (China) (n = 20) and the Daegu Catholic University Medical Center (South Korea) (n=20), randomized (1:1) to the acupuncture arm or a control. The acupuncture arm receives a standardized protocol of 1-2 sessions per week for 12 weeks (total of 14 sessions). The control arm receives relaxation exercises with nature scenery videos for 14 sessions. The follow-up period for both arms is 12 weeks. Main measures include The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-CIPN20, QLQ-30 and Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) CIPN items. The primary outcome measure is the change in CIPN severity, assessed using the EORTC QLQ-CIPN20 sensory subscale, between baseline and week 12, with secondary outcomes including occurrence of CIPN and maximum CIPN scores, pain, sleep quality, and overall quality of life. A planned pooled analysis of individual patient data will be performed. The ethics review committee of each site has approved the study. Today, 89 (64%) of the planned 140 participants have been enrolled. Clinical trial information: NCT05528263 , ChiCTR2200066714, KCT0008470.

Physical function as a predictor of chemotherapy-induced peripheral neuropathy in patients with pancreatic cancer

BackgroundA growing body of research indicates that poor functional status before chemotherapy may be correlated with the severity of chemotherapy-induced peripheral neuropathy (CIPN) after the neurotoxic treatment. However, little is known about the associations between pre-chemotherapy physical function and CIPN in patients with pancreatic cancer.PurposeTo identify the predictors of CIPN in relation to pre-chemotherapy physical function in patients with pancreatic cancer.MethodsThis secondary analysis included data from patients with pancreatic cancer who participated in a longitudinal research study at National Cheng Kung University Hospital, Tainan, Taiwan. Four physical function tests (i.e., grip strength, Timed Up and Go (TUG), 2-minute step test (2MST), and Romberg test) and two questionnaires (The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 [EORTC QLQ-C30] and Chemotherapy-Induced Peripheral Neuropathy Module [CIPN20]) were assessed at baseline (i.e., before first chemotherapy session) and 2-, 3-, 4-, and 6-month follow-up. Multiple linear regression with adjustment for confounding factors was used to assess the associations between the four functional tests at baseline and the CIPN20 total score and individual subscale scores (sensory, motor, and autonomic) at 6-month follow-up.ResultsData from a total of 209 pancreatic cancer patients (mean age: 64.4 years, 54.5% male) were analyzed. The findings showed that the severity of CIPN at 6-month follow-up was significantly associated with the baseline TUG completion time (β = 0.684, p = 0.003). The TUG completion time was also positively correlated with the 6-month CIPN sensory and autonomic subscales. In addition, a baseline positive Romberg test (β = 0.525, p = 0.009) was a significant predictor of the severity of motor neuropathy at 6-month follow-up.ConclusionThe TUG completion time and positive Romberg test before chemotherapy may be predictive factors of the CIPN severity 6 months after the commencement of chemotherapy. Accordingly, the incorporation of TUG and Romberg tests into the clinical assessment protocol emerges as imperative for individuals diagnosed with pancreatic carcinoma undergoing chemotherapy regimens.

Abstract PO3-12-11: A phase-3 randomized controlled study to evaluate the role of hydroxyprogesterone in prevention of chemotherapy induced neurotoxicity in women with breast cancer

