{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:43:35Z","timestamp":1785433415875,"version":"3.56.0"},"reference-count":30,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T00:00:00Z","timestamp":1782000000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011033","name":"Ministerio de Ciencia e Innovaci\u00f3n, Agencia Estatal de Investigaci\u00f3n and FEDER","doi-asserted-by":"publisher","award":["PID2021-128984OB-I00"],"award-info":[{"award-number":["PID2021-128984OB-I00"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"award":["PID2021-128984OB-I00"],"award-info":[{"award-number":["PID2021-128984OB-I00"]}],"id":[{"id":"https:\/\/ror.org\/003x0zc53","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Xunta de Galicia, Axencia Galega de Innovaci\u00f3n","award":["IN607D 2022\/02"],"award-info":[{"award-number":["IN607D 2022\/02"]}]},{"award":["IN607D 2022\/02"],"award-info":[{"award-number":["IN607D 2022\/02"]}],"id":[{"id":"https:\/\/ror.org\/02vcxyt85","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Clinical studies of prostate cancer treated with radically hypofractionated high-dose-rate brachytherapy (HDR-BT) have reported a significant loss of tumor control that contradicts the standard linear-quadratic (LQ) and low-\u03b1\/\u03b2-ratio paradigm for prostate cancer. In a previous study by our group, we showed that the linear\u2013quadratic\u2013linear (LQL) model could describe this response, but the underlying biological drivers remained unclear. In this follow-up study, we further investigate whether the interplay between hypoxia and reoxygenation kinetics can explain the poor response to extreme hypofractionation. Methods: We analyzed a large dataset of 3239 patients (44 schedules) using a three-compartment reoxygenation model (the MSK model) that simulates the dynamics of oxic, intermediate, and hypoxic cell populations. Results: The results show that the MSK model achieves an excellent fit to the clinical data (p&gt;0.99) while maintaining a biologically plausible low \u03b1\/\u03b2 ratio (\u22648 Gy). The reoxygenation model provided a performance comparable to the LQL model for low-risk prostate cancer and slightly inferior for intermediate-risk. Conclusions: This suggests that the observed reduction in tumor control may not necessarily be a failure of the LQ formalism but, rather, a consequence of oxygen dynamics associated with ultra-hypofractionated schedules. Nonetheless, neither this nor our previous work can provide insight into the driving mechanism and should only be interpreted as showing that both hypotheses are compatible with the clinical data.<\/jats:p>","DOI":"10.3390\/cancers18122007","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T06:13:37Z","timestamp":1782195217000},"page":"2007","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Analysis of the Response of Prostate Cancer to Ultra-Hypofractionated High-Dose-Rate Brachytherapy: The Role of Hypoxia and Reoxygenation"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4078-9519","authenticated-orcid":false,"given":"Eva G.","family":"K\u00f6lmel","sequence":"first","affiliation":[{"name":"Group of Medical Physics and Biomathematics, Instituto de Investigaci\u00f3n Sanitaria de Santiago (IDIS), 15706 Santiago de Compostela, Spain"},{"name":"Department of Medical Physics, Complexo Hospitalario Universitario de Santiago de Compostela, 15706 Santiago de Compostela, Spain"},{"name":"Department of Particle Physics, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5328-1207","authenticated-orcid":false,"given":"Pedro","family":"Otero-Casal","sequence":"additional","affiliation":[{"name":"Group of Medical Physics and Biomathematics, Instituto de Investigaci\u00f3n Sanitaria de Santiago (IDIS), 15706 Santiago de Compostela, Spain"},{"name":"Department of Particle Physics, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7990-3971","authenticated-orcid":false,"given":"Juan","family":"Pardo-Montero","sequence":"additional","affiliation":[{"name":"Group of Medical Physics and Biomathematics, Instituto de Investigaci\u00f3n Sanitaria de Santiago (IDIS), 15706 Santiago de Compostela, Spain"},{"name":"Department of Medical Physics, Complexo Hospitalario Universitario de Santiago de Compostela, 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e17","DOI":"10.1016\/j.ijrobp.2010.10.075","article-title":"Dose-fractionation sensitivity of prostate cancer deduced from