{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:33:16Z","timestamp":1789000396406,"version":"build-2803163510"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1014457","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000}}],"reference-count":53,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012165","name":"Key Technologies Research and Development Program","doi-asserted-by":"publisher","award":["2023YFA1008600"],"award-info":[{"award-number":["2023YFA1008600"]}],"id":[{"id":"10.13039\/501100012165","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["12522124"],"award-info":[{"award-number":["12522124"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["12371502"],"award-info":[{"award-number":["12371502"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Young Talent Support Plan of Xi\u2019an Jiaotong University"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Adaptive cancer therapy seeks to modulate aggressive treatment to preserve drug-sensitive tumor cells that suppress resistant populations, but existing strategies often rely on frequent treatment decisions enabled by intensive surveillance, limiting clinical feasibility. Here, we propose a clinically motivated alternative that shortens the treatment window within a fixed and relatively long surveillance cycle, thereby avoiding the need for frequent monitoring. Based on this idea, we develop a mechanistic modeling framework for single-threshold-guided adaptive therapy with partial surveillance-cycle treatment (AT-PSC) and benchmark its performance using reinforcement learning. Using clinically calibrated parameters from an individual patient, simulations show that AT-PSC prolongs the time to progression (TTP) by 402 days compared with adaptive therapy using full surveillance-cycle treatment, while substantially reducing treatment exposure (dose reduced by 10.1%). Consequently, AT-PSC achieves significantly larger TTP gains than continuous therapy (1891 days) and two-threshold-guided adaptive therapy AT50 (1123 days). Simulations using data from six additional patients and sensitivity analyses further demonstrate that these benefits are robust across heterogeneous tumor growth profiles, while individual-based treatment should be considered to maximize TTP. Reinforcement learning yields comparable outcomes under the same fixed treatment window and can further extend TTP when the treatment window is adaptively adjusted. Together, these results support AT-PSC as a clinically feasible strategy to improve disease control while reducing treatment burden, and suggest that a practical regimen, such as a 14-day treatment window within a 30-day surveillance cycle, can provide sustained benefits for a broad patient population.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1014457","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T17:58:31Z","timestamp":1782496711000},"page":"e1014457","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Single-threshold\u2013guided adaptive cancer therapy with partial-cycle treatment: A mechanistic and reinforcement learning analysis"],"prefix":"10.1371","volume":"22","author":[{"given":"Kexin","family":"Ma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningjing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zai","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7437-1934","authenticated-orcid":true,"given":"Robert A.","family":"Cheke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0418-5773","authenticated-orcid":true,"given":"Biao","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"pcbi.1014457.ref001","first-page":"47","volume-title":"Multi-drug resistance in cancer","author":"JP Gillet","year":"2009"},{"key":"pcbi.1014457.ref002","first-page":"141","article-title":"Drug resistance and combating drug resistance in cancer","volume":"2","author":"X Wang","year":"2019","journal-title":"Cancer Drug Resist"},{"issue":"7246","key":"pcbi.1014457.ref003","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1038\/459508a","article-title":"A change of strategy in the war on cancer","volume":"459","author":"RA Gatenby","year":"2009","journal-title":"Nature"},{"issue":"9","key":"pcbi.1014457.ref004","doi-asserted-by":"crossref","first-page":"3233","DOI":"10.3390\/ijms21093233","article-title":"Mechanisms of multidrug resistance in cancer chemotherapy","volume":"21","author":"K Bukowski","year":"2020","journal-title":"Int J Mol Sci"},{"issue":"19","key":"pcbi.1014457.ref005","doi-asserted-by":"crossref","first-page":"7499","DOI":"10.1158\/0008-5472.CAN-09-1354","article-title":"Lessons from applied ecology: cancer control using an evolutionary double bind","volume":"69","author":"RA Gatenby","year":"2009","journal-title":"Cancer