Chemotherapy-induced Peripheral Neuropathy Research Articles

Efficacy and Safety of Shen Fu Injection Alleviating Chemotherapy-Induced Peripheral Neurotoxicity: A Randomized Controlled Trial

Objective: To analyze the effect of Shenfu injection on Chemotherapy-Induced Peripheral Neuropathy (CIPN) at different stages of tumor chemotherapy. Method: An analysis of 153 patients who were divided into chemotherapy group and combined group was performed chemotherapy within two to six cycles with oxaliplatin or paclitaxel, and combined with or without Shenfu injection. Efficacy evaluation was divided into two phases, including the short-term incidence of CIPN and the long-term incidence of CIPN. Subgroup analysis was performed on the combined group to compare the incidence of CIPN in different usage time of Shenfu injection. Preliminary comparison of the incidence of common side effects. Results: The short-term incidence rates of CIPN in the combined group and chemotherapy group were 27.85% and 66.22%, respectively (P<0.01), and the long-term incidence rates were 17.72% and 45.95%, respectively (P<0.01). In the combined group of 5-6 cycles chemotherapy, divided into two groups according to the time used of Shenfu injection, greater than 3 weeks and less than 3 weeks, and the short-term incidence rates of CIPN were 28.57% and 69.23%, respectively, and the longterm incidence rates of CIPN was 14.29% and 46.15%, respectively. Adverse reactions evaluation showed that the occurrence of bone marrow suppression were 35.44% and 60.81% (P<0.05) in the combined group and chemotherapy group, and there was no significant difference in digestive tract reaction, liver and kidney toxicity. Conclusion: Shenfu injection significantly reduced the incidence of CIPN and had a good security.

Motor disorders related to oxaliplatin-induced peripheral neuropathy: long-term severity and impact on quality of life.

Sensory chemotherapy-induced peripheral neuropathy (CIPN) is well-recognized, but motor CIPN remains understudied. This secondary analysis focused on the long-term severity and impact of motor disorders, their relation to sensory CIPN, neuropathic pain, psychological distress, and health-related quality of life (HRQoL) after oxaliplatin-based chemotherapy in colorectal cancer (CRC) survivors. Data from a multicenter, cross-sectional study were re-analyzed to explore motor CIPN among CRC survivors up to 5years post-chemotherapy, with no longitudinal follow-up. Questionnaires assessed sensory and motor CIPN (QLQ-CIPN20), neuropathic pain (DN4), anxiety and depression (HADS), and HRQoL (QLQ-C30). Among 405 CRC survivors, 31.1% had sensory CIPN as previously described. When categorizing the 405 CRC survivors based on the years since their last oxaliplatin-based chemotherapy, the motor scores derived from the QLQ-CIPN20 showed no significant difference between years (p = 0.08). Motor CIPN scores correlated with female gender, higher oxaliplatin dose intensity, sensory CIPN, and neuropathic pain. Motor CIPN also linked to decreased HRQoL and increased psychological distress. The study underscores the detrimental impact of motor disorders on CRC survivors post-oxaliplatin-based chemotherapy. Oncologists should prioritize assessing and managing motor manifestations alongside sensory symptoms to enhance post-cancer quality of life. NCT02970526 (2016-11-22). https://classic. gov/ct2/show/NCT02970526?term=NCT02970526&draw=2&rank=1 .

The potential neuroprotective effects of cannabinoids against paclitaxel-induced peripheral neuropathy: in vitro study on neurite outgrowth.

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a shared burden for 68.1% of oncological patients undergoing chemotherapy with Paclitaxel (PTX). The symptoms are intense and troublesome, patients reporting paresthesia, loss of sensation, and dysesthetic pain. While current medications focus on decreasing the symptom intensity, often ineffective, no medication is yet recommended by the guidelines for the prevention of CIPN. Cannabinoids are an attractive option, as their neuroprotective features have already been demonstrated in neuropathies with other etiologies, by offering the peripheral neurons protection against toxic effects, which promotes analgesia. Methods: We aim to screen several new cannabinoids for their potential use as neuroprotective agents for CIPN by investigating the cellular toxicity profile and by assessing the potential neuroprotective features against PTX using a primary dorsal root ganglion neuronal culture. Results: Our study showed that synthetic cannabinoids JWH-007, AM-694 and MAB-CHMINACA and phytocannabinoids Cannabixir® Medium dried flowers (NC1) and Cannabixir® THC full extract (NC2) preserve the viability of fibroblasts and primary cultured neurons, in most of the tested dosages and time-points. The combination between the cannabinoids and PTX conducted to a cell viability of 70%-89% compared to 40% when PTX was administered alone for 48h. When assessing the efficacy for neuroprotection, the combination between cannabinoids and PTX led to better preservation of neurite length at all tested time-points compared to controls, highly drug and exposure-time dependent. By comparison, the combination of the cannabinoids and PTX administered for 24h conducted to axonal shortening between 23% and 44%, as opposed to PTX only, which shortened the axons by 63% compared to their baseline values. Discussion and Conclusion: Cannabinoids could be potential new candidates for the treatment of paclitaxel-induced peripheral neuropathy; however, our findings need to be followed by additional tests to understand the exact mechanism of action, which would support the translation of the cannabinoids in the oncological clinical practice.

