Management Of Chemotherapy-induced Peripheral Neuropathy Research Articles

Centralizing the Knowledge and Interpretation of Pain in Chemotherapy-Induced Peripheral Neuropathy: A Paradigm Shift towards Brain-Centric Approaches

Chemotherapy-induced peripheral neuropathy (CIPN) is a side effect of cancer treatment, often linked with pain complaints. Patients report mechanical and thermal hypersensitivity that may emerge during chemotherapy treatment and may persist after cancer remission. Whereas the latter situation disturbs the quality of life, life itself may be endangered by the appearance of CIPN during cancer treatment. The causes of CIPN have almost entirely been ascribed to the neurotoxicity of chemotherapeutic drugs in the peripheral nervous system. However, the central consequences of peripheral neuropathy are starting to be unraveled, namely in the supraspinal pain modulatory system. Based on our interests and experience in the field, we undertook a review of the brain-centered alterations that may underpin pain in CIPN. The changes in the descending pain modulation in CIPN models along with the functional and connectivity abnormalities in the brain of CIPN patients are analyzed. A translational analysis of preclinical findings about descending pain regulation during CIPN is reviewed considering the main neurochemical systems (serotoninergic and noradrenergic) targeted in CIPN management in patients, namely by antidepressants. In conclusion, this review highlights the importance of studying supraspinal areas involved in descending pain modulation to understand the pathophysiology of CIPN, which will probably allow a more personalized and effective CIPN treatment in the future.

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 .

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 .

Abstract PO1-20-03: Acupuncture for Preventing Progression of Taxane-Induced PeripheralNeuropathy (ATP): A Phase II Randomized, Placebo Controlled Trial

Abstract 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. However, there is no effective treatment or preventative measure for CIPN. The current management of worsening and persistent CIPN during chemotherapy is dose reduction or discontinuation of chemotherapy. Our group previously completed a single-arm phase IIA pilot trial of women who developed National Cancer Institution Common Terminology Criteria for Adverse Events (NCI-CTCAE) grade 2 CIPN during weekly paclitaxel for stage I-III breast cancer. The result suggested an acupuncture intervention for grade 2 CIPN might slow CIPN progression during chemotherapy. However, the role of acupuncture still needs to be better defined. 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. The study will include two phases: screening and intervention. In the screening phase, eligible patients will consent and receive CIPN screening each week. Patients who develop grade 1 CIPN or higher based on NCI-CTCAE version 5.0 will be consented to the intervention phase and randomized to receive either weekly RA or SA using a standardized, semi-fixed protocol developed in our preliminary studies to improve CIPN pain. Eligibility criteria for the screening phase: 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. Eligibility criteria for the intervention phase: in additional to the screening phase eligibility criteria, 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, including randomization to one of the two possible acupuncture treatments. 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 20 participants in the intervention phase by the end of June 2023; the target accrual is 80 participants. Contact information for people with a specific interest in the trial: W. Iris Zhi, MD, PhD, zhiw@mskcc.org. ClinicalTrails.gov Identifier: NCT05458284. Citation Format: W. Iris Zhi, Lauren Taylor, Raymond Baser, Matthew Weitzman, Qing Li, Christina Seluzicki, Ting Bao, Jun Mao. Acupuncture for Preventing Progression of Taxane-Induced PeripheralNeuropathy (ATP): A Phase II Randomized, Placebo Controlled Trial [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 PO1-20-03.

Exercise intervention for the management of chemotherapy-induced peripheral neuropathy: a systematic review and network meta-analysis.

Although exercise is recommended for cancer survivors with chemotherapy-induced peripheral neuropathy (CIPN), the effective types of exercise for preventing and treating CIPN remain unclear. This systematic review and network meta-analysis (NMA) aimed to evaluate the comparative effects of exercise on CIPN. We included relevant randomized controlled trials (RCTs) identified in a 2019 systematic review that evaluated the effects of exercise on CIPN and conducted an additional search for RCTs published until 2023. We evaluated the risk of bias for each RCT; the comparative effectiveness of exercise on patient-reported quality of life (QOL) through an NMA; and the effectiveness of exercise on QOL scores, patient-reported CIPN symptoms, and pain through additional meta-analyses. Twelve studies (exercise, n = 540; control, n = 527) comparing 8 exercise interventions were included in the analysis. All studies were determined to have a high risk of bias. The meta-analyses showed significantly improved QOL [standard mean differences (SMD) 0.45; 95% confidence interval (CI) = 0.12 to 0.78] and CIPN symptoms (SMD 0.46; 95% CI = 0.11 to 0.82). No severe adverse events were reported. Pain tended to improve with exercise (SMD 0.84; 95% CI = -0.11 to 1.80). An NMA suggested that the interventions of a combination of balance and strength training showed a significant improvement in QOL scores compared to the control. Exercise interventions may be beneficial for improving QOL and CIPN symptoms. High-quality large clinical trials and data are needed to conclude that exercise is beneficial and safe.