Res"},{"issue":"327","key":"pcbi.1014457.ref006","article-title":"Exploiting evolutionary principles to prolong tumor control in preclinical models of breast cancer","volume":"8","author":"PM Enriquez-Navas","year":"2016","journal-title":"Sci Transl Med"},{"key":"pcbi.1014457.ref007","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.ebiom.2019.09.023","article-title":"Leveraging transcriptional dynamics to improve BRAF inhibitor responses in melanoma","volume":"48","author":"I Smalley","year":"2019","journal-title":"EBioMedicine"},{"issue":"10","key":"pcbi.1014457.ref008","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1038\/s41591-020-1060-8","article-title":"Continuous versus intermittent BRAF and MEK inhibition in patients with BRAF-mutated melanoma: a randomized phase 2 trial","volume":"26","author":"AP Algazi","year":"2020","journal-title":"Nat Med"},{"issue":"4","key":"pcbi.1014457.ref009","doi-asserted-by":"crossref","first-page":"823","DOI":"10.3390\/cancers13040823","article-title":"Adaptive therapy for metastatic melanoma: predictions from patient calibrated mathematical models","volume":"13","author":"E Kim","year":"2021","journal-title":"Cancers (Basel)"},{"issue":"6","key":"pcbi.1014457.ref010","article-title":"To modulate or to skip: De-escalating PARP inhibitor maintenance therapy in ovarian cancer using adaptive therapy","volume":"15","author":"MAR Strobl","year":"2024","journal-title":"Cell Syst"},{"issue":"1","key":"pcbi.1014457.ref011","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1038\/s41467-017-01968-5","article-title":"Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer","volume":"8","author":"J Zhang","year":"2017","journal-title":"Nat Commun"},{"issue":"2","key":"pcbi.1014457.ref012","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/nrc.2016.2","article-title":"Acquired resistance to immunotherapy and future challenges","volume":"16","author":"NP Restifo","year":"2016","journal-title":"Nat Rev Cancer"},{"issue":"8","key":"pcbi.1014457.ref013","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1172\/JCI9872","article-title":"Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice","volume":"105","author":"D Hanahan","year":"2000","journal-title":"J Clin Invest"},{"issue":"8","key":"pcbi.1014457.ref014","doi-asserted-by":"crossref","DOI":"10.1172\/JCI8829","article-title":"Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity","volume":"105","author":"G Klement","year":"2000","journal-title":"J Clin Invest"},{"issue":"11","key":"pcbi.1014457.ref015","doi-asserted-by":"crossref","first-page":"2546","DOI":"10.1002\/1097-0142(19861201)58:11<2546::AID-CNCR2820581131>3.0.CO;2-N","volume":"58","author":"LH Klotz","year":"1986","journal-title":"Cancer"},{"issue":"1","key":"pcbi.1014457.ref016","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1038\/s41467-017-01516-1","article-title":"Spatial competition constrains resistance to targeted cancer therapy","volume":"8","author":"K Bacevic","year":"2017","journal-title":"Nat Commun"},{"issue":"2","key":"pcbi.1014457.ref017","doi-asserted-by":"crossref","first-page":"188681","DOI":"10.1016\/j.bbcan.2022.188681","article-title":"Find the path of least resistance: adaptive therapy to delay treatment failure and improve outcomes","volume":"1877","author":"C Gedye","year":"2022","journal-title":"Biochim Biophys Acta Rev Cancer"},{"key":"pcbi.1014457.ref018","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.radonc.2022.01.039","article-title":"Survival benefits for non-small cell lung cancer patients treated with adaptive radiotherapy","volume":"168","author":"DS M\u00f8ller","year":"2022","journal-title":"Radiother Oncol"},{"key":"pcbi.1014457.ref019","first-page":"7","article-title":"Adaptive treatment strategies: an emerging approach for improving treatment effectiveness","volume":"12","author":"SA Murphy","year":"2004","journal-title":"Clin Sci"},{"key":"pcbi.1014457.ref020","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.jtbi.2018.07.028","article-title":"Capitalizing on competition: an evolutionary model of competitive release in metastatic castration resistant prostate cancer treatment","volume":"455","author":"J West","year":"2018","journal-title":"J Theor Biol"},{"key":"pcbi.1014457.ref021","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.76284","article-title":"Evolution-based mathematical models significantly prolong response to abiraterone in metastatic castrate-resistant prostate cancer and identify strategies to further improve outcomes","volume":"11","author":"J Zhang","year":"2022","journal-title":"Elife"},{"issue":"11","key":"pcbi.1014457.ref022","doi-asserted-by":"crossref","first-page":"4894","DOI":"10.1158\/0008-5472.CAN-08-3658","article-title":"Adaptive therapy","volume":"69","author":"RA