A Meta-analysis Studying the Utility of Cryotherapy in the Prevention of Peripheral Neuropathy in Breast Cancer Patients Receiving Paclitaxel and Nab-Paclitaxel.

A Meta-analysis Studying the Utility of Cryotherapy in the Prevention of Peripheral Neuropathy in Breast Cancer Patients Receiving Paclitaxel and Nab-Paclitaxel. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A Meta-analysis Studying the Utility of Cryotherapy in the Prevention of Peripheral Neuropathy in Breast Cancer Patients Receiving Paclitaxel and Nab-Paclitaxel. Prashanth Ashok Kumar, Parth Sampat, Michael Sandhu, Vishnu Charan Suresh Kumar, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4744443/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Jan, 2025 Read the published version in Breast Cancer Research and Treatment → Version 1 posted 7 You are reading this latest preprint version Abstract Background Cryotherapy with taxane infusion is a non-invasive strategy to prevent PN, but its efficacy is not proven Methods A systematic search was conducted, and 477 records were identified. The titles were screened independently by 2 reviewers. 14 were included for the meta-analysis using R package meta. Only studies that analyzed cryotherapy use in BC patients who received paclitaxel or nab-paclitaxel were included. Relative risk (RR) derived from random effects model was used to compare the occurrence of PN. Results Incidence of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 2 PN was 24.85% (81/326) in the cryotherapy arm and 42.35% (72/170) in the placebo arm. Overall RR for CTCAE grade ≥ 2 PN with cryotherapy compared to placebo was 0.45 [0.27,0.77, p = 0.0031]. RR for sensory PN was 0.19 [0.05,0.66, p = 0.009] and for motor PN was 0.18 [0.03,0.99, p = 0.0491]. RR for Patient Neurotoxicity Questionnaire (PNQ) score ≥ D which connotes severe neuropathy was 0.24 [0.09,0.62, p = 0.0035]. Cold intolerance was the predominant adverse effect at 15% (37/247). Conclusions Use of cryotherapy decreased the occurrence of CTCAE grade ≥ 2 PN by 55%. Cold intolerance was the most frequently reported issue with its use but lead to relatively low discontinuation rates. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Taxanes including paclitaxel and nab-paclitaxel are an essential part of breast cancer (BC) chemotherapeutic regimes. They form integral part of regimes of all BC subtypes, which includes, sequential anthracycline-cyclophosphamide and taxane (AC-T), the most effective for node positive, tripe negative and estrogen receptor (ER+) positive disease in certain situations[ 1 ]. Paclitaxel causes a length associated sensory neuropathy in almost 60% of the cases. This increases to 97% when cumulative doses exceed 1400 mg/m2, especially through the course of a BC patients’ lifetime[ 2 ]. This was evident in contemporary studies where paclitaxel induced sensory neuropathy was noted in upto 63% of cases and lasted chronically for almost 2 years[ 3 , 4 ]. The neuropathy adversely impacts treatment outcomes as the symptom is a frequent reason for dose reductions and interruptions[ 4 ]. Cryotherapy is a strategy to apply hypothermia to the extremities via various devices such as gloves, socks, mittens, or other devices, with the hope that local blood supply reduction caused by cold will reduce the incidence of neuropathy[ 4 , 5 ]. Several studies have reported the utility of this intervention to prevent neuropathy caused by taxanes, but face limitations such as conflicting results, heterogeneity in the measures of neuropathy reported, and limited sample size, but do unanimously concur that the intervention is safe to use[ 6 – 10 ]. The debate on the efficacy of cold therapy to prevent peripheral neuropathy remains uncertain to an extent, so much so that even ASCO, in its guidelines, explicitly state that a recommendation cannot be made for its use outside of a clinical trial[ 11 ]. Given the significant impact of taxane induced neuropathy and the potential for cryotherapy in neuropathy prevention, we conducted a systematic review and meta-analysis in a quest to answer this question. Methodology Search Strategy This systematic review and meta-analysis are reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA guidelines)[12]. A health sciences librarian (AS) with experience in systematic reviews and expert searching developed the search strategies in consultation with the research team. Systematic search queries using a combination of keywords and controlled vocabulary (where available) related to breast cancer, paclitaxel, neuropathy, and cryotherapy were conducted in PubMed, CINHAL, Embase, Scopus, Web of Science Core Collection, and CENTRAL. All databases and registers were searched from inception to October 4, 2023. There were no search restrictions on language, publication status, or outcomes. The details of all the search strategies can be found in Appendix 1. The search identified 502 records. Duplicates were removed using EndNote 20 (Endnote, Clarivate, available at www.endnote.com). The remaining 439 records were uploaded into Covidence (Covidence, Veritas Health Innovation, Melbourne, Australia; available at www. covidence.org) for title and abstract screening. Screening and inclusion criteria Titles and abstracts were screened by two independent reviewers (PAK, PS). Conflicts arising between individual reviewers were resolved by a 3 rd reviewer (AS). Our inclusion criteria involved studies pertaining to BC treatment involving only paclitaxel or nab-paclitaxel in any stage of BC. Studies or patients involving docetaxel were excluded. The studies should have used any technique of cryotherapy with or without a control group. Control group could either be a separate cohort of patients or the contralateral arm on which cooling was not used. Only clinical trials and retrospective cohort studies were included. Case reports, reviews, and database analysis were excluded. 63 full texts were reviewed and screened similar to the abstracts by 2 reviewers (PAK, PS) and a 3 rd (AS) resolved conflicts. This was narrowed down to 22 studies that were further scrutinized and finally, 14 [12 Randomized control studies and 2 retrospective studies] were included for the meta-analysis using R package meta. The PRISMA flow diagram is shown (Figure 1). Data retrieval and quality control A data collection sheet was created and parameters like study characteristics, data pertaining to the required outcomes, patient characteristics, and adverse events were collected. Two authors (PAK, PS) independently collected and extracted the data. The data was reviewed by two other authors (VCSK and AS) for potential discrepancies, and if present, were resolved Quality was verified using a scale based on the Newcastle-Ottawa Scale for meta-analysis[13]. The scale consisted of 7 questions, each of which was awarded 1 or 2 points based on the question, amounting to a maximum possible 9 points per study. We scored the questions in the scale based on the outcomes that our study aimed to find. We stratified the score as >/=7, 3–6, and <2 to depict good, fair, and poor-quality studies, respectively. 