Neuroprotective Effect of Polyvalent Immunoglobulins on Mouse Models of Chemotherapy-Induced Peripheral Neuropathy.

The occurrence of neuropathic pain in chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting effect of many commonly-used anticancer agents. Polyvalent human immunoglobulins (hIg), used in the treatment of several peripheral neuropathies, may alleviate neuropathic pain. The aim of this project was to investigate the preventive effect of hIg in two mouse models of CIPN, induced by vincristine (VCR, 100 µg/kg/d) and oxaliplatin (OXP, 6 mg/kg/3d). Human Ig were administered one day before the first injection of chemotherapy. The onset of CIPN and effects of hIg were assessed via functional tests and morphological analyses of sensory nerves. To evaluate the effect of hIg on chemotherapy cytotoxicity, viability assays were performed using hIg (0 to 12 mg/mL) combined with anticancer agents on human cancer cell lines. The preventive treatment with hIg alleviated tactile hypersensitivity and nerve injuries induced by VCR. It also alleviated tactile/cold hypersensitivities and nerve injuries induced by OXP. Treatment with hIg did not affect the cytotoxicity of either chemotherapy. Furthermore, in combination with VCR, hIg potentiated chemo-induced cell death. In conclusion, hIg is a promising therapy to prevent the onset of CIPN and potentiate chemotherapy effect on cancer, reinforcing the interest in hIg in the management of CIPN.

αO-Conotoxin GeXIVA[1,2] Reduced Neuropathic Pain and Changed Gene Expression in Chronic Oxaliplatin-Induced Neuropathy Mice Model.

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting painful neuropathy that occurs commonly during cancer management, which often leads to the discontinuation of medication. Previous studies suggest that the α9α10 nicotinic acetylcholine receptor (nAChR)-specific antagonist αO-conotoxin GeXIVA[1,2] is effective in CIPN models; however, the related mechanisms remain unclear. Here, we analyzed the preventive effect of GeXIVA[1,2] on neuropathic pain in the long-term oxaliplatin injection-induced CIPN model. At the end of treatment, lumbar (L4-L6) spinal cord was extracted, and RNA sequencing and bioinformatic analysis were performed to investigate the potential genes and pathways related to CIPN and GeXIVA[1,2]. GeXIVA[1,2] inhibited the development of mechanical allodynia induced by chronic oxaliplatin treatment. Repeated injections of GeXIVA[1,2] for 3 weeks had no effect on the mice's normal pain threshold or locomotor activity and anxiety-like behavior, as evaluated in the open field test (OFT) and elevated plus maze (EPM). Our RNA sequencing results identified 209 differentially expressed genes (DEGs) in the CIPN model, and simultaneously injecting GeXIVA[1,2] with oxaliplatin altered 53 of the identified DEGs. These reverted genes were significantly enriched in immune-related pathways represented by the cytokine-cytokine receptor interaction pathway. Our findings suggest that GeXIVA[1,2] could be a potential therapeutic compound for chronic oxaliplatin-induced CIPN management.

Targeting therapy-induced senescence as a novel strategy to combat chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a treatment-limiting adverse effect of anticancer therapy that complicates the lifestyle of many cancer survivors. There is currently no gold-standard for the assessment or management of CIPN. Subsequently, understanding the underlying mechanisms that lead to the development of CIPN is essential for finding better pharmacological therapy. Therapy-induced senescence (TIS) is a form of senescence that is triggered in malignant and non-malignant cells in response to the exposure to chemotherapy. Recent evidence has also suggested that TIS develops in the dorsal root ganglia of rodent models of CIPN. Interestingly, several components of the senescent phenotype are commensurate with the currently established primary processes implicated in the pathogenesis of CIPN including mitochondrial dysfunction, oxidative stress, and neuroinflammation. In this article, we review the literature that supports the hypothesis that TIS could serve as a holistic mechanism leading to CIPN, and we propose the potential for investigating senotherapeutics as means to mitigate CIPN in cancer survivors.