Chemotherapy-induced neuropathy and pain in pediatric oncology patients: impact of combination therapies.

Combination therapy stands out as a risk factor for clinical CIPN. The high prevalence of moderate/severe pain underscores the importance of close vigilance given its potential to compromise the patient's overall well-being. • Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent adverse effect and dose-limiting factor in pediatric cancer treatment. • Prevalence varies among regions and risk factors are still under study. • Prevalence of symptomatic CIPN is 23% among pediatric patients undergoing treatment for hematopoietic tumors in a referral hospital in Argentina. Most patients report moderate or severe pain. • Combining vincristine with cytarabine and using a higher number of neurotoxic drugs in combination therapies exhibit significant association with the development of CIPN-related symptoms.

Association of Chemotherapy-Induced Peripheral Neuropathy with Diet Quality Among Post-Treatment Cancer Survivors

Nutrition is essential for peripheral nerve function, yet dietary factors associated with chronic chemotherapy-induced peripheral neuropathy (CIPN) remain poorly characterized. The purpose of this cross-sectional study was to determine differences in diet quality and macronutrients for cancer survivors with and without CIPN. Cancer survivors (e.g., ≥3 months post platinum and/or taxane-based neurotoxic chemotherapy) with (i.e., ≥1/4 PRO-CTACE™ Numbness and Tingling Severity) and without CIPN completed the VioScreen Research Graphical Food Frequency Questionnaire. The association among diet (Healthy Eating Index [HEI]), macronutrient intake (average percent caloric intake), and CIPN severity were analyzed using generalized linear regression models, adjusting for caloric intake, body mass index, age, and sex. Results revealed that for each one-point increase in diet quality, PRO-CTCAE severity decreased by −0.06 (95% CI: −0.10, −0.02, P < 0.01). Participants without CIPN reported higher diet quality than those with CIPN (HEI mean: 70.11 vs 68.45) (OR = 0.94, P = 0.03, 95% CI: 0.89, 0.99). Participants with CIPN had significantly higher carbohydrate consumption than participants without CIPN (OR = 1.11, P = 0.04, 95% CI: 1.01, 1.22). There were no significant differences in consumption of proteins or fats between groups. Further research should be pursued to discover the potential benefits of dietary interventions for CIPN management among cancers survivors.

Spinal cord stimulation attenuates paclitaxel-induced gait impairment and mechanical hypersensitivity via peripheral neuroprotective mechanisms in tumor-bearing rats

BackgroundTaxanes such as paclitaxel (PTX) induce dose-dependent chemotherapy-induced peripheral neuropathy (CIPN), which is associated with debilitating chronic pain and gait impairment. Increased macrophage-related proinflammatory activities have been reported to mediate...

Select Minor Cannabinoids from Cannabis sativa Are Cannabimimetic and Antinociceptive in a Mouse Model of Chronic Neuropathic Pain.

Chronic pain conditions affect nearly 20% of the population in the United States. Current medical interventions, such as opioid drugs, are effective at relieving pain but are accompanied by many undesirable side effects. This is one reason increased numbers of chronic pain patients have been turning to Cannabis for pain management. Cannabis contains many bioactive chemical compounds; however, current research looking into lesser-studied minor cannabinoids in Cannabis lacks uniformity between experimental groups and/or excludes female mice from investigation. This makes it challenging to draw conclusions between experiments done with different minor cannabinoid compounds between laboratories or parse out potential sex differences that could be present. We chose five minor cannabinoids found in lower quantities within Cannabis: cannabinol (CBN), cannabidivarin (CBDV), cannabigerol (CBG), Δ8-tetrahydrocannabinol (Δ8-THC), and Δ9-tetrahydrocannabivarin (THCV). These compounds were then tested for their cannabimimetic and pain-relieving behaviors in a cannabinoid tetrad assay and a chemotherapy-induced peripheral neuropathy (CIPN) pain model in male and female CD-1 mice. We found that the minor cannabinoids we tested differed in the cannabimimetic behaviors evoked, as well as the extent. We found that CBN, CBG, and high-dose Δ8-THC evoked some tetrad behaviors in both sexes, while THCV and low-dose Δ8-THC exhibited cannabimimetic tetrad behaviors only in females. Only CBN efficaciously relieved CIPN pain, which contrasts with reports from other researchers. Together these findings provide further clarity to the pharmacology of minor cannabinoids and suggest further investigation into their mechanism and therapeutic potential. SIGNIFICANCE STATEMENT: Minor cannabinoids are poorly studied ligands present in lower levels in Cannabis than cannabinoids like THC. In this study, we evaluated five minor cannabinoids (CBN, CBDV, CBG, THCV, and Δ8-THC) for their cannabimimetic and analgesic effects in mice. We found that four of the five minor cannabinoids showed cannabimimetic activity, while one was efficacious in relieving chronic neuropathic pain. This work is important in further evaluating the activity of these drugs, which are seeing wider public use with marijuana legalization.