Abstract Introduction Chemotherapy induced peripheral neuropathy (CIPN) is seen in 60% breast cancer patients who receive paclitaxel-based chemotherapy with no conclusively known pathophysiology. Hydroxyprogesterone is known to have neuroprotective and neuro-regenerative potential. We conducted a randomized controlled trial assessing the role of hydroxyprogesterone in reducing the incidence and severity of CIPN. Methodology Histologically proven, post-menopausal, non-metastatic breast cancer patients without pre-existing neuropathy, planned to receive paclitaxel (with or without trastuzumab) in the adjuvant or neoadjuvant setting were screened and consented. They were randomized to receive depot hydroxyprogesterone injection 500 mg followed by 250 mg injection every 2 weekly (trial arm) versus 1 ampoule (2 ml) of vitamin-B complex (B1-100mg, B6-100mg and B12-1000µg) injection every 2 weekly (control arm) during the entire course of paclitaxel-based chemotherapy. The primary end point was cumulative incidence of grade II-IV CIPN, at the last cycle of chemotherapy as assessed by CTCAE-V4. Secondary end point was EORTC-QLQ-CIPN20 assessment 8 weeks after last cycle of chemotherapy. Patients were stratified for stage, diabetes mellitus, and frequency of paclitaxel administration. Sample size was calculated for a 20% reduction in CIPN from 60% with α-0.05 and power of 80%, for 2-sided significance of p-0.05, with a drop-out rate of 10%. Results A total of 240 patients were randomized between November 2015 and February 2023- 120 each on the trial and control arm. The median age was 54 (43-73) and 55 (43-74) years; 35% and 31.7% patients were early breast cancer (cT1-2, N0-1) in the trial and control arms respectively. The median pT size was 2.6 cm and 65% patients were node positive overall. The incidence of grade II-IV CIPN (motor and/or sensory) at the end of chemotherapy was 55.9% and 56.8% in the trial and control arms respectively (p=0.90, 95%CI-0.12-0.13). Overall, chemotherapy related adverse events (CTCAE-V4) were seen in 41.39 and 39.9% in trial and control arms respectively. The average EORTC-QLQ-CIPN20 score at 8 weeks after last cycle of chemotherapy for motor neuropathy was 11.18 (0-70) and 13.53 (0-74), for sensory neuropathy was 8.51 (0-76) and 9.27 (0-81) and that for autonomic neuropathy was 4.94 (0-67) and 4.65 (0-67) in the trial and control arms respectively (p=NS). Conclusion Hydroxyprogesterone did not reduce the incidence of paclitaxel related CIPN when assessed immediately post-chemotherapy. The absolute incidence of CIPN (any grade) was 61% in our study which is like that reported in literature. Long term follow-up of these patients will assess the recovery of CIPN and long-term impact of the study interventions on CIPN. The study was approved by Institutional Review Board and Drug Controller General of India (CTRI/2015/11/006381). Citation Format: Rajendra Badwe, Shalaka Joshi, Rohini Hawaldar, Tejal Panhale, Nita Nair, Sandesh Sawant, Vaibhav Vanmali, Mitchelle Engineer, Anuradha Daptardar, Vani Parmar, Seema Gulia, Sudeep Gupta. A phase-3 randomized controlled study to evaluate the role of hydroxyprogesterone in prevention of chemotherapy induced neurotoxicity in women with breast cancer [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 PO3-12-11.

Feasibility of exercise during oxaliplatin infusions to reduce neuropathy in patients with gastrointestinal cancer.

244 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of oxaliplatin, often leading to discontinuation of therapy and persistent functional impairment. Limited evidence suggests that exercise may reduce risk and severity of CIPN. This pilot study assessed feasibility and acceptability of an exercise intervention during oxaliplatin infusions over a 3-month period. Methods: Patients (≥18 years) with gastrointestinal malignancies receiving oxaliplatin participated in this prospective, single-arm study. Patients exercised for 30 minutes during 6 infusions, using hand and foot pedal machines for upper and lower extremity exercise. Feasibility and acceptability were evaluated by patient report, using Weiner’s Feasibility and Acceptability of Intervention Measures (FIM and AIM, scored 1-5). We defined feasibility and acceptability as a composite score of ≥4 on the FIM and AIM for ≥60% of subjects, respectively. We evaluated CIPN severity (via EORTC-CIPN20) and quality of life (via PROMIS-29) at baseline, 8 weeks (wks), and 14 wks. We calculated descriptive statistics and tested for changes over time using a mixed effects model. Results: Ten patients (median age 64 years, 50% men) enrolled, comprising all patients approached. Nine of 10 patients completed all planned exercise sessions. Nine of 10 patients found the intervention feasible (median FIM score = 4, IQR 4-4.75) and 6 of 10 found it acceptable (median AIM = 4, IQR 3.56-4.19). Patients reported decreasing anxiety (p=0.02) and increasing fatigue (p=0.02) over the 3-month period. In an exit survey, 3 of 9 patients agreed with the statement “I found myself wanting to exercise more over the past several weeks”. In free-text, 6/9 patients stated that they enjoyed the intervention. Conclusions: The intervention of upper and lower extremity exercise during oxaliplatin infusions over a 3-month period met the pre-defined study objectives of patient-reported feasibility and acceptability. Most patients indicated that they enjoyed the exercise intervention and that participating in this study encouraged them to exercise more on their own time. Further study is needed to evaluate the effectiveness of the intervention for reducing CIPN. Clinical trial information: NCT05916118 .[Table: see text]

