{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T17:52:20Z","timestamp":1781632340473,"version":"3.54.5"},"reference-count":23,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T00:00:00Z","timestamp":1769040000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T00:00:00Z","timestamp":1771200000000},"content-version":"vor","delay-in-days":25,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI23\/01324"],"award-info":[{"award-number":["PI23\/01324"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100023554","name":"Fundaci\u00f3n Canaria Instituto de Investigaci\u00f3n Sanitaria de Canarias","doi-asserted-by":"publisher","award":["PIFIISC24\/37"],"award-info":[{"award-number":["PIFIISC24\/37"]}],"id":[{"id":"10.13039\/501100023554","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015968","name":"Cabildo de Gran Canaria","doi-asserted-by":"publisher","award":["CIGC\u201923-24"],"award-info":[{"award-number":["CIGC\u201923-24"]}],"id":[{"id":"10.13039\/501100015968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Cancer"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent, disabling side effect of taxanes and platinum drugs, often compromising quality of life and treatment continuity. Existing therapies are few and largely ineffective. Given this unmet need, our prior experience suggests ozone therapy may offer clinical benefit as an adjuvant treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      OzoParQT is a Phase II\u2013III randomized, triple-blind trial including 42 adults (\u2265\u200918 years) with any cancer and Grade\u2009\u2265\u20092 CIPN (numbness and\/or tingling) lasting\u2009\u2265\u20093 months. Eligible patients must be off neurotoxic chemotherapy for \u2265\u20093 months, with stable\/remitted disease and \u2265\u20096-month life expectancy. Participants will be randomized (1:1) to Ozone or Control (placebo) groups. All patients will continue standard care by their oncologists and undergo 40 rectal insufflation sessions over 16 weeks (3\u00d7\/week for 8 weeks, then 2\u00d7\/week). The Ozone group receives O\u2083\/O\u2082 (10\u201330\u00a0\u00b5g\/mL); the Control group receives O\u2082 (O\n                      <jats:sub>3<\/jats:sub>\n                      \/O\n                      <jats:sub>2<\/jats:sub>\n                      : 0\u00a0\u00b5g\/mL). Volumes range from 180 to 300 mL as tolerated.\n                    <\/jats:p>\n                    <jats:p>The primary objectives are to evaluate the effect of adding ozone on change from baseline at week 28 (end of follow-up) in: i) patients' self-perceived level of paraesthesia (numbness and\/or tingling), and ii) patients' self-perceived health-related quality of life (HRQoL).<\/jats:p>\n                    <jats:p>Secondary objectives include evaluating the effect of ozone on: i) additional direct costs, ii) evolution of neuropathy symptoms (CTCAE v5.0, QLQ-CIPN20), iii) evolution of quality of life (EQ-5D-5L, and QLQ-C30), iv) evolution of anxiety and depression, v) evolution of biochemical parameters related to oxidative stress and chronic inflammation, vi) evolution of infrared images and spectral signatures (450 to 900 nm) in hyperspectral images obtained from hands and feet, and vii) toxicity of rectal ozone treatment. Except for direct costs and toxicity, all variables will be assessed at week 16 (end of insufflations) and week 28 (end of follow-up). Masking will be triple: participant, care provider, and outcomes assessor.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>This study aims to provide robust evidence on the effectiveness and cost-effectiveness of ozone therapy as an adjuvant treatment for CIPN, a condition with very limited therapeutic options. The trial will clarify whether ozone therapy can significantly improve patient-reported symptoms and quality of life, potentially leading to a new management strategy with low morbidity.\u00a0<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>EU CT ID: 2024-517196-20-00. ClinicalTrials.gov Identifier NCT06706544, Registered January 22, 2025. https:\/\/clinicaltrials.gov\/study\/NCT06706544.