Impact on chemotherapy induced peripheral neuropathy of nadunolimab, a first-in-class monoclonal antibody against IL1RAP, in patients with pancreatic cancer, with supportive mouse model data.

4148 Background: Chemotherapy induced peripheral neuropathy (CIPN) is one of the major nonhematological adverse events arising from chemotherapies. CIPN is a neuroinflammatory condition that can be driven by immune cell activation and interleukin-1 (IL-1) release. Nadunolimab is a fully humanized monoclonal IgG1 antibody targeting IL1 receptor accessory protein (IL1RAP). Through binding IL1RAP, nadunolimab can induce ADCC of IL1RAP-expressing tumor cells and inhibits tumor-promoting signals mediated by both IL-1α and IL-1β in the tumor microenvironment. The phase I/IIa CANFOUR trial of nadunolimab in combination with nab-paclitaxel and gemcitabine (GN) in previously untreated, unresectable, locally advanced or metastatic PDAC, showed promising efficacy with median OS: 13.2 months; median iPFS: 7.2 months; 1-year survival: 58% and iORR: 33%, with a good safety profile. Notably, only 1 of 73 patients reported a grade ≥ 3 peripheral neuropathy suggesting that targeting IL1RAP may also alleviate the neuroinflammation leading to CIPN. Methods: To assess the potential neuroprotective activity of nadunolimab, we investigated the impact of nadunolimab on CIPN in the CANFOUR trial where 73 PDAC patients received nadunolimab at 1 mg/kg (n=20), 2.5 mg/kg (n=20), 5 mg/kg (n=25) or 7.5 mg/kg (n=8) in combination with GN. Adverse events were monitored at weekly to biweekly intervals. Relations between study drugs dosing and occurrence, severity and timing of adverse events indicative of CIPN were investigated using exploratory statistical analyses. In mice, CIPN was induced by i.p. administration of vincristine at 0.5 mg/kg, or nab-paclitaxel at 4 mg/kg. The effects of an anti-mouse IL1RAP surrogate antibody (i.p. at 10 mg/kg) on CIPN were evaluated using electronic von Frey apparatus, Parallel Rod Floor apparatus and grip strength meter. Results: Among the 73 PDAC patients in CANFOUR, patients in the individual 2.5 mg/kg, 5 mg/kg and 7.5 mg/kg dose groups all had trends towards lower incidence of onset and longer time to onset of CIPN compared to the 1 mg/kg group. When pooled, patients in the 2.5-7.5 mg/kg dose groups compared to the 1 mg/kg dose group had a lower incidence of any-grade CIPN; 36% vs 60% (Chi-square test p=0.06) and a significantly longer time to onset; median not estimable vs 112 days (hazard ratio=0.48, log-rank p=0.04). In mice, vincristine and nab-paclitaxel caused long-lasting (2 weeks) CIPN. This was abrogated by co-administration of the anti-mouse IL1RAP surrogate antibody, without a negative impact on motor performance, blood values or animal body weight. Conclusions: Data from PDAC patients receiving nadunolimab + GN and experiments in preclinical models suggest that targeting IL1RAP by nadunolimab may combine antitumor activity with potent reduction of CIPN. Clinical trial information: NCT03267316 .

Understanding discordance in systematic reviews for treating chemotherapy-induced peripheral neuropathy: A focused umbrella review.