2 authors (PAK and PS) independently assessed the quality of the studies. The senior author (AS) reviewed the final quality assessment table and resolved discrepancies if there were any found. This has been included as a supplement (supplement 3). Outcomes The primary outcome of this study was to determine the incidence of NCI Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or greater neuropathy with cryotherapy use and see if there is a reduction in incidence compared to placebo. Grade 2 or greater neuropathy is considered as significant neuropathy, as it denotes limitation in activities of daily living[14–16]. Stratification such as overall neuropathy, sensory and motor neuropathy were done. Other available measures of neuropathy were measures like Patient Neurotoxicity Questionnaire (PNQ) was utilized. PNQ is a patient reported questionnaire that grades neuropathy from A to E based on severity, with D denoting neuropathy interfering with activities of daily living[17, 18]. Other clinical parameters like drug discontinuation rates, adverse event rates were also charted and extracted. Biostatistics Cumulative descriptive statistics in the form of counts (N), percentages (%) and proportions were utilized. Relative risk (RR) with 95% confidence intervals (CI) derived from random effects model with Mantel-Haenszel method was used to compare the occurrence of neuropathy between cryotherapy vs placebo groups. Pooled proportions were determined using random intercept logistic regression model and clopper-pearson CI. Funnel plots were generated. 5 studies had a test and a control group within the study and provided overall incidence of Grade 2 or > CTCAE neuropathy. 2 studies with a test and control group provided incidence of sensory and motor neuropathy. 3 studies provided data on PNQ D or greater with test and control groups. 8-11 studies were available for calculating proportions for adverse effects. Results The characteristics of all the studies included and distribution of patients between various study parameters are shown in Supplement Table 1[ 19 – 40 ]. Of the 14 studies, 11 were single center studies and 3 were multicenter. The age range of the patients in the cryotherapy group was 32–78 years, where in the control arm, it was 29–78 years. Paclitaxel dosing was 80 mg/m2 weekly and nab-paclitaxel was 260 mg/m2 every 3 weeks. 12 studies applied cryotherapy with frozen gloves/mittens/socks, while 3 studies utilized cooling device like the hilotherm device used by Oneda et al[ 41 ]. There were 326 combined reported instances of cryotherapy use of which 81 (24.85%) developed CTCAE grade 2 or > neuropathy. Among 170 occurrences in the control arm, 72 (42.35%) developed neuropathy. Overall RR by random effects model for CTCAE grade ≥ 2 neuropathy with cryotherapy compared to placebo was 0.45 (0.27; 0.77 z= -2.95, p = 0.0031, I 2 27%) (Fig. 2 ) RR for sensory PN was 0.19 (0.05; 0.66, z=-2.61, p = 0.0090) and for motor PN was 0.18 (0.0336; 0.9936, z=-1.97, p = 0.0491) (Fig. 3 A and B) RR for Patient Neurotoxicity Questionnaire (PNQ) score ≥ D which connotes severe neuropathy was 0.24 (0.09; 0.62, z=-2.92, p = 0.0035) (Fig. 4 ). RR by random effects for motor and sensory neuropathy separately is shown in the Supplement Figures S1 and S2. Cold intolerance was the predominant adverse effect at 15% (37/247). Fingernail paronychia and skin irritation were reported at 0.8% (2/247) each. 5.1% (15/294) stopped cryotherapy use prior to completion. However, this number was driven by a single study (10/16 patients stopped using cryotherapy due to cold intolerance) and 7/11 studies had no discontinuations. Proportions using random effects model showed that the chance of having any adverse effect was 13% (4%, 32%), and cold intolerance was 12% (3%, 35%) with cryotherapy use, as shown in the proportion plots in Fig. 5 A and 4 B. The proportion of patients who stopped using cryotherapy from random effects model was 1% (0%, 9%) (Fig. 4 C). Proportion of patients in the cryotherapy arm who needed dose reduction of taxane was 43% (15%, 121%) (Figure S3 ) and those who needed drug discontinuation was at 22% (3%, 183%) (Figure S4 ). Skin irritation and redness was a side effect that was reported in some studies. None of the studies reported any major debilitating adverse effect. Discussion Paclitaxel is a taxane used to treat various malignancies, of which node-positive and triple negative breast cancer see common usage. Common adverse effects of paclitaxel include hair loss, skin reactions, cytopenias, and peripheral neuropathy[ 42 ]. In our meta-analysis of multiple databases to review the utility of cryotherapy in the preventing taxane induced peripheral neuropathy in breast cancer patients, the incidence of CTCAE ≥ 2 paclitaxel induced peripheral neuropathy[ 43 , 44 ] was reduced by 55%. Many of our secondary outcomes like sensory and motor neuropathy incidences (decreased by 81% and 82% respectively), PNQ score D or greater (decreased by 76%) and adverse effect incidence (13%) were also supportive of cryotherapy use. Cryotherapy therefore could be a safe intervention that can be utilized to prevent taxane induced neuropathy for breast cancer patients. When used as adjuvant therapy for breast cancer, weekly paclitaxel has showed superiority in relapse-free survival and overall survival when compared to every 3-week dosage. This, however, has a high incidence of neurotoxicity, including peripheral neuropathy[ 45 ]. In a study evaluating the association between patient reported outcomes and quantitative sensory tests for measuring long-term neurotoxicity in breast cancer survivors who were treated with adjuvant paclitaxel, 81% of women reported symptoms of numbness and/or discomfort in the hands and/or feet, with severe symptoms reported in 27% and 25% of women for hands and feet respectively[ 46 ]. The patients in this trial also reported that symptoms of distal sensory neuropathy persisted up to 2 years after the completion of treatment[ 46 ]. Not only is neurotoxicity a dose-limiting adverse effect, but chemotherapy-induced peripheral neuropathy adversely impacts quality of life in breast cancer survivors. Taxanes work through stabilization of the microtubule thereby interfering with cell division and inducing cancer cell death[ 47 ]. Taxane-associated peripheral neuropathy may be sensory or motor, although most cases involve predominantly sensory distal neuropathy[ 48 ]. The mechanism of taxane-induced peripheral neuropathy is controversial. Preclinical studies have demonstrated accumulation of microtubules in the Schwann cells and axons of the sciatic nerve[ 48 ]. Taxanes have been shown to preferentially affect thick myelinated nerve fibers responsible for proprioception and vibratory sensation suggesting a “dying back” process of axonal degeneration[ 49 , 50 ]. To date, no medications have been established for the prevention of taxane-induced peripheral neuropathy. Tricyclic antidepressants have been studies extensively, however, have not been proven to be effective in preventing this phenomenon[ 51 ], and may lead to potential adverse effects. Cryotherapy and compression therapy have been suggested as alternatives