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12885-025-15399-9","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T07:35:25Z","timestamp":1769067325000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Effectiveness and cost-effectiveness of ozone treatment in patients with paraesthesia (numbness, tingling) secondary to chemotherapy-induced peripheral neuropathy: randomized, triple-blind clinical trial (OzoParQT)"],"prefix":"10.1186","volume":"26","author":[{"given":"Bernardino","family":"Clavo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angeles","family":"C\u00e1novas-Molina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Cazorla-Rivero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregorio","family":"Mart\u00ednez-S\u00e1nchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saray","family":"Galv\u00e1n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gretel","family":"Ben\u00edtez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Federico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Himar","family":"Fabelo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas M.","family":"Gonz\u00e1lez-Mart\u00edn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel A.","family":"Garc\u00eda-Bello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elba","family":"Lago-Moreno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Antonilli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avinash","family":"Ramchandani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan A.","family":"D\u00edaz-Garrido","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minerva","family":"Navarro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Mart\u00edn-Alfaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haid\u00e9","family":"Hern\u00e1ndez-L\u00f3pez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo M.","family":"Callico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Rodr\u00edguez-Esparrag\u00f3n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,22]]},"reference":[{"issue":"6","key":"15399_CR1","doi-asserted-by":"publisher","first-page":"1451","DOI":"10.3390\/ijms20061451","volume":"20","author":"R Zajaczkowska","year":"2019","unstructured":"Zajaczkowska R, Kocot-Kepska M, Leppert W, Wrzosek A, Mika J, Wordliczek J. Mechanisms of Chemotherapy-Induced peripheral neuropathy. Int J Mol Sci. 2019;20(6):1451.","journal-title":"Int J Mol Sci"},{"issue":"2","key":"15399_CR2","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1007\/s40487-021-00168-y","volume":"9","author":"J Burgess","year":"2021","unstructured":"Burgess J, Ferdousi M, Gosal D, Boon C, Matsumoto K, Marshall A, et al. Chemotherapy-Induced peripheral neuropathy: Epidemiology, pathomechanisms and treatment. Oncol Ther. 2021;9(2):385\u2013450.","journal-title":"Oncol Ther"},{"issue":"28","key":"15399_CR3","doi-asserted-by":"publisher","first-page":"3325","DOI":"10.1200\/JCO.20.01399","volume":"38","author":"CL Loprinzi","year":"2020","unstructured":"Loprinzi CL, Lacchetti C, Bleeker J, Cavaletti G, Chauhan C, Hertz DL, et al. Prevention and management of Chemotherapy-Induced peripheral neuropathy in survivors of adult cancers: ASCO guideline update. J Clin Oncol. 2020;38(28):3325\u201348.","journal-title":"J Clin Oncol"},{"issue":"8","key":"15399_CR4","doi-asserted-by":"publisher","first-page":"949","DOI":"10.6004\/jnccn.2019.7290","volume":"17","author":"JM McCrary","year":"2019","unstructured":"McCrary JM, Goldstein D, Trinh T, Timmins HC, Li T, Menant J, et al. Balance deficits and functional disability in cancer survivors exposed to neurotoxic cancer treatments. J Natl Compr Canc Netw. 2019;17(8):949\u201355.","journal-title":"J Natl Compr Canc Netw"},{"issue":"13","key":"15399_CR5","doi-asserted-by":"publisher","first-page":"1359","DOI":"10.1001\/jama.2013.2813","volume":"309","author":"EM Smith","year":"2013","unstructured":"Smith EM, Pang H, Cirrincione C, Fleishman S, Paskett ED, Ahles T, et al. Effect of Duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA. 2013;309(13):1359\u201367.","journal-title":"JAMA"},{"key":"15399_CR6","doi-asserted-by":"crossref","unstructured":"Mattar M, Umutoni F, Hassan MA, Wamburu MW, Turner R, Patton JS, et al. Chemotherapy-Induced peripheral neuropathy: A recent update on pathophysiology and treatment. Life (Basel) 2024;14(8).","DOI":"10.3390\/life14080991"},{"key":"15399_CR7","doi-asserted-by":"publisher","first-page":"1080888","DOI":"10.3389\/fphar.2022.1080888","volume":"13","author":"C Wang","year":"2022","unstructured":"Wang C, Chen S, Jiang W. Treatment for chemotherapy-induced peripheral neuropathy: A systematic review of randomized control trials. Front Pharmacol. 2022;13:1080888.","journal-title":"Front Pharmacol"},{"key":"15399_CR8","doi-asserted-by":"crossref","unstructured":"Markham MJ, Wachter K, Agarwal N, Bertagnolli MM, Chang SM, Dale W, et al. Clinical cancer advances 2020: annual report on progress against cancer from the American society of clinical oncology. J Clin Oncol. 