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.

Use of acupuncture with acupressure in addition to standard-of-care cryotherapy to decrease chemotherapy-associated neuropathy in patients with gastrointestinal malignancies receiving oxaliplatin-based chemotherapy: Study protocol for a randomized, controlled pilot and feasibility study

BackgroundOxaliplatin is a key chemotherapeutic agent in the treatment of local and metastatic gastrointestinal (GI) malignancies. Dose density and treatment adherence can be limited by chemotherapy-induced peripheral neuropathy (CIPN). Early research suggests CIPN incidence and severity may be mitigated by acupuncture, but rigorous data in GI oncology patients is limited. Here, we describe the protocol of a randomized, waitlist-controlled pilot study testing the use of preemptive of acupuncture plus acupressure to decrease CIPN and chemotherapy-related toxicities. MethodsPatients with a GI malignancy (n = 56) with planned 5-fluorouracil (5-FU) and oxaliplatin IV (FOLFOX, FOLFIRINOX) every 2 weeks are being recruited. Additional concurrent anti-neoplastic agents may be used. Enrolled patients are randomized 1:1 to a 3-month intervention of Arm A: acupuncture with acupressure and standard-of-care treatment, or Arm B: standard-of-care alone. In Arm A, on days 1 and 3 of each chemotherapy cycle a standardized acupuncture protocol is administered and patients are taught self-acupressure to perform daily between chemotherapy treatments. Patients in both arms are given standard-of-care oral and peripheral (hands/feet) ice chip cryotherapy during oxaliplatin administration. CIPN and other symptoms are assessed at baseline, 6 weeks, and 3 months from registration. The primary endpoint is CIPN severity at 3 months (EORTC-CIPN 20). Additional endpoints evaluate CIPN incidence (CTCAE, Neuropen, tuning fork); incidence of pain, fatigue, nausea, oral dysesthesia, and anxiety; and feasibility (recruitment, retention, adherence, acceptability). If warranted, trial results will inform the design of a multi-center trial to expand testing of the intervention to a larger patient cohort.

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&lt;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&lt;0.001). 70 lipid species were associated with shorter time to DR/CD (Cox regression p&lt;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&lt;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&lt;0.006); however, these clinical factors were not associated with time to DR/CD in the multivariable models (p&gt;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.

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

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

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

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

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

Clinical Predictors And Levels Of Physical Activity Among Cancer Survivors Treated With Neurotoxic Chemotherapy

