{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:30:30Z","timestamp":1787020230601,"version":"build-2736575974"},"reference-count":19,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T00:00:00Z","timestamp":1704844800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T00:00:00Z","timestamp":1704844800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"The Key Research-Development Program of Zhejiang Province under Grant","award":["2022C03015"],"award-info":[{"award-number":["2022C03015"]}]}],"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>Anus preservation has been a challenge in the treatment of patients with low rectal adenocarcinoma (within 5\u00a0cm from the anal verge) because it is difficult to spare the anus with its functioning sphincter complex under the safe margin of tumour resection. Patients with dMMR\/MSI-H can achieve a favourable complete response (CR) rate by using a single immune checkpoint inhibitor. For patients with pMMR\/MSS\/MSI-L, intensified neoadjuvant three-drug chemotherapy may be the preferred option for anal preservation. In addition, the watch and wait (W&amp;W) strategy has been proven safe and feasible for patients with rectal cancer who achieve a clinical complete response (cCR). Therefore, we initiated this clinical trial to explore the optimal neoadjuvant treatment pattern for patients with low locally advanced rectal cancer (LARC) with different MMR\/MSI statuses, aiming to achieve a higher cCR rate with the W&amp;W strategy and ultimately provide more patients with a chance of anus preservation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This is a randomised, controlled, open-label, multicentre phase III trial. Patients with clinical stage T2-4 and\/or N\u2009+\u2009tumours located within 5\u00a0cm from the anal verge are considered eligible. Based on the results of pathological biopsy, the patients are divided into two groups: dMMR\/MSI-H and pMMR\/MSS. Patients in the dMMR\/MSI-H group will be randomly allocated in a 1:1 ratio to either arm A (monoimmunotherapy) or arm B (short-course radiotherapy followed by monoimmunotherapy). Patients in the pMMR\/MSS group will be initially treated with long-term pelvic radiation with concurrent capecitabine combined with irinotecan. Two weeks after the completion of chemoradiotherapy (CRT), the patients will be randomly allocated in a 1:1 ratio to arm C (XELIRI six cycle regime) or arm D (FOLFIRINOX nine cycle regime). The irinotecan dose will be adjusted according to the UGT1A1-genotype. After treatment, a comprehensive assessment will be performed to determine whether a cCR has been achieved. If achieved, the W&amp;W strategy will be adopted; otherwise, total mesorectal excision (TME) will be performed. The primary endpoint is cCR with the maintenance of 12 months at least, determined using digital rectal examination, endoscopy, and rectal MRI or PET\/CT as a supplementary method.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>APRAM will explore the best anus preservation model for low LARC, combining the strategies of consolidation chemotherapy, immunotherapy, and short-course radiotherapy, and aims to preserve the anus of more patients using W&amp;W. Our study provides an accurate individual treatment mode based on the MMR\/MSI status for patients with low LARC, and more patients will receive the opportunity for anus preservation under our therapeutic strategy, which would transform into long-term benefits.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>Clinicaltrials.gov NCT05669092 (Registered 28th Nov 2022).