e24111 Background: Despite the abundance of publications on chemotherapy-induced peripheral neuropathy (CIPN), we are still lacking effective management options. CIPN-focused systematic reviews (SRs) are increasingly encountered but have not aided much in clarifying treatment guidance. Additionally, there is a rising concern that SRs are now over-saturating the clinical literature, leading to redundant and misleading publications. Umbrella reviews (URs) are an attempt to appraise SRs but do not yet have firm methodologic frameworks. The aims of our UR were to appraise the discordance in recently published CIPN SRs and use content analysis as a method for identifying risks of discordance. Methods: This is a focused UR as part of a larger study to characterize the number of efficacy trials for established CIPN. Following PRISMA guidelines, we conducted a systematic literature search of databases MEDLINE, Embase, and Cochrane Library for publications in English from 1/1/2023 to 11/21/2023. Inclusion criteria were published systematic reviews attempting a comprehensive effort to synthesize any treatment outcomes for established CIPN. The AMSTAR 2 framework was used to appraise results for bias. Measures of randomized controlled trial (RCT) overlap are presented using a novel measure of time-adjusted CA, which accounts for RCT publication dates and SR search dates. Grounded theory coding was used for content analysis on efficacy. Results: We identified 18 SRs containing CIPN treatment RCTs published in less than 1 year, resulting in 32 unique CIPN RCTs. Seven SRs assessed exercise interventions, covering 6 exercise RCTs (41% time-adjusted CA). Five SRs assessed acupuncture, with 9 RCTs (50% time-adjusted CA). One SR searched for all CIPN treatments for pain but missed 4 RCTs. One SR was concerning for spurious data. Bias was variable and imperfect across SRs. Contextual analysis identified the themes of SRs combining preventative and treatment RCTs, confusing comparative vs. controlled trials, and frequent use of p-value only reporting to conclude treatment efficacy as major risks of SR discordance. Conclusions: UR was useful in identifying 32 CIPN RCTs that were not comprehensively identified by SRs. We presented a time-adjusted CA measure to indicate concordance percentage. A higher percentage indicates more re-citation of the same RCTs across SRs, with likely better chances of more concordant conclusions. This measure showed that SRs for CIPN treatment are discordant across the topics of exercise and acupuncture interventions. Content analysis revealed multiple potential causes of discordance. However, SR redundancy was helpful for identifying more unique RCTs. CIPN SR content standards should be developed to minimize discordancy and improve clinical applicability. Clinicians should be cautious when applying CIPN SR recommendations given the high discordance.

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.

Acupuncture as a modality of treatment for chemotherapy-induced peripheral neuropathy in breast cancer: A phase 3 randomized controlled trial (ABC-CIPN).

12126 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a major adverse effect in early breast cancer (EBC) and is an unmet need. The study aimed to evaluate the efficacy &amp; safety, of acupuncture on CIPN. Methods: We conducted a prospective, single-center, open-label, phase 3 randomized controlled trial at a tertiary care Indian center. EBC, ≥18 years with ≥grade (gr) 1 CIPN after paclitaxel chemotherapy were block randomized (1:1), &amp; stratified by age (≥/&lt;60 years), to Test (Acupuncture with usual care including pregabalin 75 mg &amp; duloxetine 30 mg, both twice a day per orally, for 4 weeks) &amp; control arm (Usual care alone). Acupuncture was delivered for 12 sessions in gr 1 &amp; 18 sessions in ≥2 CIPN. The primary endpoint was to assess the efficacy of acupuncture in improving QOL as assessed by the sensory score (SS) of QLQ-CIPN20, Pain symptom score (PSS) of QLQ-C30, and total pain score (TPS) by Pain detect scale, and overall QoL by QLQ-C30 at 8 weeks in comparison to baseline (CTRI/2021/01/030480). Results: The median (IQR) age was 50 (43-57) years. Women in test arm in comparison to the control had a significantly higher improvement (decrease) of 26.23 (95% CI 18.52-33.93) versus (Vs) 6.32 (95% CI -1.23 to 13.87) points respectively in CIPN SS at week 8 compared to baseline(least-squares mean difference (LSMD), 19.90 points (95%CI, 11.80-28, P&lt;0.0001). Similarly, patients in test arm had a higher improvement (decrease) of 7.31 (95% CI 5.47-9.13) points Vs 1.12 (95% CI -0.67-2.91) points (LSMD, 6.20 points; 95% CI, 4.30- 8.10; P&lt;0.0001) in TPS of pain detect scale and improvement (decrease) of about 11.56 (95% CI 4.22-18.91) points Vs 3.27 (95% CI -3.93 to 10.47, P=0.0151, in PSS of EORTC QOL-C-30 scale. Additionally, higher improvement (enhanced) in overall QOL, in the test Vs control arm, -7.143(95% CI -13.95 to -0.331) Vs -0.654 (95% CI -7.33 to 6.023); P=0.0020, was noted at week 8. Using the mixed-model approach over the 6 months (secondary end points), average EORTC QLQ-CIPN20 SS was 29.8 (SE, 2.34) in test Vs 38.2 (SE, 2.3) in control arm [difference -8.0 points (95% CI, -14.9 to -1.9; P = 0.0020)]. Average QoL score was 9.71(SE, 0.729) in test Vs 12.21 (SE, 0.716) in control arm [difference 14.3 points (95% CI, 8.2 to 20.5; P = 0.0007)] &amp; average TPS (pain detect) was 18.0 (SE, 2.72) Vs 18.3 (SE, 2.67) [difference -2.5 points (95% CI, -4.5 to -0.5; P=0.0001)] &amp; PSS ( QLQ-C30 scale) was 29.4 (SE, 2.45) Vs 37.2 (SE, 2.41) [ difference -7.8 points (95% CI, -14.6 to -0.9; P=0.0001)] in test Vs control arm respectively. Conclusions: Early breast cancer women with CIPN after (neo) adjuvant taxane therapy experienced a significant and clinically meaningful improvement in taxane induced CIPN related quality of life as a result of an 8 week acupuncture protocol. The results are potentially practice changing and merits consideration as a new standard of care globally in this unmet need. Clinical trial information: CTRI/2021/01/030480.