Gatenby","year":"2009","journal-title":"Cancer Res"},{"issue":"7","key":"pcbi.1014457.ref023","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1158\/0008-5472.CAN-19-2669","article-title":"Towards Multidrug Adaptive Therapy","volume":"80","author":"J West","year":"2020","journal-title":"Cancer Res"},{"issue":"5","key":"pcbi.1014457.ref024","doi-asserted-by":"crossref","first-page":"6305","DOI":"10.3934\/mbe.2021315","article-title":"Do mechanisms matter? Comparing cancer treatment strategies across mathematical models and outcome objectives","volume":"18","author":"CK Buhler","year":"2021","journal-title":"Math Biosci Eng"},{"key":"pcbi.1014457.ref025","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.84263","article-title":"A survey of open questions in adaptive therapy: bridging mathematics and clinical translation","volume":"12","author":"J West","year":"2023","journal-title":"Elife"},{"issue":"4","key":"pcbi.1014457.ref026","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1158\/0008-5472.CAN-20-0806","article-title":"Turnover modulates the need for a cost of resistance in adaptive therapy","volume":"81","author":"MAR Strobl","year":"2021","journal-title":"Cancer Res"},{"issue":"11","key":"pcbi.1014457.ref027","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1158\/0008-5472.CAN-23-2040","article-title":"Mathematical model-driven deep learning enables personalized adaptive therapy","volume":"84","author":"K Gallagher","year":"2024","journal-title":"Cancer Res"},{"issue":"10","key":"pcbi.1014457.ref028","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1007\/s11538-025-01525-y","article-title":"Deriving optimal treatment timing for adaptive therapy: matching the model to the tumor dynamics","volume":"87","author":"K Gallagher","year":"2025","journal-title":"Bull Math Biol"},{"key":"pcbi.1014457.ref029","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.jtbi.2018.09.022","article-title":"Optimal control to develop therapeutic strategies for metastatic castrate resistant prostate cancer","volume":"459","author":"JJ Cunningham","year":"2018","journal-title":"J Theor Biol"},{"issue":"4","key":"pcbi.1014457.ref030","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1073\/pnas.1409403112","article-title":"The value of monitoring to control evolving populations","volume":"112","author":"A Fischer","year":"2015","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pcbi.1014457.ref031","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1137\/24M1629560","article-title":"Dynamic behaviors of a periodic system with threshold policy-guided periodic and intermittent therapy of tumor","volume":"85","author":"B Tang","year":"2025","journal-title":"SIAM J Appl Math"},{"issue":"6","key":"pcbi.1014457.ref032","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1002\/j.1939-4640.1992.tb00337.x","article-title":"Androgen regulation of programmed death of normal and malignant prostatic cells","volume":"13","author":"JT Isaacs","year":"1992","journal-title":"J Androl"},{"key":"pcbi.1014457.ref033","article-title":"AR, the cell cycle, and prostate cancer","volume":"6","author":"SP Balk","year":"2008","journal-title":"Nucl Recept Signal"},{"issue":"5928","key":"pcbi.1014457.ref034","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1126\/science.1168175","article-title":"Development of a second-generation antiandrogen for treatment of advanced prostate cancer","volume":"324","author":"C Tran","year":"2009","journal-title":"Science"},{"issue":"6","key":"pcbi.1014457.ref035","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1007\/s00332-008-9031-0","article-title":"A mathematical model of intermittent androgen suppression for prostate cancer","volume":"18","author":"AM Ideta","year":"2008","journal-title":"J Nonlinear Sci"},{"issue":"6","key":"pcbi.1014457.ref036","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1038\/s41559-021-01428-w","article-title":"A theoretical analysis of tumour containment","volume":"5","author":"Y Viossat","year":"2021","journal-title":"Nat Ecol Evol"},{"issue":"5","key":"pcbi.1014457.ref037","doi-asserted-by":"crossref","first-page":"448","DOI":"10.7326\/0003-4819-117-5-448_4","article-title":"The chemotherapy source book","volume":"117","year":"1992","journal-title":"Ann Intern Med"},{"issue":"10","key":"pcbi.1014457.ref038","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1093\/jnci\/djp079","article-title":"Dose escalation methods in phase I cancer clinical trials","volume":"101","author":"C Le Tourneau","year":"2009","journal-title":"J Natl Cancer Inst"},{"issue":"7","key":"pcbi.1014457.ref039","first-page":"1307","article-title":"Tumor size, sensitivity to therapy, and design of treatment schedules","volume":"61","author":"L Norton","year":"1977","journal-title":"Cancer