radiotherapy outcomes of 5969 patients in seven international institutional datasets: \u03b1\/\u03b2 = 1.4 (0.9-2.2) Gy","volume":"82","author":"Miralbell","year":"2012","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1080\/02841860410002824","article-title":"The radiobiology of prostate cancer including new aspects of fractionated radiotherapy","volume":"44","author":"Fowler","year":"2005","journal-title":"Acta Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.radonc.2005.06.009","article-title":"The alpha\/beta ratio for prostate cancer: What is it, really?","volume":"76","author":"Bentzen","year":"2005","journal-title":"Radiother. Oncol. J. Eur. Soc. Ther. Radiol. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"193","DOI":"10.5114\/jcb.2020.94492","article-title":"A radiobiological study of the schemes with a low number of fractions in high-dose-rate brachytherapy as monotherapy for prostate cancer","volume":"12","author":"Guirado","year":"2020","journal-title":"J. Contemp. Brachyther."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"K\u00f6lmel, E.G., Pombar, M., and Pardo-Montero, J. (2025). Radiobiological Meta-Analysis of the Response of Prostate Cancer to High-Dose-Rate Brachytherapy: Investigation of the Reduction in Control for Extreme Hypofractionation. Cancers, 17.","DOI":"10.3390\/cancers17081338"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4825","DOI":"10.1088\/0031-9155\/49\/20\/012","article-title":"Extending the linear-quadratic model for large fraction doses pertinent to stereotactic radiotherapy","volume":"49","author":"Guerrero","year":"2004","journal-title":"Phys. Med. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.semradonc.2008.04.005","article-title":"The linear-quadratic model is inappropriate to model high dose per fraction effects in radiosurgery","volume":"18","author":"Kirkpatrick","year":"2008","journal-title":"Semin. Radiat. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/S0360-3016(03)00534-0","article-title":"Incorporating clinical measurements of hypoxia into tumor local control modeling of prostate cancer: Implications for the alpha\/beta ratio","volume":"57","author":"Nahum","year":"2003","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Stavrev, P., Stavreva, N., Genova, B., Ruggieri, R., Alongi, F., Nahum, A.E., and Pressyanov, D. (2021). The Impact of Different Timing Schedules on Prostate HDR-Mono-Brachytherapy. A TCP Modeling Investigation. Cancers, 13.","DOI":"10.3390\/cancers13194899"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4897","DOI":"10.1088\/0031-9155\/58\/14\/4897","article-title":"Modelling the interplay between hypoxia and proliferation in radiotherapy tumour response","volume":"58","author":"Jeong","year":"2013","journal-title":"Phys. Med. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1667\/RR2663.1","article-title":"Effects of radiation quality and oxygen on clustered DNA lesions and cell death","volume":"176","author":"Stewart","year":"2011","journal-title":"Radiat. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5469","DOI":"10.1158\/1078-0432.CCR-16-3277","article-title":"Modeling the cellular response of lung cancer to radiation therapy for a broad range of fractionation schedules","volume":"23","author":"Jeong","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"110006","DOI":"10.1016\/j.radonc.2023.110006","article-title":"\u201cPrimer shot\u201d fractionation with an early treatment break is theoretically superior to consecutive weekday fractionation schemes for early-stage non-small cell lung cancer","volume":"190","author":"Gouw","year":"2024","journal-title":"Radiother. Oncol. J. Eur. Soc. Ther. Radiol. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Pardo-Montero, J., Gonz\u00e1lez-Crespo, I., G\u00f3mez-Caama\u00f1o, A., and Gago-Arias, A. (2023). Radiobiological Meta-Analysis of the Response of Prostate Cancer to Different Fractionations: Evaluation of the Linear-Quadratic Response at Large Doses and the Effect of Risk and ADT. Cancers, 15.","DOI":"10.1101\/2023.02.28.23286507"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5020","DOI":"10.18632\/oncotarget.27088","article-title":"Prognostic value of tumor growth kinetic parameters in prostate cancer patients","volume":"10","author":"Zharinov","year":"2019","journal-title":"Oncotarget"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1016\/j.ijrobp.2005.03.049","article-title":"Hypoxic cell turnover in different solid tumor lines","volume":"62","author":"Ljungkvist","year":"2005","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1158\/0008-5472.CAN-07-5472","article-title":"Chronic hypoxia decreases synthesis of homologous recombination proteins to offset chemoresistance and radioresistance","volume":"68","author":"Chan","year":"2008","journal-title":"Cancer Res."