2020;38(10):1081.","DOI":"10.1200\/JCO.19.03141"},{"key":"15399_CR9","doi-asserted-by":"publisher","first-page":"750507","DOI":"10.3389\/fphar.2022.750507","volume":"13","author":"H Was","year":"2022","unstructured":"Was H, Borkowska A, Bagues A, Tu L, Liu JYH, Lu Z, et al. Mechanisms of Chemotherapy-Induced neurotoxicity. Front Pharmacol. 2022;13:750507.","journal-title":"Front Pharmacol"},{"issue":"6","key":"15399_CR10","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1007\/s12026-022-09307-7","volume":"70","author":"P Gupta","year":"2022","unstructured":"Gupta P, Makkar TK, Goel L, Pahuja M. Role of inflammation and oxidative stress in chemotherapy-induced neurotoxicity. Immunol Res. 2022;70(6):725\u201341.","journal-title":"Immunol Res"},{"key":"15399_CR11","doi-asserted-by":"publisher","first-page":"1345811","DOI":"10.3389\/fnmol.2024.1345811","volume":"17","author":"X Chen","year":"2024","unstructured":"Chen X, Gan Y, Au NPB, Ma CHE. Current Understanding of the molecular mechanisms of chemotherapy-induced peripheral neuropathy. Front Mol Neurosci. 2024;17:1345811.","journal-title":"Front Mol Neurosci"},{"key":"15399_CR12","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/1479-5876-9-66","volume":"9","author":"VA Bocci","year":"2011","unstructured":"Bocci VA, Zanardi I, Travagli V. Ozone acting on human blood yields a hormetic dose-response relationship. J Transl Med. 2011;9:66.","journal-title":"J Transl Med"},{"key":"15399_CR13","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.freeradbiomed.2018.05.093","volume":"124","author":"M Galie","year":"2018","unstructured":"Galie M, Costanzo M, Nodari A, Boschi F, Calderan L, Mannucci S, et al. Mild ozonisation activates antioxidant cell response by the Keap1\/Nrf2 dependent pathway. Free Radic Biol Med. 2018;124:114\u201321.","journal-title":"Free Radic Biol Med"},{"key":"15399_CR14","doi-asserted-by":"publisher","unstructured":"Travagli V, Iorio EL. The biological and molecular action of Ozone and its derivatives: State-of-the-Art, enhanced Scenarios, and quality insights. Int J Mol Sci. 2023;24(10):8465. https:\/\/doi.org\/10.3390\/ijms24108465.","DOI":"10.3390\/ijms24108465"},{"key":"15399_CR15","doi-asserted-by":"publisher","unstructured":"Viebahn-Haensler R, Leon Fernandez OS. Ozone as redox bioregulator in preventive medicine: the molecular and Pharmacological basis of the Low-Dose Ozone Concept-A review. Int J Mol Sci. 2023;24(21):15747. https:\/\/doi.org\/10.3390\/ijms242115747.","DOI":"10.3390\/ijms242115747"},{"key":"15399_CR16","doi-asserted-by":"publisher","unstructured":"Clavo B, Martinez-Sanchez G, Rodriguez-Esparragon F, Rodriguez-Abreu D, Galvan S, Aguiar-Bujanda D, et al. Modulation by Ozone therapy of oxidative stress in Chemotherapy-Induced peripheral neuropathy: the background for a randomized clinical trial. Int J Mol Sci. 2021;22(6):2802. https:\/\/doi.org\/10.3390\/ijms22062802.","DOI":"10.3390\/ijms22062802"},{"issue":"14","key":"15399_CR17","doi-asserted-by":"publisher","first-page":"2278","DOI":"10.3390\/cancers17142278","volume":"17","author":"B Clavo","year":"2025","unstructured":"Clavo B, C\u00e1novas-Molina A, Federico M, Mart\u00ednez-S\u00e1nchez G, Ben\u00edtez G, Galv\u00e1n S, et al. Ozone treatment in the management of Chemotherapy-Induced peripheral neuropathy: A review of rationale and research directions. Cancers. 2025;17(14):2278.","journal-title":"Cancers"},{"key":"15399_CR18","doi-asserted-by":"publisher","unstructured":"Szklener K, Rudzi\u0144ska A, Juchaniuk P, Kaba\u0142a Z, Ma\u0144dziuk S. Ozone in Chemotherapy-Induced peripheral Neuropathy\u2014Current state of Art, Possibilities, and perspectives. Int J Mol Sci. 2023;24(6):5279. https:\/\/doi.org\/10.3390\/ijms24065279.","DOI":"10.3390\/ijms24065279"},{"key":"15399_CR19","doi-asserted-by":"publisher","first-page":"935269","DOI":"10.3389\/fphys.2022.935269","volume":"13","author":"B Clavo","year":"2022","unstructured":"Clavo B, Rodr\u00edguez-Abreu D, Galv\u00e1n S, Federico M, Mart\u00ednez-S\u00e1nchez G, Ramallo-Fari\u00f1a Y, et al. Long-term improvement by Ozone treatment in chronic pain secondary to chemotherapy-induced peripheral neuropathy: A preliminary report. Front Physiol. 