to suppress peripheral circulation of the drug, thereby mitigating the onset and severity of peripheral neuropathy[ 52 ]. A multicenter study using a frozen glove showed reduced incidence of both onycholysis and peripheral neuropathy[ 53 ] in patients treated with docetaxel. Furthermore, Shigematsu et. al demonstrated a significant decrease in both peripheral sensory neuropathy and dermatological adverse events in breast cancer patients receiving weekly paclitaxel[ 52 ]. In our meta-analysis, we found that cryotherapy was statistically significant in reducing the incidence of both motor and sensory peripheral neuropathy caused by paclitaxel or nab-paclitaxel and shown to significantly decrease the occurrence of severe peripheral neuropathy, categorized as Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or higher. The main adverse effect noted with cryotherapy in our meta-analysis was cold intolerance, however this led to a relatively low discontinuation rate like in most other studies. In published literature, studies have evaluated the use of cryotherapy for the prevention of chemotherapy-induced peripheral neuropathy. A retrospective cohort study by Rosenbaek et. al demonstrated that prophylactic use of cryotherapy has the potential to reduce the risk of a dose-limiting toxicity due to chemotherapy-induced peripheral neuropathy and can increase the proportion of patients that can complete the planned dose of paclitaxel for early-stage breast cancer[ 20 ]. In a meta-analysis by Jia et. al, clinical trials were included and examined the efficacy of cryotherapy for prevention of taxane-induced peripheral neuropathy. 2250 patients were included from 9 trials, and their meta-analysis showed that cryotherapy could significantly reduce the incidence of both motor and sensory neuropathy of grade 2 or greater. They found that the cryotherapy reduced the risk of peripheral neuropathy, and the relative risk for sensory neuropathy was 0.65 (p < 0.00001) and for motor neuropathy was 0.18 (p = 0.04). The study included prostate and gynecologic cancers in addition to BC and included paclitaxel as well as docetaxel[ 26 ]. Furthermore, a systematic review of patients receiving treatment with paclitaxel, docetaxel, or oxaliplatin included 11 studies with a total of 2356 patients, and showed mixed efficacy for prevention of peripheral neuropathy with various methods of cryotherapy[ 54 ]. When compared to control, cooling gloves and socks showed a significant reduction in the incidence of severe symptoms of peripheral neuropathy in both the hands and feet. Compared to the above studies, our study differed as we specifically investigated paclitaxel and nab-paclitaxel in breast cancer alone. Limitations of our study pertains mainly to the nature of the analysis. Heterogeneity between the studies used in the meta-analysis in various factors like the cooling technique and devices used, and inter-operator variability in measuring neuropathy may result in confounding. In conclusion, cryotherapy may serve as a safe and effective strategy to prevent taxane induced neuropathy in BC patients. Given the absence of major drawbacks, it can be safely recommended for use in clinical practice. Declarations Conflicts of interest/Disclosures The authors have no relevant financial or non-financial interests to disclose. Previous publication statement: An abstract of the study was published as an online abstract at the ASCO 2023 annual meeting. Ethics approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors. Since this was a Meta-analysis and systematic search, ethics approval was not needed. Consent to participate Not applicable. Funding Source The work was funded by the Division of Hematology-Oncology, Upstate Cancer Center, of the Upstate Medical University. The abstract of the study presented in ASCO 2023 received the ASCO Merit award worth 1000 US $ . Author Contribution Prashanth Ashok Kumar conceptualized and designed the study, wrote the manuscript, served as a reviewer, acquired the data, and analyzed the data. Parth Sampat wrote a part of the manuscript, served as a reviewer, analyzed the data, and revised and edited the manuscript. Michael Sandhu, Vishnu Charan Suresh Kumar, Ghanshyam Ghelani and Shweta Paulraj wrote a portion of the manuscript, formulated the methodology, revised, and edited the manuscript. Abigail Smith formulated the search strategy, performed the search, and wrote a portion of the methodology. Dongliang Wang performed data analysis, statistics, and review of the paper. Danning Huang performed data analysis, statistics, and review of the paper. Abirami Sivapiragasam formulated the original idea and contributed to the design, analysis, review, and supervision of the manuscript. All authors reviewed the manuscript and agreed for the publication. Acknowledgement Our sincere gratitude to the Division of Hematology Oncology at SUNY Upstate Medical University for supporting the study. We also like to thank the Upstate Library and the Division of Public Health and Preventive Medicine for their contribution. Data availability statement The datasets analyzed during the in study are publicly available as they were obtained through literature search. References Fujii T, Le Du F, Xiao L, et al (2015) Effectiveness of an Adjuvant Chemotherapy Regimen for Early-Stage Breast Cancer: A Systematic Review and Network Meta-analysis. JAMA Oncol 1:1311. https://doi.org/10.1001/JAMAONCOL.2015.3062 Klein I, Lehmann HC (2021) Pathomechanisms of Paclitaxel-Induced Peripheral Neuropathy. Toxics 9:. https://doi.org/10.3390/TOXICS9100229 Molassiotis A, Cheng HL, Lopez V, et al (2019) Are we mis-estimating chemotherapy-induced peripheral neuropathy? 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Breast Cancer Res Treat 125:767–774. https://doi.org/10.1007/S10549-010-1278-0 Phase I study of paclitaxel as a 3-hour infusion followed by carboplatin in untreated patients with stage IV non-small cell lung cancer - PubMed. https://pubmed.ncbi.nlm.nih.gov/7644928/. Accessed 11 Mar 2024 Argyriou AA, Koltzenburg M, Polychronopoulos P, et al (2008) Peripheral nerve damage associated with administration of taxanes in patients with cancer. Crit Rev Oncol Hematol 66:218–228. https://doi.org/10.1016/J.CRITREVONC.2008.01.008 Rowinsky EK, Cazenave LA, Donehower RC (1990) Taxol: a novel investigational antimicrotubule agent. J Natl Cancer Inst 82:1247–1259. https://doi.org/10.1093/JNCI/82.15.1247 Montero A, Fossella F, Hortobagyi G, Valero V (2005) Docetaxel for treatment of solid tumours: A systematic review of clinical data. Lancet Oncology 6:229–239. https://doi.org/10.1016/S1470-2045(05)70094-2 Hershman DL, Lacchetti C, Dworkin RH, et al (2014) Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American society of clinical oncology clinical practice guideline. Journal of Clinical Oncology 32:1941–1967. https://doi.org/10.1200/JCO.2013.54.0914/SUPPL_FILE/TABLE2_JCO.2013.54.0914.PDF Shigematsu H, Hirata T, Nishina M, et al (2020) Cryotherapy for the prevention of weekly paclitaxel-induced peripheral adverse events in breast cancer patients. Supportive Care in Cancer 28:5005. https://doi.org/10.1007/S00520-020-05345-9 