A randomized phase III clinical trial of acupuncture for chemotherapy-induced peripheral neuropathy treatment (ACT).

TPS12151 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially dose-limiting side effect of neurotoxic chemotherapy among people who experience cancer, presenting pain, numbness, tingling, and motor weakness. CIPN worsens quality of life and disrupts active treatment regimens. Currently, duloxetine is the only ASCO-recommended painful CIPN treatment after chemotherapy completion. Still, it has undesirable side effects, i.e., fatigue, sleep disturbance, and digestive symptoms, posing a pressing need for well-tolerated, evidence-based interventions. Our pilot study demonstrated the feasibility and preliminary efficacy of acupuncture in relieving CIPN pain. Based on that, we developed the ACT trial to evaluate the effect of acupuncture on improving pain and other related symptoms among cancer survivors with CIPN pain. Methods: ACT is a prospective phase III multicenter, parallel two-arm randomized clinical trial at Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering Cancer Center (MSK) (ClinicalTrials.gov Identifier: NCT04917796). ACT aims to determine the efficacy of an eight-week electroacupuncture (EA) treatment vs. sham acupuncture (SA) on improving CIPN symptoms severity in cancer survivors. We plan to enroll 250 participants to detect an effect size of at least 0.45 for the primary pain outcome at 12 weeks post-randomization between EA vs. SA, with 80% power and a 1% Type I error rate, assuming a 10% loss to follow-up. Major eligibility criteria include 1) adults who have no evidence of disease or stable diseases, 2) who have completed neurotoxic chemotherapy such as platinum agents, taxanes, vinca alkaloids, and bortezomib at least three months before enrollment, and 3) who have a clinical diagnosis of CIPN with moderate to severe pain, defined as a score of at least four on the Brief Pain Inventory (BPI) average pain item. We randomly allocate participants to receive ten real or sham acupuncture treatments over eight weeks at two centers and their regional clinics. Aside from patient-reported outcome measures (i.e., BPI, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity, EORTC Quality of Life Questionnaire-CIPN 20), we conduct quantitative sensory testing to assess changes in sensory function. The primary study endpoint is week 12, and the secondary study endpoint is week 24. Progress: 1) We are currently transitioning this trial to a multicenter trial, with DFCI being the coordinating center and MSK a subsite; 2) As of January 18, 2024, a total of 133 of the planned 250 participants have been enrolled; 3) The DSMB last reviewed the trial in December 2023, and suggested that the trial continue as planned at MSK. We anticipate initiating participant enrollment at DFCI in February 2024. Accrual completion is expected by December 2024. Clinical trial information: NCT04917796 .

Acupuncture for preventing progression of taxane-induced peripheral neuropathy (ATP): A phase II randomized, placebo-controlled trial.

TPS12154 Background: Chemotherapy-induced peripheral neuropathy (CIPN) from chemotherapy drugs such as taxanes can be detrimental to cancer survival, increasing the risk of falls and worsening physical functions. The current management of worsening and persistent CIPN during chemotherapy is dose reduction or discontinuation of chemotherapy. There is no effective treatment or preventative measure for CIPN. Methods: Trial design: The ATP trial is a two-arm, parallel, randomized controlled trial comparing weekly real acupuncture (RA) versus sham acupuncture (SA) during preplanned curative intent taxane containing regimens in patients with breast cancer. Eligibility criteria: English or Spanish-proficient; aged ≥18 years; histological diagnoses of invasive carcinoma of the breast; and plan to receive curative intent chemotherapy regimen containing paclitaxel or nab-paclitaxel weekly or biweekly as standard of care, developed CIPN grade ≥1 based on the NCI-CTCAE version 5.0, while receiving taxane; ≥ four weeks of paclitaxel or nab-paclitaxel weekly or biweekly planned, as standard of care and at treating physician’s discretion; willing to adhere to requirement that no new pain medication or dose changes be taken throughout the first 12 weeks of the study period; and willing to adhere to all study-related procedures. Specific aims: The primary aim is to evaluate the effectiveness of RA versus SA in preventing taxane-induced peripheral neuropathy progression as measured by Neuropathic Pain Scale (NPS) in patients with early-stage breast cancer who are receiving curative intent neurotoxic chemotherapy. The secondary aim is to evaluate the effectiveness of RA versus SA on chemotherapy relative dose intensity (RDI) and CIPN-related chemotherapy discontinuation. Statistical methods: We will randomize 80 patients, 40 to each arm. All randomized patients will be evaluable in the Intent to Treat (ITT) analyses because all will have completed the baseline assessment before randomization. We will use a linear mixed model (LMM) to compare the change in NPS between the arms from baseline to week 4. Based on our pilot data, a difference in CIPN grade from 1 to 2 corresponded to a difference in NPS from 12 to 22, a difference of ten points in 27 patients. The NPS standard deviation (SD) in patients with grade 1 CIPN was 17. With 80 patients we will have 80% power to detect a difference between arms as small as 10 points on the NPS, assuming a one-sided test, type I error of 5%, correlation between baseline and follow-up measurements of 0.5, SD of 17, and 15% attrition at week 4. Present accrual and target accrual: We accrued 43 participants in the intervention phase by the end of January 2024; the target accrual is 80 participants. Clinical trial information: NCT05458284 .