2022;13:935269.","journal-title":"Front Physiol"},{"key":"15399_CR20","doi-asserted-by":"publisher","first-page":"153473542413070","DOI":"10.1177\/15347354241307038","volume":"24","author":"B Clavo","year":"2025","unstructured":"Clavo B, Rodriguez-Abreu D, Galvan-Ruiz S, Federico M, Canovas-Molina A, Ramallo-Farina Y, et al. Long-Term effects of Ozone treatment in patients with persistent numbness and tingling secondary to Chemotherapy-Induced peripheral Neuropathy. A retrospective study. Integr Cancer Ther. 2025;24:15347354241307038.","journal-title":"Integr Cancer Ther"},{"key":"15399_CR21","doi-asserted-by":"publisher","first-page":"840623","DOI":"10.3389\/fphys.2022.840623","volume":"13","author":"FJ Hidalgo-Tallon","year":"2022","unstructured":"Hidalgo-Tallon FJ, Torres-Morera LM, Baeza-Noci J, Carrillo-Izquierdo MD, Pinto-Bonilla R. Updated review on Ozone therapy in pain medicine. Front Physiol. 2022;13:840623.","journal-title":"Front Physiol"},{"issue":"5","key":"15399_CR22","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1080\/01919512.2016.1191992","volume":"38","author":"R Viebahn-Hansler","year":"2016","unstructured":"Viebahn-Hansler R, Leon Fernandez OS, Fahmy Z. Ozone in medicine: clinical evaluation and evidence classification of the systemic Ozone Applications, major autohemotherapy and rectal Insufflation, according to the requirements for evidence-Based medicine. Ozone-Sci Eng. 2016;38(5):322\u201345.","journal-title":"Ozone-Sci Eng"},{"key":"15399_CR23","doi-asserted-by":"crossref","unstructured":"Martinez-Vega B, Leon R, Fabelo H, Ortega S, Quevedo E, Canovas-Molina A, et al. Analysis of the behavior of ozone therapy in chemotherapy-induced neuropathy using hyperspectral imaging technology. In: 26th Euromicro Conference on Digital System Design (DSD), 2023. Durres, Albania. 2023:500\u2013506. https:\/\/ieeexplore.ieee.org\/document\/10456852.","DOI":"10.1109\/DSD60849.2023.00075"}],"container-title":["BMC Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12885-025-15399-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12885-025-15399-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12885-025-15399-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T16:57:16Z","timestamp":1781629036000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12885-025-15399-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,22]]},"references-count":23,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["15399"],"URL":"https:\/\/doi.org\/10.1186\/s12885-025-15399-9","relation":{},"ISSN":["1471-2407"],"issn-type":[{"value":"1471-2407","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,22]]},"assertion":[{"value":"2 October 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 November 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 January 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study protocol was approved by (i) the Ethics Committee of Las Palmas (Spain) on July 25, 2024 (reference number 2023-210-1) and (ii) the Spanish Medicines Agency (AEMPS) and European Medicines Agency (EMA) on November 19, 2024 (EU CT ID 2024-517196-20-00). It was registered in i) the Spanish Clinical Studies Registry (REEC) (ID: 2024-517196-20-00, Protocol Code: OzoParQT) and Clinicaltrials.gov (ID: NCT06706544) on January 22, 2025.The trial will be conducted in accordance with this protocol, the Good Clinical Practice (GCP) guidelines of the AEMPS, and the current EU\/Spanish legislation on biomedical research. The trial will also be conducted in accordance with the principles outlined in the Declaration of Helsinki (Fortaleza, Brazil, 2013). Written informed consent will be obtained from all participants prior to their enrolment in the study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable. This manuscript does not contain any individual person\u2019s data, images, or videos.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Several approved O3T devices will be used interchangeably in this study. One of them (Ozonosan Alpha-plus\n                      \u00ae\n                      ) was provided by H\u00e4nsler Medical GmbH, Iffezheim, Germany). Three other devices (Ozonobaric-P, SEDECAL, Madrid, Spain) were supported by a grant (COV20\/00702) from the Instituto de Salud Carlos III (Spanish Ministry of Science and Innovation, Madrid, Spain). In 2023, B.C. received financial support for a European grant application from H\u00e4nsler Medical GmbH (Iffezheim, Germany).The authors declare that the research will be conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that the funders had no role in the design of the study, in the collection, analysis, or interpretation of data, nor in the writing of this protocol, nor in the decision to publish the results, nor in the final manuscript. The authors declare no other potential conflict of interest than those described above.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"260"}}