Scotté F, Tourani JM, Banu E, et al (2005) Multicenter study of a frozen glove to prevent docetaxel-induced onycholysis and cutaneous toxicity of the hand. Journal of Clinical Oncology 23:4424–4429. https://doi.org/10.1200/JCO.2005.15.651/ASSET/IMAGES/ZLJ0190523730003.JPEG Chan A, Elsayed A, Ng DQ, et al (2022) A global survey on the utilization of cryotherapy and compression therapy for the prevention of chemotherapy-induced peripheral neuropathy. Supportive Care in Cancer 30:10001–10007. https://doi.org/10.1007/S00520-022-07383-X/FIGURES/2 Additional Declarations No competing interests reported. Supplementary Files Appendix1SearchStrategiesJuly15.doc Supplemental1Table1.xlsx Supplement2Figures.doc Supplement3NewCastleOttawaQualityControl.xlsx Cite Share Download PDF Status: Published Journal Publication published 19 Jan, 2025 Read the published version in Breast Cancer Research and Treatment → Version 1 posted Editorial decision: Revision requested 06 Aug, 2024 Reviews received at journal 01 Aug, 2024 Reviewers agreed at journal 18 Jul, 2024 Reviewers invited by journal 18 Jul, 2024 Editor assigned by journal 16 Jul, 2024 Submission checks completed at journal 16 Jul, 2024 First submitted to journal 15 Jul, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4744443","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":336901326,"identity":"8f3d23bb-e4cb-4226-a167-bccda4e7f2e1","order_by":0,"name":"Prashanth Ashok 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17:00:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4744443/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4744443/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10549-024-07597-z","type":"published","date":"2025-01-19T15:56:54+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":62632023,"identity":"167d20bc-08a7-4f87-9074-d437f447bdf6","added_by":"auto","created_at":"2024-08-16 16:08:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":75381,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flow diagram showing screening, identification, and inclusion of studies for meta-analysis\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4744443/v1/b51938b5e12fb2f5941f35a5.png"},{"id":62632024,"identity":"ef6a467d-bebb-4b1d-8ebf-05a99020e4e6","added_by":"auto","created_at":"2024-08-16 16:08:43","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":103962,"visible":true,"origin":"","legend":"\u003cp\u003eRR estimation and funnel plots for overall incidence of CTCAE grade 2 or \u0026gt; neuropathy.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4744443/v1/24ae7b5cf9ed6a519173b973.jpg"},{"id":62630926,"identity":"b57ea6a8-d789-4211-baed-5166153d1a83","added_by":"auto","created_at":"2024-08-16 16:00:43","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":151618,"visible":true,"origin":"","legend":"\u003cp\u003eRR estimation and funnel plots for incidence of A. sensory and B. Motor CTCAE grade 2 or \u0026gt; neuropathy.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4744443/v1/3ba2d2e83b8f135a098ebd08.jpg"},{"id":62630921,"identity":"30cc8956-d0d6-4c74-aadf-f3a5da39f2a4","added_by":"auto","created_at":"2024-08-16 16:00:43","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":85949,"visible":true,"origin":"","legend":"\u003cp\u003eRR estimation and funnel plots for incidence of overall PNQ D or \u0026gt;.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4744443/v1/a140fc77e5fc561bea7f152f.jpg"},{"id":62630923,"identity":"ee383364-6d63-4a9a-a319-3325e67645aa","added_by":"auto","created_at":"2024-08-16 16:00:43","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":274278,"visible":true,"origin":"","legend":"\u003cp\u003ePooled random effects proportion of patients A. Any adverse effect B. Cold intolerance C. Stopped cryotherapy.\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4744443/v1/6ab8c9531b005819b4e93668.jpg"},{"id":74284746,"identity":"362b121a-96ca-4c70-b32f-e9ae5c1f6a89","added_by":"auto","created_at":"2025-01-20 16:12:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1264326,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4744443/v1/92b8e6da-83aa-43e5-b9de-b774bd2ee2da.pdf"},{"id":62630925,"identity":"5b80795c-cc0c-43da-a3d4-837a36a76842","added_by":"auto","created_at":"2024-08-16 16:00:43","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":45568,"visible":true,"origin":"","legend":"","description":"","filename":"Appendix1SearchStrategiesJuly15.doc","url":"https://assets-eu.researchsquare.com/files/rs-4744443/v1/20c323560c03ef3002280668.doc"},{"id":62630924,"identity":"fdd215b1-00ee-422d-acc6-204b4838ca59","added_by":"auto","created_at":"2024-08-16 16:00:43","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":13076,"visible":true,"origin":"","legend":"","description":"","filename":"Supplemental1Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4744443/v1/9327e112d40c412064eb5a45.xlsx"},{"id":62632026,"identity":"bc3b9309-6694-40aa-aa3c-ed6ccabafc31","added_by":"auto","created_at":"2024-08-16 16:08:43","extension":"doc","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":204800,"visible":true,"origin":"","legend":"","description":"","filename":"Supplement2Figures.doc","url":"https://assets-eu.researchsquare.com/files/rs-4744443/v1/dd3dcea0b0e30e204801655a.doc"},{"id":62632025,"identity":"a5c7cdd2-ca1f-42f3-b87d-f4559825d5b5","added_by":"auto","created_at":"2024-08-16 16:08:43","extension":"xlsx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":14048,"visible":true,"origin":"","legend":"","description":"","filename":"Supplement3NewCastleOttawaQualityControl.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4744443/v1/6853b449b4d37727be1dcb80.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Meta-analysis Studying the Utility of Cryotherapy in the Prevention of Peripheral Neuropathy in Breast Cancer Patients Receiving Paclitaxel and Nab-Paclitaxel.","fulltext":[{"header":"Introduction","content":"\u003cp\u003eTaxanes including paclitaxel and nab-paclitaxel are an essential part of breast cancer (BC) chemotherapeutic regimes. They form integral part of regimes of all BC subtypes, which includes, sequential anthracycline-cyclophosphamide and taxane (AC-T), the most effective for node positive, tripe negative and estrogen receptor (ER+) positive disease in certain situations[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Paclitaxel causes a length associated sensory neuropathy in almost 60% of the cases. This increases to 97% when cumulative doses exceed 1400 mg/m2, especially through the course of a BC patients\u0026rsquo; lifetime[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. This was evident in contemporary studies where paclitaxel induced sensory neuropathy was noted in upto 63% of cases and lasted chronically for almost 2 years[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The neuropathy adversely impacts treatment outcomes as the symptom is a frequent reason for dose reductions and interruptions[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Cryotherapy is a strategy to apply hypothermia to the extremities via various devices such as gloves, socks, mittens, or other devices, with the hope that local blood supply reduction caused by cold will reduce the incidence of neuropathy[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Several studies have reported the utility of this intervention to prevent neuropathy caused by taxanes, but face limitations such as conflicting results, heterogeneity in the measures of neuropathy reported, and limited sample size, but do unanimously concur that the intervention is safe to use[\u003cspan additionalcitationids=\"CR7 CR8 CR9\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The debate on the efficacy of cold therapy to prevent peripheral neuropathy remains uncertain to an extent, so much so that even ASCO, in its guidelines, explicitly state that a recommendation cannot be made for its use outside of a clinical trial[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Given the significant impact of taxane induced neuropathy and the potential for cryotherapy in neuropathy prevention, we conducted a systematic review and meta-analysis in a quest to answer this question.