Safety and efficacy of cannabidiol in the management of chemotherapy-induced peripheral neuropathy.

12020 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting complication of cancer treatment that can negatively impact survival and quality of life. Cannabidiol (CBD) has been shown to attenuate CIPN in rodent models although its ability to reduce CIPN symptoms in humans is unexplored. Methods: A phase 3 randomized double-blind, placebo-controlled clinical trial was conducted between 6/1/2020 and 8/8/2022. Participants with nonmetastatic breast, colorectal, endometrial, and ovarian cancer (all stages) experiencing grade 2-3 CIPN (duration ≤ 2 years) were enrolled after completing taxane or platin-based chemotherapy. They were randomized into active and placebo groups, and followed x 16 weeks. The active group received 135 mg/day of CBD, provided as hemp-based whole plant extract in gelcaps, while placebo consisted of coconut oil gelcaps, delivered x 12 weeks. Participants were evaluated every 2 weeks using the EORTC QLQ-CIPN20, which assesses three categories of symptoms: sensory (numbness, tingling, pain), motor (weakness, difficulty walking), and autonomic (blurriness, hearing loss). Side effect and safety data were logged daily. Results: Of 230 participants with CIPN identified, 124 met eligibility, 54 consented and enrolled, and 46 completed ≥8 of the 12-week treatment phase and were included in the analysis. Mean age was 59.6 years; 89.1% were female. Of those participants, 63% had breast cancer, 19.6% colorectal, 15.2% ovarian, and 2.2% uterine. CIPN20 scores were summated and standardized. With placebo as the reference group, main effects for sensory and motor scales were adjusted for time from enrollment and baseline CIPN grade. Participants receiving CBD had greater improvement of sensory function (p=0.048), with reduced numbness and tingling, but without significant pain reduction (p=.282) or change in motor function (p=.158) vs placebo. No autonomic changes were observed. CBD was well tolerated without serious adverse events. Conclusions: CBD reduced numbness/tingling and improved sensory function vs. placebo, as assessed by the CIPN20 scale. These symptoms are among the most common and challenging symptoms of CIPN, for which there are limited available treatment options. However, CBD did not affect pain and motor function. Thus, this preliminary study provides evidence that CBD, dosed at 135 mg/day, might serve as a treatment for some CIPN symptoms without serious adverse events. Further research is needed to confirm these results and to assess the safety and efficacy of CBD combined with chemotherapy to prevent or attenuate CIPN. Such an advance could deliver a survival benefit by helping more people complete and better tolerate chemotherapy. Clinical trial information: NCT04398446 . [Table: see text]

Effect of proprioceptive neuromuscular facilitation technique and TENS on improving lower limb sensorimotor function, balance and quality of life in chemotherapy induced peripheral neuropathy in gynecological cancer: A randomized controlled trial protocol

Gynecological cancers are the most prevalent cancers in women, making it a significant public health concern. Chemotherapy drugs are an extremely effective approach for reducing cancer progression since they have various targets and mechanism of action focused at killing quickly multiplying cancer cells. Unfortunately, these drugs also affect normal cells and structures of the body, resulting in a variety of deleterious effects. Most common among them is chemotherapy induced peripheral neuropathy (CIPN). Taxanes, platinum medicines, vinca alkaloids and thalidomide are examples of popular pharmaceuticals that are prone to cause CIPN. When CIPN develops during active chemotherapy phase, it may result in the discontinuation or reduction of chemotherapy dose, which may render the dosage ineffective in cancer management. As a result, it is essential that physiotherapists investigate novel approaches to successfully manage the side effects that survivors must deal with. Here’s the idea we suggest by conducting a study which aim to assess the effectiveness of Proprioceptive Neuromuscular Facilitation Technique (PNF) with Transcutaneous Electrical Nerve Stimulation (TENS) and closed kinetic chain exercises with TENS on subjects with CIPN in Gynecological Cancer in two arm parallel superiority randomized control trial (RCT) on improving lower limb sensorimotor function, balance & quality of life. The total participants in the study will be divided into two equal groups and then the intervention will be given for 8 weeks to both the groups with 5 days in a week with 50 minute session each day. The results will be evaluated after 8 weeks of treatment and 3 weeks after completion of intervention for follow up. If the hypothesis of our study proves to be effective, this physiotherapy intervention could be included in management of CIPN. Along with it, it will help in reducing the rate of discontinuation of chemotherapy dose due to neuropathy.