Treat Rep"},{"issue":"14","key":"pcbi.1014457.ref040","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1056\/NEJMoa1212299","article-title":"Intermittent versus continuous androgen deprivation in prostate cancer","volume":"368","author":"M Hussain","year":"2013","journal-title":"N Engl J Med"},{"issue":"7","key":"pcbi.1014457.ref041","first-page":"1878","article-title":"Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer","volume":"60","author":"T Browder","year":"2000","journal-title":"Cancer Res"},{"issue":"6","key":"pcbi.1014457.ref042","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1016\/j.trecan.2022.02.005","article-title":"Optimizing the future: how mathematical models inform treatment schedules for cancer","volume":"8","author":"D Mathur","year":"2022","journal-title":"Trends Cancer"},{"issue":"6","key":"pcbi.1014457.ref043","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1007\/s00285-025-02220-1","article-title":"Optimal adaptive therapeutic schedules for metastatic castrate-resistant prostate cancer based on bilevel optimization problem","volume":"90","author":"D Wang","year":"2025","journal-title":"J Math Biol"},{"key":"pcbi.1014457.ref044","author":"J Schulman","year":"2017"},{"issue":"2","key":"pcbi.1014457.ref045","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1002\/cncr.21989","article-title":"Final results of the Canadian prospective phase II trial of intermittent androgen suppression for men in biochemical recurrence after radiotherapy for locally advanced prostate cancer: clinical parameters","volume":"107","author":"N Bruchovsky","year":"2006","journal-title":"Cancer"},{"issue":"8","key":"pcbi.1014457.ref046","doi-asserted-by":"crossref","first-page":"2127","DOI":"10.1158\/0008-5472.CAN-17-2649","article-title":"Spatial heterogeneity and evolutionary dynamics modulate time to recurrence in continuous and adaptive cancer therapies","volume":"78","author":"JA Gallaher","year":"2018","journal-title":"Cancer Res"},{"issue":"4","key":"pcbi.1014457.ref047","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/labinvest.2014.155","article-title":"Mapping spatial heterogeneity in the tumor microenvironment: a new era for digital pathology","volume":"95","author":"A Heindl","year":"2015","journal-title":"Lab Invest"},{"key":"pcbi.1014457.ref048","article-title":"Spatial tumor heterogeneity: the next frontier in understanding cancer resistance","volume":"1","author":"KE Taylor","year":"2025","journal-title":"Oncol Nucl Med Transplantol"},{"issue":"20","key":"pcbi.1014457.ref049","doi-asserted-by":"crossref","first-page":"13085","DOI":"10.1073\/pnas.202139299","article-title":"Metapopulation dynamics and spatial heterogeneity in cancer","volume":"99","author":"I Gonz\u00e1lez-Garc\u00eda","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"8","key":"pcbi.1014457.ref050","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a026583","article-title":"Spatial heterogeneity in the tumor microenvironment","volume":"6","author":"Y Yuan","year":"2016","journal-title":"Cold Spring Harb Perspect Med"},{"issue":"7","key":"pcbi.1014457.ref051","doi-asserted-by":"crossref","first-page":"2608","DOI":"10.1021\/acs.jproteome.4c00338","article-title":"Proteomics analysis of interactions between drug-resistant and drug-sensitive cancer cells: comparative studies of monoculture and coculture cell systems","volume":"23","author":"Z Peng","year":"2024","journal-title":"J Proteome Res"},{"issue":"14","key":"pcbi.1014457.ref052","doi-asserted-by":"crossref","first-page":"3673","DOI":"10.1158\/0008-5472.CAN-13-3162","article-title":"Mechanisms of resistance to intermittent androgen deprivation in patients with prostate cancer identified by a novel computational method","volume":"74","author":"JD Morken","year":"2014","journal-title":"Cancer Res"},{"issue":"15","key":"pcbi.1014457.ref053","doi-asserted-by":"crossref","first-page":"2975","DOI":"10.1158\/0008-5472.CAN-14-3830","article-title":"Neuroendocrine transdifferentiation in human prostate cancer cells: an integrated approach","volume":"75","author":"M Cerasuolo","year":"2015","journal-title":"Cancer Res"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1014457","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1014457","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T18:00:24Z","timestamp":1783360824000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1014457"}},"subtitle":[],"editor":[{"given":"Roger Dimitri","family":"Kouyos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,6,26]]},"references-count":53,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6,26]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1014457","relation":{},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,26]]}}}