\u003c/p\u003e"},{"header":"Methodology","content":"\u003cp\u003e\u003cstrong\u003eSearch Strategy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis systematic review and meta-analysis are reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA guidelines)[12]. A health sciences librarian (AS) with experience in systematic reviews and expert searching developed the search strategies in consultation with the research team. Systematic search queries using a combination of keywords and controlled vocabulary (where available) related to breast cancer, paclitaxel, neuropathy, and cryotherapy were conducted in PubMed, CINHAL, Embase, Scopus, Web of Science Core Collection, and CENTRAL. All databases and registers were searched from inception to October 4, 2023. There were no search restrictions on language, publication status, or outcomes. The details of all the search strategies can be found in Appendix 1. The search identified 502 records. Duplicates were removed using EndNote 20 (Endnote, Clarivate, available at www.endnote.com). The remaining 439 records were uploaded into Covidence (Covidence, Veritas Health Innovation, Melbourne, Australia; available at www. covidence.org) for title and abstract screening.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eScreening and inclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTitles and abstracts were screened by two independent reviewers (PAK, PS). Conflicts arising between individual reviewers were resolved by a 3\u003csup\u003erd\u003c/sup\u003e reviewer (AS). Our inclusion criteria involved studies pertaining to BC treatment involving only paclitaxel or nab-paclitaxel in any stage of BC. Studies or patients involving docetaxel were excluded. The studies should have used any technique of cryotherapy with or without a control group. Control group could either be a separate cohort of patients or the contralateral arm on which cooling was not used. Only clinical trials and retrospective cohort studies were included. Case reports, reviews, and database analysis were excluded. 63 full texts were reviewed and screened similar to the abstracts by 2 reviewers (PAK, PS) and a 3\u003csup\u003erd\u003c/sup\u003e(AS) resolved conflicts. This was narrowed down to 22 studies that were further scrutinized and finally, 14 [12 Randomized control studies and 2 retrospective studies] were included for the meta-analysis using R package meta. The PRISMA flow diagram is shown (Figure 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData retrieval and quality control\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA data collection sheet was created and parameters like study characteristics, data pertaining to the required outcomes, patient characteristics, and adverse events were collected. Two authors (PAK, PS) independently collected and extracted the data. The data was reviewed by two other authors (VCSK and AS) for potential discrepancies, and if present, were resolved\u003c/p\u003e\n\u003cp\u003eQuality was verified using a scale based on the Newcastle-Ottawa Scale for meta-analysis[13]. The scale consisted of 7 questions, each of which was awarded 1 or 2 points based on the question, amounting to a maximum possible 9 points per study. We scored the questions in the scale based on the outcomes that our study aimed to find. We stratified the score as \u0026gt;/=7, 3–6, and \u0026lt;2 to depict good, fair, and poor-quality studies, respectively. 2 authors (PAK and PS) independently assessed the quality of the studies. The senior author (AS) reviewed the final quality assessment table and resolved discrepancies if there were any found. This has been included as a supplement (supplement 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcome of this study was to determine the incidence of NCI Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or greater neuropathy with cryotherapy use and see if there is a reduction in incidence compared to placebo. Grade 2 or greater neuropathy is considered as significant neuropathy, as it denotes limitation in activities of daily living[14–16]. Stratification such as overall neuropathy, sensory and motor neuropathy were done. Other available measures of neuropathy were measures like Patient Neurotoxicity Questionnaire (PNQ) was utilized. PNQ is a patient reported questionnaire that grades neuropathy from A to E based on severity, with D denoting neuropathy interfering with activities of daily living[17, 18]. Other clinical parameters like drug discontinuation rates, adverse event rates were also charted and extracted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBiostatistics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCumulative descriptive statistics in the form of counts (N), percentages (%) and proportions were utilized. Relative risk (RR) with 95% confidence intervals (CI) derived from random effects model with Mantel-Haenszel method was used to compare the occurrence of neuropathy between cryotherapy vs placebo groups. Pooled proportions were determined using random intercept logistic regression model and clopper-pearson CI. Funnel plots were generated.\u003c/p\u003e\n\u003cp\u003e5 studies had a test and a control group within the study and provided overall incidence of Grade 2 or \u0026gt; CTCAE neuropathy. 2 studies with a test and control group provided incidence of sensory and motor neuropathy. 3 studies provided data on PNQ D or greater with test and control groups. 8-11 studies were available for calculating proportions for adverse effects. \u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe characteristics of all the studies included and distribution of patients between various study parameters are shown in Supplement Table\u0026nbsp;1[\u003cspan additionalcitationids=\"CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28 CR29 CR30 CR31 CR32 CR33 CR34 CR35 CR36 CR37 CR38 CR39\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Of the 14 studies, 11 were single center studies and 3 were multicenter. The age range of the patients in the cryotherapy group was 32\u0026ndash;78 years, where in the control arm, it was 29\u0026ndash;78 years. Paclitaxel dosing was 80 mg/m2 weekly and nab-paclitaxel was 260 mg/m2 every 3 weeks. 