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

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

Neurofilament light as a predictive biomarker of unresolved chemotherapy-induced peripheral neuropathy in subjects receiving paclitaxel and carboplatin

Management of chemotherapy-induced peripheral neuropathy (CIPN) remains a significant challenge in the treatment of cancer. Risk mitigation for CIPN involves preemptive reduction of cumulative dose or reduction of dose intensity upon emergence of symptoms, despite the risk of reduced tumor efficacy. A predictive biomarker for dose-limiting CIPN could improve treatment outcomes by allowing providers to make informed decisions that balance both safety and efficacy. To identify a predictive biomarker of CIPN, markers of neurodegeneration neurofilament-light (NfL), glial fibrillary acidic protein (GFAP), tau and ubiquitin c-terminal hydrolase L1 (UCHL1) were assessed in serum of up to 88 subjects drawn 21 days following the first of 6 treatments with chemotherapeutics paclitaxel and carboplatin. Serum NfL and GFAP were increased with chemotherapy. Further, NfL change predicted subsequent onset of grade 2–3 CIPN during the remainder of the trial (mean treatment duration = 200 days) and trended toward stronger prediction of CIPN that remained unresolved at the end of the study. These results confirm previous reports that serum NfL is increased in CIPN and provide the first evidence that NfL can be used to identify subjects susceptible to dose-limiting paclitaxel and carboplatin induced CIPN prior to onset of symptoms.

Emerging Approaches for the Management of Chemotherapy-Induced Peripheral Neuropathy (CIPN): Therapeutic Potential of the C5a/C5aR Axis.

Chemotherapy-induced peripheral neuropathy (CIPN) is the most common neurologic complication of chemotherapy, resulting in symptoms like pain, sensory loss, and numbness in the hands and feet that cause lots of uneasiness in patients with cancer. They often suffer from pain so severe that it interrupts the treatment, thus invalidating the entire chemotherapy-based healing process, and significantly reducing their quality of life. In this paper, we underline the role of the complement system in CIPN, highlighting the relevance of the C5a fragment and its receptor C5aR1, whose activation is thought to be involved in triggering a cascade of events that can lead to CIPN onset. Recent experimental data showed the ability of docetaxel and paclitaxel to specifically bind and activate C5aR1, thus shining light on one of the molecular mechanisms by which taxanes may activate a cascade of events leading to neuropathy. According to these new evidence, it was possible to suggest new mechanisms underlying the pathophysiology of CIPN. Hence, the C5a/C5aR1 axis may represent a new target for CIPN treatment, and the use of C5aR1 inhibitors can be proposed as a potential new therapeutic option to manage this high unmet medical need.

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.

Comparative Efficacy of Tapentadol versus Tapentadol Plus Duloxetine in Patients with Chemotherapy-Induced Peripheral Neuropathy (CIPN): A Randomized Non-Inferiority Clinical Trial.

Simple SummaryChemotherapy-induced peripheral neuropathy (CIPN) is a common complication due to treatment with anti-cancer agents. Our aim was therefore to assess the non-inferiority of the analgesic effect and safety of tapentadol alone compared to duloxetine plus tapentadol administered to patients with chemotherapy-induced peripheral neuropathy. The use of tapentadol is a safe and effective analgesic therapy in patients with CIPN. Positive effects of tapentadol were noted on the patients’ quality-of-life assessments.Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a common complication due to treatment with many commonly used anti-cancer agents. CIPN is a mainly sensory neuropathy that can be characterized by the appearance of motor and autonomic alterations. Clinicians may offer duloxetine (DLX) for patients with cancer experiencing CIPN. Our aim was to assess the non-inferiority of the analgesic effect and safety of tapentadol (TP) alone compared to duloxetine plus tapentadol administered to patients with CIPN. Methods: A total of 114 patients were enrolled in the study and randomized to receive tapentadol in a dosage of 50 to 500 mg/day (n = 56) or tapentadol plus duloxetine in a dosage of 60 to 120 mg/day (n = 58) for a period of 4 weeks. We evaluated the analgesia efficacy, defined as a decrease in pain on the NRS between the first administration and 28 days later. Secondary endpoints included analgesia efficacy at 28 and 42 days, defined by a decrease in DN4 and LEPs, decrease in quality of life, and the incidence of any serious or non-serious adverse events after the first administration. Results: In this randomized, double-blind trial comparing TP and TP plus DLX for CIPN management, TP was feasible and non-inferior to the association with DLX as far as the reduction of pain after chemotherapy at 28 days is concerned. Scores on other rating scales evaluating the quality of life, anxiety and depression, and the characteristics of pain revealed similar improvements associated with tapentadol versus duloxetine at these time points. Conclusion: The use of TP is a safe and effective analgesic therapy in patients with CIPN. Positive effects of TP were noted on the patients’ quality-of-life assessments.