Prospective, randomized trial on efficacy and safety of cryotherapy and cryocompression therapy as prevention of chemotherapy-induced peripheral neuropathy.

1079 Background: As constant advancements in cancer therapy were able to improve overall survival for gynecological cancers drastically, impact on patients’ quality of life (QoL) and longtime effects of therapy gain importance in treatment planning. Chemotherapy-induced peripheral neuropathy (CIPN) is one the most detrimental side effects of taxane-based chemotherapy (CT). According to recent literature up to 87% of patients receiving taxane-based CT suffer from CIPN grade two or above. Symptoms include sensory and motor deficits, which often lead to dose reduction or discontinuation of the taxane-based CT. Some studies with small patient populations indicated that adding compression to cryotherapy could increase its preventative effect regarding CIPN. The aim of our randomized study was to evaluate whether compression added to cryotherapy could improve the efficacy in the prevention of CIPN. Methods: This prospective randomized study was conducted between May 2020 and January 2023 at the Department of Obstetrics and Gynecology, Medical University of Innsbruck. Patients who met the inclusion criteria were randomized 1:1 to either receive cryotherapy or cryocompression therapy on their upper extremity during CT. We performed a wide range of tests and assessments during their course of treatment and follow-up, that lasted up to 9 months. Tests included temperature measurements, two QoL questionnaires and neurological tests like nerve conduction velocity and sensory tests. Results: A total of 200 participants were recruited for this study. At their end of CT assessment 13.7% of participants in the cryotherapy group (C) had grade two polyneuropathy. In comparison, in the cryocompression therapy group (CC) there were 17.2% with grade two polyneuropathy. Six to nine months after CT, in the C 14.7% of participants presented with grade two polyneuropathy, compared to 21.8% in the CC. There was no significant difference between the two groups regarding occurrence of grade two or above polyneuropathy. In the C 11.3% of participants discontinued therapy and in the cryocompression therapy group CC 23.7% did so. No participants discontinued the study due to adverse events caused by cryotherapy or cryocompression therapy. In both groups a significant reduction of temperature was observed. With regards to the neurological tests and QoL questionnaires, there was no significant difference between the two groups. Conclusions: The trial did not demonstrate superiority of cryocompression over cryotherapy. Compared to recent literature participants treated with cryotherapy as well as cryocompression therapy developed substantially less CIPN. Our study suggests that cryotherapy as well as cryocompression therapy is a safe way to cool patients’ extremities to prevent CIPN. Clinical trial information: NCT04632797 .

A randomized phase III clinical trial of yoga for chemotherapy-induced peripheral neuropathy treatment (YCT).

TPS12152 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is common and debilitating among cancer survivors receiving neurotoxic chemotherapy, which can cause functional disabilities and significantly increase the risk of falls. There are limited approaches to managing CIPN symptoms and related functional limitations. Our pilot study demonstrated yoga therapy's feasibility and preliminary efficacy in improving CIPN pain and functional outcomes. We developed the YCT trial to assess the effect of yoga therapy on improving pain and balance symptoms among cancer survivors with CIPN pain. Methods: YCT is a prospective phase III multicenter, parallel three-arm randomized clinical trial at Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering Cancer Center (MSK) (ClinicalTrials.gov Identifier: NCT05121558). YCT aims to determine the efficacy of an eight-week yoga treatment vs. education control (EC) vs. usual care (UC) in improving CIPN pain and balance in cancer survivors. We plan to enroll and randomize 268 participants (2:1:1) to yoga, EC, and UC groups to detect an effect size of at least 0.48 for the primary pain outcome at eight weeks post-randomization between yoga vs. EC, with 80% power and a 2.5% Type I error rate, assuming 12% attrition by week 8 and 20% attrition by week 24. Major eligibility criteria include 1) adults who have no evidence of disease or stable diseases, 2) who have completed neurotoxic chemotherapy such as platinum agents, taxanes, vinca alkaloids, and bortezomib at least three months before enrollment, 3) who have a clinical diagnosis of CIPN with moderate to severe pain, defined as a score of at least four on the Brief Pain Inventory (BPI) average pain item, and 4) who experience self-identified CIPN balance difficulty. Eligible subjects in the yoga arm will receive hourly gentle therapeutic yoga classes taught by protocol-trained oncology yoga instructors, twice weekly for eight weeks, and practice home-based yoga. Subjects in the EC arm will receive hourly education classes taught by protocol-trained healthcare instructors twice weekly for eight weeks. Subjects in the UC arm will continue usual care for eight weeks. We offer free yoga sessions for participants in control groups after study completion. Aside from patient-reported outcome measures (i.e., BPI, FACT/GOG-Ntx, QLQ-CIPN 20), we measured functional improvements by functional reach, timed up-and-go, and chair-to-stand tests. We also conducted quantitative sensory testing to assess changes in sensory function. Progress: 1) We are transitioning this trial to a multicenter trial, with DFCI being the coordinating center and MSK a subsite; 2) As of January 18, 2024, 104 of the planned 268 participants have been enrolled. We anticipate initiating participant enrollment at DFCI in February 2024. Anticipated accrual completion: March 2025. Clinical trial information: NCT05121558 .