12 studies applied cryotherapy with frozen gloves/mittens/socks, while 3 studies utilized cooling device like the hilotherm device used by Oneda et al[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere were 326 combined reported instances of cryotherapy use of which 81 (24.85%) developed CTCAE grade 2 or \u0026gt;\u0026thinsp;neuropathy. Among 170 occurrences in the control arm, 72 (42.35%) developed neuropathy. Overall RR by random effects model for CTCAE grade\u0026thinsp;\u0026ge;\u0026thinsp;2 neuropathy with cryotherapy compared to placebo was 0.45 (0.27; 0.77 z= -2.95, p\u0026thinsp;=\u0026thinsp;0.0031, I\u003csup\u003e2\u003c/sup\u003e 27%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eRR for sensory PN was 0.19 (0.05; 0.66, z=-2.61, p\u0026thinsp;=\u0026thinsp;0.0090) and for motor PN was 0.18 (0.0336; 0.9936, z=-1.97, p\u0026thinsp;=\u0026thinsp;0.0491) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA and B)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eRR for Patient Neurotoxicity Questionnaire (PNQ) score\u0026thinsp;\u0026ge;\u0026thinsp;D which connotes severe neuropathy was 0.24 (0.09; 0.62, z=-2.92, p\u0026thinsp;=\u0026thinsp;0.0035) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). RR by random effects for motor and sensory neuropathy separately is shown in the Supplement Figures \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e and S2.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eCold intolerance was the predominant adverse effect at 15% (37/247). Fingernail paronychia and skin irritation were reported at 0.8% (2/247) each. 5.1% (15/294) stopped cryotherapy use prior to completion. However, this number was driven by a single study (10/16 patients stopped using cryotherapy due to cold intolerance) and 7/11 studies had no discontinuations. Proportions using random effects model showed that the chance of having any adverse effect was 13% (4%, 32%), and cold intolerance was 12% (3%, 35%) with cryotherapy use, as shown in the proportion plots in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA and \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB. The proportion of patients who stopped using cryotherapy from random effects model was 1% (0%, 9%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC). Proportion of patients in the cryotherapy arm who needed dose reduction of taxane was 43% (15%, 121%) (Figure \u003cspan refid=\"MOESM3\" class=\"InternalRef\"\u003eS3\u003c/span\u003e) and those who needed drug discontinuation was at 22% (3%, 183%) (Figure \u003cspan refid=\"MOESM4\" class=\"InternalRef\"\u003eS4\u003c/span\u003e). Skin irritation and redness was a side effect that was reported in some studies. None of the studies reported any major debilitating adverse effect.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePaclitaxel is a taxane used to treat various malignancies, of which node-positive and triple negative breast cancer see common usage. Common adverse effects of paclitaxel include hair loss, skin reactions, cytopenias, and peripheral neuropathy[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. In our meta-analysis of multiple databases to review the utility of cryotherapy in the preventing taxane induced peripheral neuropathy in breast cancer patients, the incidence of CTCAE\u0026thinsp;\u0026ge;\u0026thinsp;2 paclitaxel induced peripheral neuropathy[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e] was reduced by 55%. Many of our secondary outcomes like sensory and motor neuropathy incidences (decreased by 81% and 82% respectively), PNQ score D or greater (decreased by 76%) and adverse effect incidence (13%) were also supportive of cryotherapy use. Cryotherapy therefore could be a safe intervention that can be utilized to prevent taxane induced neuropathy for breast cancer patients.\u003c/p\u003e \u003cp\u003eWhen used as adjuvant therapy for breast cancer, weekly paclitaxel has showed superiority in relapse-free survival and overall survival when compared to every 3-week dosage. This, however, has a high incidence of neurotoxicity, including peripheral neuropathy[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. In a study evaluating the association between patient reported outcomes and quantitative sensory tests for measuring long-term neurotoxicity in breast cancer survivors who were treated with adjuvant paclitaxel, 81% of women reported symptoms of numbness and/or discomfort in the hands and/or feet, with severe symptoms reported in 27% and 25% of women for hands and feet respectively[\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. The patients in this trial also reported that symptoms of distal sensory neuropathy persisted up to 2 years after the completion of treatment[\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. Not only is neurotoxicity a dose-limiting adverse effect, but chemotherapy-induced peripheral neuropathy adversely impacts quality of life in breast cancer survivors. Taxanes work through stabilization of the microtubule thereby interfering with cell division and inducing cancer cell death[\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. Taxane-associated peripheral neuropathy may be sensory or motor, although most cases involve predominantly sensory distal neuropathy[\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. The mechanism of taxane-induced peripheral neuropathy is controversial. Preclinical studies have demonstrated accumulation of microtubules in the Schwann cells and axons of the sciatic nerve[\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. Taxanes have been shown to preferentially affect thick myelinated nerve fibers responsible for proprioception and vibratory sensation suggesting a \u0026ldquo;dying back\u0026rdquo; process of axonal degeneration[\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo date, no medications have been established for the prevention of taxane-induced peripheral neuropathy. Tricyclic antidepressants have been studies extensively, however, have not been proven to be effective in preventing this phenomenon[\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e], and may lead to potential adverse effects. Cryotherapy and compression therapy have been suggested as alternatives to suppress peripheral circulation of the drug, thereby mitigating the onset and severity of peripheral neuropathy[\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. A multicenter study using a frozen glove showed reduced incidence of both onycholysis and peripheral neuropathy[\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e] in patients treated with docetaxel. Furthermore, Shigematsu et. al demonstrated a significant decrease in both peripheral sensory neuropathy and dermatological adverse events in breast cancer patients receiving weekly paclitaxel[\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our meta-analysis, we found that cryotherapy was statistically significant in reducing the incidence of both motor and sensory peripheral neuropathy caused by paclitaxel or nab-paclitaxel and shown to significantly decrease the occurrence of severe peripheral neuropathy, categorized as Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or higher. The main adverse effect noted with cryotherapy in our meta-analysis was cold intolerance, however this led to a relatively low discontinuation rate like in most other studies. In published literature, studies have evaluated the use of cryotherapy for the prevention of chemotherapy-induced peripheral neuropathy. A retrospective cohort study by Rosenbaek et. al demonstrated that prophylactic use of cryotherapy has the potential to reduce the risk of a dose-limiting toxicity due to chemotherapy-induced peripheral neuropathy and can increase the proportion of patients that can complete the planned dose of paclitaxel for early-stage breast cancer[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn a meta-analysis by Jia et. al, clinical trials were included and examined the efficacy of cryotherapy for prevention of taxane-induced peripheral neuropathy. 