Exploring Patients' Understanding of Chemotherapy-Induced Peripheral Neuropathy.

Little quantitative evidence exists surrounding patients' level of understanding of chemotherapy-induced peripheral neuropathy (CIPN) symptoms (numbness, tingling, pain in the hands/feet) and consequences (e.g., negatively affect physical functioning or chemotherapy dosing) at the beginning of chemotherapy. The purpose of this cross-sectional, secondary analysis was to describe CIPN knowledge and education patterns among adults early in a course of neurotoxic chemotherapy for the treatment of cancer (< three infusions). Following consent, participants completed an electronic questionnaire about their perceptions of CIPN symptoms, incidence, and education. Participants (N = 92) were mainly female (76%), white (91%), and diagnosed with breast (46%) or gastrointestinal (40%) cancers. Most participants without CIPN (n = 48) did not expect to develop CIPN (45%) or were unaware of CIPN as a side-effect (30%). Furthermore, 71% of participants without CIPN (n = 31) estimated CIPN to occur in ≤ 30% of patients receiving neurotoxic chemotherapy. Overall, participants learned about CIPN from their doctor or nurse prior to beginning chemotherapy (90%). Clinicians delivered education about CIPN symptoms (75%), but less frequently delivered education about CIPN management (14%), or the impact of CIPN on the ability to continue chemotherapy (16%) or physical functioning (24%). Finally, participants reported that a discussion with their doctor/nurse would be the best way to learn about CIPN (92%). Results revealed that participants without CIPN were largely unaware of the adverse consequences or incidence of CIPN during treatment. Further research is needed to investigate optimal methods to promote patient-clinician communication about CIPN during chemotherapy to enhance patients' retention of CIPN information and activation in their care.

Evaluating the safety, feasibility, and efficacy of non-invasive neuromodulation techniques in chemotherapy-induced peripheral neuropathy: A systematic review

This systematic review was conducted to evaluate the best available evidence regarding the use of non-invasive neuromodulation techniques for managing chemotherapy-induced peripheral neuropathy (CIPN). A systematic literature search of the following databases from their inception to October 17, 2021 was performed and was updated on March 2, 2022: AMED via Ovid, CINAHL via the EBSCO Host, Cochrane Library, Embase, PEDro, PubMed, and Web of Science. Randomized controlled trials (RCTs) and quasi-experimental studies examining the safety, feasibility, and efficacy of non-invasive neuromodulation techniques for managing established CIPN were identified. Narrative synthesis was used to analyze data collected from the included studies. Nine RCTs and nine quasi-experimental studies were included. A variety of non-invasive peripheral and central neuromodulation techniques were investigated in those studies, including scrambler therapy, electrical stimulations, photobiomodulation, magnetic field therapy, therapeutic ultrasound, neurofeedback, and repetitive transcranial magnetic stimulation. Non-invasive neuromodulation techniques for the management of established CIPN are generally safe and feasible. The efficacy of peripheral neuromodulation techniques such as scrambler therapy and transcutaneous electrical nerve stimulation was mostly unsatisfactory, while central neuromodulation techniques such as neurofeedback and repetitive transcranial magnetic stimulation were promising. The use of non-invasive neuromodulation techniques for managing CIPN is still in its infancy. Non-invasive central neuromodulation techniques have significant potential for relieving chronic pain and neuropathic symptoms related to CIPN, meriting further exploration.