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side-effect for cancer survivors and may negatively impact on physical activity (PA). The primary aim of our study was to descriptively quantify PA levels among cancer survivors treated with neurotoxic chemotherapy regimens. Our secondary aims: 1) investigated the proportion of survivors with CIPN symptoms interfering with PA participation, and 2) investigated CIPN-related predictors of walking and moderate-vigorous PA. METHODS: 361 participants were assessed cross-sectionally post-neurotoxic chemotherapy (68% female, median (IQR) age 59.5 (50-68) years, 12 (6-24) months post-treatment completion). PA was self-reported (IPAQ) and classified as meeting recommended moderate-vigorous PA guidelines (≥150 minutes/week) or not. CIPN severity (NCI-CTCAE, FACT/GOG-Ntx13), sural and tibial nerve conduction studies, and balance (Swaymeter) were assessed. RESULTS: 47% of participants did not meet recommended PA guidelines. 25% did not participate in any moderate-vigorous PA. 71% presented with CIPN symptoms (≥grade 1 NCI). 25% reported that their CIPN symptoms interfered with PA, who had impaired balance (p = .02), but not reduced sural (p = .10) or tibial nerve (p = .17) nerve amplitudes. Univariate analyses identified that survivors aged ≥60, with grade ≥ 1 NCI CIPN, diagnosed with stage III/IV disease or were obese were less likely to meet PA guidelines (all p < .05), although regression models identified older age, higher BMI and female sex were associated with lower levels of walking and moderate-vigorous PA. CONCLUSIONS: Many cancer survivors exposed to neurotoxic chemotherapy have low PA levels. Female cancer survivors, who are older, and with higher BMIs are less likely to participate in walking and moderate-vigorous PA post-neurotoxic chemotherapy. Tailored interventions are needed to increase PA in this population to improve physical function and quality of life.

Cancer Survivors' Perspectives of Virtual Yoga for Chronic Chemotherapy-Induced Peripheral Neuropathy Pain During the COVID-19 Pandemic.

With the rise in telehealth due to the COVID-19 pandemic, further research is needed to determine how to optimize virtual delivery of existing integrative oncology interventions for cancer treatment–related symptoms. The purpose of this qualitative analysis was to explore cancer survivors' perspectives of the acceptability and satisfaction of an 8-week, virtual yoga intervention for cancer survivors with chronic chemotherapy-induced peripheral neuropathy pain. Fourteen participants with chronic chemotherapy-induced peripheral neuropathy pain who completed the virtual yoga intervention were interviewed using a semistructured interview guide. Themes were derived from the data using inductive content analysis methods. Main findings from the interviews included the following: (1) participants were willing to try new nonpharmacological treatments for chemotherapy-induced peripheral neuropathy due to the high symptom burden and prior lack of success with medications; (2) participants highly rated the flexibility offered by the virtual format, but desired the social support potentially offered by practicing in-person yoga; and (3) the impact of virtual yoga on chemotherapy-induced peripheral neuropathy severity was unclear. There were several barriers to participants' use of virtual yoga for chronic chemotherapy-induced peripheral neuropathy pain (eg, technology, lack of space/equipment). The results may be used to improve the design and delivery of future trials testing virtual yoga for chronic chemotherapy-induced peripheral neuropathy pain.

Chemotherapy-Induced Peripheral Neuropathy and New Therapeutic Targets: Preclinical Data of Drug Repositioning

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of neurotoxic anticancer drugs. Its prevalence is close to 60%, but it can vary considerably depending on the anticancer drugs and doses administered. CIPN remains a problematic and long-lasting adverse effect associated with a decline of patient’s quality of life. Moreover, no preventive treatment can be recommended and only duloxetine has a moderate recommendation in the management of CIPN (American Society of Clinical Oncology [ASCO] and the European Society for Medical Oncology [ESMO]). Consequently, oncologists must decrease or stop neurotoxic anticancer regimen to limit CIPN severity, which may in turn have a negative oncological impact on disease control and progression-free survival. Thus, improvement in pharmacological neuropathy management is needed. We consider according to a reverse translational research strategy that this can be achieved either by proposing innovative strategies, improving the use of current analgesic drugs, or drug repositioning. In this article, two strategies of drug repositioning, riluzole and donepezil, will be presenting in the management of CIPN based on the studies in animal models of CIPN.