2250 patients were included from 9 trials, and their meta-analysis showed that cryotherapy could significantly reduce the incidence of both motor and sensory neuropathy of grade 2 or greater. They found that the cryotherapy reduced the risk of peripheral neuropathy, and the relative risk for sensory neuropathy was 0.65 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.00001) and for motor neuropathy was 0.18 (p\u0026thinsp;=\u0026thinsp;0.04). The study included prostate and gynecologic cancers in addition to BC and included paclitaxel as well as docetaxel[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Furthermore, a systematic review of patients receiving treatment with paclitaxel, docetaxel, or oxaliplatin included 11 studies with a total of 2356 patients, and showed mixed efficacy for prevention of peripheral neuropathy with various methods of cryotherapy[\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. When compared to control, cooling gloves and socks showed a significant reduction in the incidence of severe symptoms of peripheral neuropathy in both the hands and feet. Compared to the above studies, our study differed as we specifically investigated paclitaxel and nab-paclitaxel in breast cancer alone. Limitations of our study pertains mainly to the nature of the analysis. Heterogeneity between the studies used in the meta-analysis in various factors like the cooling technique and devices used, and inter-operator variability in measuring neuropathy may result in confounding.\u003c/p\u003e \u003cp\u003eIn conclusion, cryotherapy may serve as a safe and effective strategy to prevent taxane induced neuropathy in BC patients. Given the absence of major drawbacks, it can be safely recommended for use in clinical practice.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflicts of interest/Disclosures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cstrong\u003ePrevious publication statement:\u0026nbsp;\u003c/strong\u003eAn abstract of the study was published as an online abstract at the ASCO 2023 annual meeting.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\u003cp\u003e \u003ch2\u003eEthics approval\u003c/h2\u003e \u003cp\u003eAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors. Since this was a Meta-analysis and systematic search, ethics approval was not needed.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent to participate\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding Source\u003c/h2\u003e \u003cp\u003eThe work was funded by the Division of Hematology-Oncology, Upstate Cancer Center, of the Upstate Medical University. The abstract of the study presented in ASCO 2023 received the ASCO Merit award worth 1000 US\u003cspan\u003e$\u003c/span\u003e.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003ePrashanth Ashok Kumar conceptualized and designed the study, wrote the manuscript, served as a reviewer, acquired the data, and analyzed the data. Parth Sampat wrote a part of the manuscript, served as a reviewer, analyzed the data, and revised and edited the manuscript. Michael Sandhu, Vishnu Charan Suresh Kumar, Ghanshyam Ghelani and Shweta Paulraj wrote a portion of the manuscript, formulated the methodology, revised, and edited the manuscript. Abigail Smith formulated the search strategy, performed the search, and wrote a portion of the methodology. Dongliang Wang performed data analysis, statistics, and review of the paper. Danning Huang performed data analysis, statistics, and review of the paper. Abirami Sivapiragasam formulated the original idea and contributed to the design, analysis, review, and supervision of the manuscript. All authors reviewed the manuscript and agreed for the publication.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eOur sincere gratitude to the Division of Hematology Oncology at SUNY Upstate Medical University for supporting the study. We also like to thank the Upstate Library and the Division of Public Health and Preventive Medicine for their contribution.\u003c/p\u003e\u003ch2\u003eData availability statement\u003c/h2\u003e \u003cp\u003eThe datasets analyzed during the in study are publicly available as they were obtained through literature search.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFujii T, Le Du F, Xiao L, et al (2015) Effectiveness of an Adjuvant Chemotherapy Regimen for Early-Stage Breast Cancer: A Systematic Review and Network Meta-analysis. JAMA Oncol 1:1311. https://doi.org/10.1001/JAMAONCOL.2015.3062\u003c/li\u003e\n\u003cli\u003eKlein I, Lehmann HC (2021) Pathomechanisms of Paclitaxel-Induced Peripheral Neuropathy. Toxics 9:. https://doi.org/10.3390/TOXICS9100229\u003c/li\u003e\n\u003cli\u003eMolassiotis A, Cheng HL, Lopez V, et al (2019) Are we mis-estimating chemotherapy-induced peripheral neuropathy? 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Cancer Res 78:P6-11\u0026ndash;17. https://doi.org/10.1158/1538-7445.SABCS17-P6-11-17\u003c/li\u003e\n\u003cli\u003eOneda E, Meriggi F, Zanotti L, et al (2020) Innovative Approach for the Prevention of Chemotherapy-Induced Peripheral Neuropathy in Cancer Patients: A Pilot Study With the Hilotherm Device, the Poliambulanza Hospital Experience. Integr Cancer Ther 19:. https://doi.org/10.1177/1534735420943287/ASSET/IMAGES/LARGE/10.1177_1534735420943287-FIG1.JPEG\u003c/li\u003e\n\u003cli\u003eSparano JA, Wang M, Martino S, et al (2008) Weekly Paclitaxel in the Adjuvant Treatment of Breast Cancer. New England Journal of Medicine 358:1663\u0026ndash;1671. https://doi.org/10.1056/NEJMOA0707056/SUPPL_FILE/NEJM_SPARANO_1663SA1.PDF\u003c/li\u003e\n\u003cli\u003eLe-Rademacher J, Kanwar R, Seisler D, et al (2017) Patient-Reported (EORTC QLQ-CIPN20) Versus Physician-Reported (CTCAE) Quantification of Oxaliplatin- and Paclitaxel/Carboplatin-Induced Peripheral Neuropathy in NCCTG/Alliance Clinical Trials. Support Care Cancer 25:3537. https://doi.org/10.1007/S00520-017-3780-Y\u003c/li\u003e\n\u003cli\u003eCommon Terminology Criteria for Adverse Events (CTCAE) | Protocol Development | CTEP. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm. Accessed 11 Mar 2024\u003c/li\u003e\n\u003cli\u003eEisenhauer EA, Ten Bokkel Huinink WW, Swenerton KD, et al (2016) European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: high-dose versus low-dose and long versus short infusion. https://doi.org/101200/JCO199412122654 12:2654\u0026ndash;2666. https://doi.org/10.1200/JCO.1994.12.12.2654\u003c/li\u003e\n\u003cli\u003eHershman DL, Weimer LH, Wang A, et al (2011) Association between patient reported outcomes and quantitative sensory tests for measuring long-term neurotoxicity in breast cancer survivors treated with adjuvant paclitaxel chemotherapy. Breast Cancer Res Treat 125:767\u0026ndash;774. https://doi.org/10.1007/S10549-010-1278-0\u003c/li\u003e\n\u003cli\u003ePhase I study of paclitaxel as a 3-hour infusion followed by carboplatin in untreated patients with stage IV non-small cell lung cancer - PubMed. https://pubmed.ncbi.nlm.nih.gov/7644928/. Accessed 11 Mar 2024\u003c/li\u003e\n\u003cli\u003eArgyriou AA, Koltzenburg M, Polychronopoulos P, et al (2008) Peripheral nerve damage associated with administration of taxanes in patients with cancer. Crit Rev Oncol Hematol 66:218\u0026ndash;228. https://doi.org/10.1016/J.CRITREVONC.2008.01.008\u003c/li\u003e\n\u003cli\u003eRowinsky EK, Cazenave LA, Donehower RC (1990) Taxol: a novel investigational antimicrotubule agent. J Natl Cancer Inst 82:1247\u0026ndash;1259. https://doi.org/10.1093/JNCI/82.15.1247\u003c/li\u003e\n\u003cli\u003eMontero A, Fossella F, Hortobagyi G, Valero V (2005) Docetaxel for treatment of solid tumours: A systematic review of clinical data. Lancet Oncology 6:229\u0026ndash;239. https://doi.org/10.1016/S1470-2045(05)70094-2\u003c/li\u003e\n\u003cli\u003eHershman DL, Lacchetti C, Dworkin RH, et al (2014) Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American society of clinical oncology clinical practice guideline. Journal of Clinical Oncology 32:1941\u0026ndash;1967. https://doi.org/10.1200/JCO.2013.54.0914/SUPPL_FILE/TABLE2_JCO.2013.54.0914.PDF\u003c/li\u003e\n\u003cli\u003eShigematsu H, Hirata T, Nishina M, et al (2020) Cryotherapy for the prevention of weekly paclitaxel-induced peripheral adverse events in breast cancer patients. Supportive Care in Cancer 28:5005. https://doi.org/10.1007/S00520-020-05345-9\u003c/li\u003e\n\u003cli\u003eScott\u0026eacute; F, Tourani JM, Banu E, et al (2005) Multicenter study of a frozen glove to prevent docetaxel-induced onycholysis and cutaneous toxicity of the hand. Journal of Clinical Oncology 23:4424\u0026ndash;4429. https://doi.org/10.1200/JCO.2005.15.651/ASSET/IMAGES/ZLJ0190523730003.JPEG\u003c/li\u003e\n\u003cli\u003eChan A, Elsayed A, Ng DQ, et al (2022) A global survey on the utilization of cryotherapy and compression therapy for the prevention of chemotherapy-induced peripheral neuropathy. Supportive Care in Cancer 30:10001\u0026ndash;10007. https://doi.org/10.1007/S00520-022-07383-X/FIGURES/2\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"breast-cancer-research-and-treatment","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brea","sideBox":"Learn more about [Breast Cancer Research and Treatment](https://www.springer.com/journal/10549)","snPcode":"10549","submissionUrl":"https://submission.nature.com/new-submission/10549/3","title":"Breast Cancer Research and Treatment","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4744443/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4744443/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eCryotherapy with taxane infusion is a non-invasive strategy to prevent PN, but its efficacy is not proven\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA systematic search was conducted, and 477 records were identified. The titles were screened independently by 2 reviewers. 14 were included for the meta-analysis using R package meta. Only studies that analyzed cryotherapy use in BC patients who received paclitaxel or nab-paclitaxel were included. Relative risk (RR) derived from random effects model was used to compare the occurrence of PN.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIncidence of Common Terminology Criteria for Adverse Events (CTCAE) grade\u0026thinsp;\u0026ge;\u0026thinsp;2 PN was 24.85% (81/326) in the cryotherapy arm and 42.35% (72/170) in the placebo arm. Overall RR for CTCAE grade\u0026thinsp;\u0026ge;\u0026thinsp;2 PN with cryotherapy compared to placebo was 0.45 [0.27,0.77, p\u0026thinsp;=\u0026thinsp;0.0031]. RR for sensory PN was 0.19 [0.05,0.66, p\u0026thinsp;=\u0026thinsp;0.009] and for motor PN was 0.18 [0.03,0.99, p\u0026thinsp;=\u0026thinsp;0.0491]. RR for Patient Neurotoxicity Questionnaire (PNQ) score\u0026thinsp;\u0026ge;\u0026thinsp;D which connotes severe neuropathy was 0.24 [0.09,0.62, p\u0026thinsp;=\u0026thinsp;0.0035]. Cold intolerance was the predominant adverse effect at 15% (37/247).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eUse of cryotherapy decreased the occurrence of CTCAE grade\u0026thinsp;\u0026ge;\u0026thinsp;2 PN by 55%. Cold intolerance was the most frequently reported issue with its use but lead to relatively low discontinuation rates.\u003c/p\u003e","manuscriptTitle":"A Meta-analysis Studying the Utility of Cryotherapy in the Prevention of Peripheral Neuropathy in Breast Cancer Patients Receiving Paclitaxel and Nab-Paclitaxel.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-16 16:00:38","doi":"10.21203/rs.3.rs-4744443/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-08-06T22:46:10+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-01T12:00:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"43484382489687231823620359039440264366","date":"2024-07-18T07:08:06+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-18T06:55:40+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-16T07:27:24+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-16T07:26:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"Breast Cancer Research and Treatment","date":"2024-07-15T16:58:42+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"breast-cancer-research-and-treatment","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brea","sideBox":"Learn more about [Breast Cancer Research and Treatment](https://www.springer.com/journal/10549)","snPcode":"10549","submissionUrl":"https://submission.nature.com/new-submission/10549/3","title":"Breast Cancer Research and Treatment","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"9e5abc7f-f742-49e4-80df-bb5d8e5cc11a","owner":[],"postedDate":"August 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-01-20T16:05:54+00:00","versionOfRecord":{"articleIdentity":"rs-4744443","link":"https://doi.org/10.1007/s10549-024-07597-z","journal":{"identity":"breast-cancer-research-and-treatment","isVorOnly":false,"title":"Breast Cancer Research and Treatment"},"publishedOn":"2025-01-19 15:56:54","publishedOnDateReadable":"January 19th, 2025"},"versionCreatedAt":"2024-08-16 16:00:38","video":"","vorDoi":"10.1007/s10549-024-07597-z","vorDoiUrl":"https://doi.org/10.1007/s10549-024-07597-z","workflowStages":[]},"version":"v1","identity":"rs-4744443","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4744443","identity":"rs-4744443","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}