Risk Factors for Nab-Paclitaxel and Gemcitabine-Induced Peripheral Neuropathy in Patients with Pancreatic Cancer

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequent adverse events observed with taxane use, whose disability often required modification or treatment discontinuation. The aim of this study was to assess the value of several variables as risk factors for CIPN development. Material and Methods: Eligible patients with metastatic pancreatic cancer receiving chemotherapy with nab-paclitaxel and gemcitabine were assessed in a multicenter study. Peripheral neuropathy was categorized using the National Cancer Institute Common Toxicity Criteria scale, version 4.02, and a physical/neurological examination. Univariate and multivariate regression analyses were used to identify blood-based and clinical factors associated with CIPN. Results: Data were available from 153 patients from five Italian centers. Key risk factors of CIPN in univariate regression models included age, number of chemotherapy cycles, statin assumption, and concomitant comorbidities. However, in the multivariate analysis, only for age (OR 1.0, p < 0.01, 95% CI: 1.01–1.11) and the number of cycles (OR 1.22, p < 0.01, 95% CI: 1.09–1.36), the correlation with CIPN development has been confirmed. Conclusion: Our study confirms age and the number of chemotherapy cycles as CIPN risk factors. The identification and validation of different risk factors could be advantageous to prevent or optimize management of CIPN which outstandingly affect the patient’s quality of life.

Development and consensus process for a clinical pathway for the assessment and management of chemotherapy-induced peripheral neuropathy

BackgroundCancer patients treated with neurotoxic chemotherapy are at risk of developing neurological symptoms that can impact functional capacity and quality of life. However, there are no standardised pathways to assess and manage chemotherapy-induced peripheral neurotoxicity (CIPN). This study aimed to determine consensus on statements regarding a CIPN assessment and management clinical pathway.MethodsA CIPN clinical pathway (CIPN-path) was developed and reviewed by an expert multi-disciplinary panel and consumers. Agreement with 18 statements regarding four content themes (pretreatment review, screening and assessment, management and referral, and CIPN-path feasibility) were assessed by 70 Australian respondents (68 health professionals, 2 consumers), using a 2-stage Delphi survey process to reach consensus. Respondents rated statements using a 5-point Likert scale to determine the level of agreement, with consensus defined as ≥ 80% of respondents agreeing with each statement.ResultsThe consensus was reached for 14 of 18 items after stage 1 and all items after stage 2. Feedback was obtained for all items to refine the CIPN-path. There was an agreement on important characteristics of the CIPN-path, including pretreatment screening, regular patient-reported assessment, and a stepped-care approach to investigating and managing symptom burden. There was a lack of agreement on who should oversee CIPN assessment, which may differ according to the structure and resources of each site.ConclusionsThere was an overall agreement concerning the CIPN-path to assess and manage CIPN, which may be adapted accordingly to the resources of each clinic. The CIPN-path may assist teams across different health services in identifying CIPN symptoms, aiding decision-making, and reducing morbidity from CIPN.

Analgesic and preventive effects of donepezil in animal models of chemotherapy-induced peripheral neuropathy: Involvement of spinal muscarinic acetylcholine M2 receptors

BackgroundDonepezil, a cholinesterase inhibitor approved in Alzheimer’s disease, has demonstrated analgesic and preventive effects in animal models of oxaliplatin-induced neuropathy. To improve the clinical interest of donepezil for the management and prevention of chemotherapy-induced peripheral neuropathy (CIPN), a broader validation is required in different animal models of CIPN. Methods: using rat models of CIPN (bortezomib, paclitaxel, and vincristine), the analgesic and preventive efficacies of donepezil were evaluated on tactile, cold and heat hypersensitivities. The involvement of muscarinic M2 acetylcholine receptors (m2AChRs) in analgesic effects was investigated at the spinal level. The absence of interference of donepezil with the cytotoxic effect of chemotherapy has been controlled in cancer cell lines. Results: the analgesic efficacy of donepezil was demonstrated for all CIPN models, mainly on tactile hypersensitivity (maximal efficacy at 60 min, p < 0.05 vs. vehicle group). This effect was suppressed by an intrathecal injection of methoctramine (m2AChR antagonist). Regarding preventive effects, donepezil limited tactile hypersensitivity induced by paclitaxel, but not for other CIPN models. Donepezil did not modify the viability of cancer cells or the efficacy of anticancer drugs. Conclusions: donepezil had a broad analgesic effect on animal models of CIPN and this effect involved spinal m2AChRs. This work validates the repositioning of donepezil in the management of CIPN.