Chemotherapy-Induced Peripheral Neuropathy and Falls in Cancer Survivors Relate to Digital Balance and Gait Impairments.

Chemotherapy-induced peripheral neuropathy (CIPN) and falls can be persistent side effects of cancer treatment. Standing postural sway and gait tests with body-worn, inertial sensors provide objective digital balance and gait measures that represent several different domains controlling mobility. Specific domains of balance and gait that related to neuropathy and falls are unknown. The aim of this study was to determine which domains of balance and gait differed between cancer survivors who report (1) CIPN symptoms versus no symptoms, (2) a history of falls in the past 6 months versus no falls, and (3) prospective falls over 12 months versus no falls. Postural sway during 30 seconds of quiet standing and gait characteristics from a 7-m timed up and go test were recorded with six synchronized inertial sensors (Opals by APDM Wearable Technologies, a Clario Company) in 425 older, female cancer survivors (age: 62 ± 6 years). A principal component analysis (PCA) approach was used to identify independent domains of mobility from 15 balance and gait measures. PCA analysis revealed five independent domains (PC1 = sway amplitude, PC2 = gait pace, PC3 = sway frequency, PC4 = gait spatial-temporal, and PC5 = turning) that accounted for 81% of the variance of performance. Cancer survivors who reported CIPN symptoms had significantly higher sway frequency (PC3) than asymptomatic survivors. Past fallers had significantly larger sway area (PC1) and slower gait pace (PC2) than nonfallers. Prospective fallers showed a significantly smaller stride length (PC4) than nonfallers. Digital balance and gait measures using wearable sensors during brief standing and walking tests provide objective metrics of CIPN-related mobility impairment and fall risk that could be useful for oncology clinical trials.

A single-center retrospective review of the impact of cryotherapy on peripheral neuropathy scores in patients with breast cancer who received chemotherapy with a taxane-based treatment regimen.

e24106 Background: Taxanes are a class of chemotherapy frequently used for neoadjuvant and adjuvant treatment of breast cancer. While effective, taxane use is not without adverse effects, the most well-known being chemotherapy-induced peripheral neuropathy (CIPN). As CIPN is dose-related, it can lead to dose reductions and interruptions in therapy that may be detrimental to the patient. Cryotherapy has been used as a prevention strategy, but its efficacy remains unclear. Methods: We performed a retrospective review of the cryotherapy program in our center. Included patients had breast cancer of any stage treated with a taxane in the neoadjuvant or adjuvant setting. All patients were offered cryotherapy at the time of their treatment and were separated into cohorts whether they opted in or out (“cryotherapy” and “non cryotherapy,” respectively). Neuropathy scores were collected by nursing staff via survey and scaled from 0-4. Patient demographics and neuropathy scoring were compared between the “cryotherapy” and “non cryotherapy” cohorts. Results: In total, 41 patients were included. Nearly half of patients in each cohort experienced neuropathy, 10 patients (41.7%) treated with cryotherapy and 8 patients (47.1%) without cryotherapy use. Younger age (46.5 years vs 57 years, p = 0.060), and patients using Medicaid (35.3% vs 75.0%, when compared to all other insurance types, p = 0.023) predicted cryotherapy use. Use of paclitaxel also predicted cryotherapy used when compared to docetaxel (76.0% and 31.2%, respectively, p = 0.009). There was not a significant difference in predicted neuropathy score between the cohorts (Adjusted Multiplicative Effect = .81, 95% CI = .34-1.96, p = .645). Conclusions: Our data did not suggest that the use of cryotherapy could predict lower neuropathy scores, but our study suffered from small sample size and short-duration of follow-up. Additional large, randomized trials with standard neuropathy scoring scales are needed to better evaluate the efficacy of cryotherapy in prevention of CIPN for breast cancer patients receiving taxane-based therapy.