},{"key":"ref_18","first-page":"473","article-title":"Implication of cell kinetic changes during the progression of human prostatic cancer","volume":"1","author":"Berges","year":"1995","journal-title":"Clin. Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.cpc.2009.09.018","article-title":"Variance based sensitivity analysis of model output. Design and estimator for the total sensitivity index","volume":"181","author":"Saltelli","year":"2010","journal-title":"Comput. Phys. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/j.ijrobp.2015.07.2290","article-title":"High-Dose-Rate Monotherapy for Localized Prostate Cancer: 10-Year Results","volume":"94","author":"Hauswald","year":"2016","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1016\/j.ijrobp.2010.09.006","article-title":"High-dose-rate brachytherapy as a monotherapy for favorable-risk prostate cancer: A Phase II trial","volume":"82","author":"Barkati","year":"2012","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.radonc.2017.09.038","article-title":"High dose rate brachytherapy as monotherapy for localised prostate cancer","volume":"126","author":"Strouthos","year":"2018","journal-title":"Radiother. Oncol. J. Eur. Soc. Ther. Radiol. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.brachy.2015.01.004","article-title":"High-dose-rate brachytherapy as a monotherapy for prostate cancer\u2013Single-institution results of the extreme fractionation regimen","volume":"14","author":"Walasek","year":"2015","journal-title":"Brachytherapy"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.ijrobp.2015.10.011","article-title":"Outcomes Associated with 3 Treatment Schedules of High-Dose-Rate Brachytherapy Monotherapy for Favorable-Risk Prostate Cancer","volume":"94","author":"Jawad","year":"2016","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"110381","DOI":"10.1016\/j.radonc.2024.110381","article-title":"Prostate high dose-rate brachytherapy as monotherapy for low and intermediate-risk prostate cancer: Efficacy results from a randomized phase II clinical trial of one fraction of 19 Gy or two fractions of 13.5 Gy: A 9-year update","volume":"198","author":"Hudson","year":"2024","journal-title":"Radiother. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.brachy.2024.02.005","article-title":"21 Gy single fraction prostate HDR brachytherapy: 5-year results of a single institution prospective pilot study","volume":"23","author":"Salari","year":"2024","journal-title":"Brachytherapy"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"39ra48","DOI":"10.1126\/scitranslmed.3000864","article-title":"A generalized linear-quadratic model for radiosurgery, stereotactic body radiation therapy, and high-dose rate brachytherapy","volume":"2","author":"Wang","year":"2010","journal-title":"Sci. Transl. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4774","DOI":"10.1158\/0008-5472.CAN-17-3806","article-title":"Combined MR imaging of oxygen consumption and supply reveals tumor hypoxia and aggressiveness in prostate cancer patients","volume":"78","author":"Hompland","year":"2018","journal-title":"Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Burnham, K.P., and Anderson, D.R. (2004). Model Selection and Multimodel Inference, Springer.","DOI":"10.1007\/b97636"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2108","DOI":"10.1158\/1078-0432.CCR-11-2711","article-title":"Tumor hypoxia predicts biochemical failure following radiotherapy for clinically localized prostate cancer","volume":"18","author":"Milosevic","year":"2012","journal-title":"Clin. Cancer Res."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/12\/2007\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T06:40:04Z","timestamp":1782196804000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/12\/2007"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,21]]},"references-count":30,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["cancers18122007"],"URL":"https:\/\/doi.org\/10.3390\/cancers18122007","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,21]]}}}