{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T01:21:25Z","timestamp":1755220885494,"version":"3.43.0"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T00:00:00Z","timestamp":1754611200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82272738"],"award-info":[{"award-number":["82272738"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Neoadjuvant chemoradiotherapy has become the standard treatment for mid-to-low location LARC. Recently, total neoadjuvant therapy (TNT) has been used in patients with \u2018high-risk\u2019 or \u2018very high-risk\u2019 LARC according to ESMO guideline (2017). TNT not only increases the pathological complete response (pCR) rate, but also provides patients with more opportunities to preserve organ function. However, TNT mode seems to have reached a plateau. Some clinical studies published in recent years have also confirmed that different modes of neoadjuvant chemoradiotherapy combined with ICIs can further improve the pCR rate to varying degrees. It is necessary to explore an appropriate treatment mode for patients with mid-to-low location, who are unresectable or difficult to achieve R0 resection at the initial stage of surgery and have a strong desire to preserve anal cavity. Numerous basic researches have demonstrated that radiotherapy can remodel the tumor immune microenvironment and play a potential synergistic effect on ICIs. Therefore, this study will aim to explore whether TNT combined with ICIs could improve pCR rates in patients with \u2018high-risk\u2019 or \u2018very high-risk\u2019 LARC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This prospective, single-center, single-arm phase II trial aims to assess the pCR rate of neoadjuvant long-course concurrent chemoradiotherapy sequential 6 cycles CapeOX regimen combined with sintilimab in \u2018high-risk\/very high-risk\u2019 LARC patients with mid-to-low location and with pMMR phenotype. The primary endpoint for this study is the pCR rate. Secondary endpoints include 2-year sustained of clinical complete response (cCR) rate; CR rate (the rate of patients with sustained cCR for 2 years and pCR); major pathological remission; neoadjuvant rectal score; 3-year non-regrowth disease free survival; 3-year disease-free survival; 3-year overall survival; 3-year localized recurrence-free survival; 3-year distant metastasis free survival; 3-year stoma-free survival, anal sphincter preservation rate; surgical R0 resection rate and safety (adverse events during neoadjuvant therapy and 30 days after surgery, as well as tolerance).<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>This study will investigate whether neoadjuvant long-course concurrent chemoradiotherapy sequential total neoadjuvant chemotherapy combined with immunotherapy could further enhances tumor pCR rate in \u2018high-risk\/very high-risk\u2019 LARC patients with mid-to-low location and with pMMR phenotype and is expected to improve prognosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial registration<\/jats:title><jats:p>ClinicalTrials.gov NCT05998122.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2025.1594927","type":"journal-article","created":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T04:11:30Z","timestamp":1754626290000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Total neoadjuvant chemoradiotherapy plus anti PD-1 for mid-to-low locally advanced rectal cancer: study protocol of a prospective, single arm, phase II study (STARS - RC06)"],"prefix":"10.3389","volume":"15","author":[{"given":"Meichen","family":"Gu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuchen","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liang","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuan","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tingting","family":"Liang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhuo","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zheng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiang","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liang","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pengyu","family":"Chang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Quan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA: Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1097\/CM9.0000000000002108","article-title":"Cancer statistics in China and United States, 2022: profiles, trends, and determinants","volume":"135","author":"Xia","year":"2022","journal-title":"Chin Med J"},{"key":"B3","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/1477-7819-10-39","article-title":"Results after multivisceral resections of locally advanced colorectal cancers: an analysis on clinical and pathological t4 tumors","volume":"10","author":"Gezen","year":"2012","journal-title":"World J Surg Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2022.0051","article-title":"Rectal cancer, version 2.2022, NCCN clinical practice guidelines in oncology","volume":"20","author":"Benson","year":"2022","journal-title":"J Natl Compr Canc Netw"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(10)70172-8","article-title":"Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data","volume":"11","author":"Maas","year":"2010","journal-title":"Lancet Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.01667","article-title":"Multicenter, randomized, phase III trial of short-Term radiotherapy plus chemotherapy versus long-Term chemoradiotherapy in locally advanced rectal cancer (STELLAR)","volume":"40","author":"Jin","year":"2022","journal-title":"J Clin Oncol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(21)00079-6","article-title":"Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial","volume":"22","author":"Conroy","year":"2021","journal-title":"Lancet Oncol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/S1470-2045(20)30555-6","article-title":"Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial","volume":"22","author":"Bahadoer","year":"2021","journal-title":"Lancet Oncol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2020.30097","article-title":"Total neoadjuvant therapy vs standard therapy in locally advanced rectal cancer: A systematic review and meta-analysis","volume":"3","author":"Kasi","year":"2020","journal-title":"JAMA Netw Open"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdx224","article-title":"Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"28","author":"Glynne-Jones","year":"2017","journal-title":"Ann Oncol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(15)00007-8","article-title":"Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy","volume":"16","author":"Sharabi","year":"2015","journal-title":"Lancet Oncol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-21-3213","article-title":"Preoperative Chemoradiotherapy plus Nivolumab before Surgery in Patients with Microsatellite Stable and Microsatellite Instability-High Locally Advanced Rectal Cancer","volume":"28","author":"Bando","year":"2022","journal-title":"Clin Cancer Res"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1392499","article-title":"The efficacy and safety of neoadjuvant chemoradiotherapy combined with immunotherapy for locally advanced rectal cancer patients: a systematic review","volume":"15","author":"Yang","year":"2024","journal-title":"Front Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djw171","article-title":"Long-term outcome of an organ preservation program after neoadjuvant treatment for rectal cancer","volume":"108","author":"Martens","year":"2016","journal-title":"J Natl Cancer Inst"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2014.0056","article-title":"Neoadjuvant chemotherapy first, followed by chemoradiation and then surgery, in the management of locally advanced rectal cancer","volume":"12","author":"Cercek","year":"2014","journal-title":"J Natl Compr Cancer Network: JNCCN"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e230146","DOI":"10.1001\/jamasurg.2023.0146","article-title":"Long-term quality of life and functional outcome of patients with rectal cancer following a watch-and-wait approach","volume":"158","author":"Custers","year":"2023","journal-title":"JAMA Surg"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.22.00032","article-title":"Organ preservation in patients with rectal adenocarcinoma treated with total neoadjuvant therapy","volume":"40","author":"Garcia-Aguilar","year":"2022","journal-title":"J Clin Oncol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.19.00308","article-title":"Randomized phase II trial of chemoradiotherapy plus induction or consolidation chemotherapy as total neoadjuvant therapy for locally advanced rectal cancer: CAO\/ARO\/AIO-12","volume":"37","author":"Fokas","year":"2019","journal-title":"J Clin oncology: Off J Am Soc Clin Oncol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2201445","article-title":"PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer","volume":"386","author":"Cercek","year":"2022","journal-title":"New Engl J Med"},{"key":"B20","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/s41392-024-01762-y","article-title":"Efficacy and safety of PD-1 blockade plus long-course chemoradiotherapy in locally advanced rectal cancer (NECTAR): a multi-center phase 2 study","volume":"9","author":"Yang","year":"2024","journal-title":"Signal Transduct Target Ther"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1001\/jamasurg.2023.7996","article-title":"Total neoadjuvant therapy with PD-1 blockade for high-risk proficient mismatch repair rectal cancer","volume":"159","author":"Li","year":"2024","journal-title":"JAMA Surg"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.23.02261","article-title":"Randomized phase II trial of immunotherapy-based total neoadjuvant therapy for proficient mismatch repair or microsatellite stable locally advanced rectal cancer (TORCH)","volume":"42","author":"Xia","year":"2024","journal-title":"J Clin Oncol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2024.06.015","article-title":"Neoadjuvant short-course radiotherapy followed by camrelizumab and chemotherapy in locally advanced rectal cancer (UNION): early outcomes of a multicenter randomized phase III trial","volume":"35","author":"Lin","year":"2024","journal-title":"Ann Oncol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.42.9597","article-title":"Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04","volume":"30","author":"Ngan","year":"2012","journal-title":"J Clin oncology: Off J Am Soc Clin Oncol"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2025.1594927\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T04:11:30Z","timestamp":1754626290000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2025.1594927\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,8]]},"references-count":24,"alternative-id":["10.3389\/fonc.2025.1594927"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2025.1594927","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,8]]},"article-number":"1594927"}}