New drugs to prevent oxaliplatin-induced peripheral neuropathy: A double-blind, randomized study.

3568 Background: Postoperative adjuvant chemotherapy for colorectal cancer reduces postoperative recurrence; however, it often causes undesirable adverse events. Oxaliplatin, the mainstay of postoperative adjuvant chemotherapy is particularly likely to cause chemotherapy-induced peripheral neuropathy (CIPN) and hypersensitivity reactions (HSR) that may make it difficult to continue treatment. Various agents have been tested for prevention or treatment of CIPN caused by oxaliplatin, but none have proven effective. Reactive oxygen species contribute oxaliplatin-induced PN; therefore, super oxide dismutase (SOD) could potentially suppress them, but its very short serum half-life has made clinical application difficult. We developed a lecithinized human copper/zinc SOD (Cu/Zn-SOD) (PC-SOD) in which four phosphatidylcholine derivative molecules are bound covalently to each SOD dimer. Compared with SOD, PC-SOD enhanced stability in plasma and stronger tissue affinity, and exerts therapeutic effects in animal models of several diseases, including CIPN. Methods: This double-blind, randomized study included 90 patients with stage II/III colorectal cancer. All patients were slated to receive 12 cycles of mFOLFOX6. In each cycle, patients received PC-SOD or a placebo immediately before oxaliplatin. The primary endpoint of this study was the number of cycles before NCI-CTCAE Grade 2 (G2) CIPN occurred. One of the secondary endpoints was the number of cycles before DEB-NTC G2 PN occurred. Results: Forty-three patients received PC-SOD. No serious adverse events were observed that could be related to PC-SOD. The incidence of neutropenia, diarrhea, stomatitis, and malaise were lower in the study group, but the differences were not significant. Additionally, 3 patients (7.0%) in the study group and 11 (23.4%) in the placebo group had HSR. Although there was no difference in the number of cycles between the two groups until NCI-CTCAE G2 PN occurred, the study group had a significantly greater number of cycles before DEB-NTC G2 PN compared to the placebo group (P=0.08). The study group had a significantly greater number of cycles before NCI-CTC G1 PN (P=0.01) and HSR (P=0.03) compared to the placebo group. The number of cycles before HSR or NCI-CTCAE G2 PN occurred was greater in the study group , but the difference was not significant. The average total oxaliplatin dose was higher in the study group but the difference was not statistically significant. Conclusions: The primary endpoint did not occur; however, the study group had a significantly greater number of cycles before DEB-NTC G2 PN. Notably, the study group also had a significantly greater number of cycles before HSR. These results show that PC-SOD may suppress HSR as well as PN, both of which limit administration of oxaliplatin. Thus, this drug is expected to improve not only patient quality of life, but also the prognosis of patients. Clinical trial information: 2031210466.

Prazosin as an Adjuvant to Increase Effectiveness of Duloxetine in a Rat Model of Oxaliplatin-Induced Peripheral Neuropathy

ObjectivesDuloxetine, the only American Society of Clinical Oncology (ASCO) treatment recommended for chemotherapy-induced peripheral neuropathy (CIPN) in cancer survivors, is not effective for 40% of survivors. This study examined the ability of a duloxetine-prazosin combination to prevent the development of allodynia and hyperalgesia in a rat model of oxaliplatin-induced peripheral neuropathy (OPIN). MethodsFemale (n = 24) and male (n = 41) rats were started on duloxetine (15 mg), prazosin (2 mg), or a duloxetine-prazosin combination one week prior to administration of the chemotherapy drug, oxaliplatin, and continued the duloxetine-prazosin combination for 32 days. Behavioral testing for mechanical allodynia and mechanical hyperalgesia was done with selected von Frey filaments over the course of the study. ResultsOverall percent paw withdrawal for rats that received the duloxetine-prazosin combination was significantly lower in female (p < .001 for both conditions) and male (p = .029 for allodynia; p < .001 for hyperalgesia) than those that received water. No significant posttreatment differences were found for allodynia or hyperalgesia between rats treated with duloxetine and rats that received the duloxetine-prazosin combination in either sex. ConclusionsThese finding provide preliminary evidence that a duloxetine-prazosin combination can prevent the posttreatment development of allodynia and hyperalgesia in both male and female rats; however, the results suggest that the duloxetine-prazosin combination is no more efficacious than duloxetine alone in preventing chronic OIPN. Implications for Nursing PracticeThe profession of nursing is built on clinical practice supported by scientific research. The current study addressed the clinical practice problem of prevention and management of painful OIPN, which is a priority area in oncology nursing.