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12885-024-11829-2","type":"journal-article","created":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T09:04:30Z","timestamp":1704877470000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Anus preservation in low rectal adenocarcinoma based on MMR\/MSI status (APRAM): a study protocol for a randomised, controlled, open-label, multicentre phase III trial"],"prefix":"10.1186","volume":"24","author":[{"given":"Cheng-Yi","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Hua","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Wen","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan-Quan","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Ru","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian-Ping","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-Xing","family":"Ju","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,1,10]]},"reference":[{"key":"11829_CR1","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1016\/S1470-2045(10)70172-8","volume":"11","author":"M Maas","year":"2010","unstructured":"Maas M, Nelemans PJ, Valentini V, Das P, R\u00f6del C, Kuo L-J, et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol. 2010;11:835\u201344.","journal-title":"Lancet Oncol"},{"key":"11829_CR2","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.1056\/NEJMoa060829","volume":"355","author":"J-F Bosset","year":"2006","unstructured":"Bosset J-F, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006;355:1114\u201323.","journal-title":"N Engl J Med"},{"key":"11829_CR3","doi-asserted-by":"publisher","first-page":"1562","DOI":"10.1016\/j.ejso.2015.09.008","volume":"41","author":"GL Beets","year":"2015","unstructured":"Beets GL, Figueiredo NL, Habr-Gama A, van de Velde CJH. A new paradigm for rectal cancer: Organ preservation: introducing the International Watch & Wait Database (IWWD). Eur J Surg Oncol. 2015;41:1562\u20134.","journal-title":"Eur J Surg Oncol"},{"key":"11829_CR4","doi-asserted-by":"publisher","first-page":"2537","DOI":"10.1016\/S0140-6736(18)31078-X","volume":"391","author":"MJM van der Valk","year":"2018","unstructured":"van der Valk MJM, Hilling DE, Bastiaannet E, Meershoek-Klein Kranenbarg E, Beets GL, Figueiredo NL, et al. Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study. Lancet. 2018;391:2537\u201345.","journal-title":"Lancet"},{"key":"11829_CR5","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/S1470-2045(20)30557-X","volume":"22","author":"LM Fernandez","year":"2021","unstructured":"Fernandez LM, S\u00e3o Juli\u00e3o GP, Figueiredo NL, Beets GL, van der Valk MJM, Bahadoer RR, et al. Conditional recurrence-free survival of clinical complete responders managed by watch and wait after neoadjuvant chemoradiotherapy for rectal cancer in the International Watch & wait database: a retrospective, international, multicentre registry study. Lancet Oncol. 2021;22:43\u201350.","journal-title":"Lancet Oncol"},{"key":"11829_CR6","doi-asserted-by":"publisher","first-page":"3703","DOI":"10.1002\/cncr.25943","volume":"117","author":"J-h Park","year":"2011","unstructured":"Park J-h, Yoon SM, Yu CS, Kim JH, Kim TW, Kim JC. Randomized phase 3 trial comparing preoperative and postoperative chemoradiotherapy with capecitabine for locally advanced rectal cancer. Cancer. 2011;117:3703\u201312.","journal-title":"Cancer"},{"key":"11829_CR7","doi-asserted-by":"publisher","first-page":"4231","DOI":"10.1200\/JCO.20.01932","volume":"38","author":"J Zhu","year":"2020","unstructured":"Zhu J, Liu A, Sun X, Liu L, Zhu Y, Zhang T, et al. Multicenter, Randomized, Phase III Trial of Neoadjuvant Chemoradiation with Capecitabine and Irinotecan guided by UGT1A1 status in patients with locally advanced rectal Cancer. J Clin Oncology: Official J Am Soc Clin Oncol. 2020;38:4231\u20139.","journal-title":"J Clin Oncology: Official J Am Soc Clin Oncol"},{"key":"11829_CR8","doi-asserted-by":"publisher","first-page":"e58","DOI":"10.1016\/j.clcc.2020.01.004","volume":"19","author":"J Wang","year":"2020","unstructured":"Wang J, Fan J, Li C, Yang L, Wan J, Zhang H, et al. The impact of Chemotherapy Completion on the efficacy of Irinotecan in the Preoperative Chemoradiotherapy of locally advanced rectal Cancer: an expanded analysis of the CinClare Phase III Trial. Clin Colorectal Cancer. 2020;19:e58\u2013e69.","journal-title":"Clin Colorectal Cancer"},{"key":"11829_CR9","doi-asserted-by":"publisher","first-page":"2546","DOI":"10.1200\/JCO.22.00032","volume":"40","author":"J Garcia-Aguilar","year":"2022","unstructured":"Garcia-Aguilar J, Patil S, Gollub MJ, Kim JK, Yuval JB, Thompson HM, et al. Organ preservation in patients with rectal adenocarcinoma treated with total neoadjuvant therapy. J Clin Oncology: Official J Am Soc Clin Oncol. 2022;40:2546\u201356.","journal-title":"J Clin Oncology: Official J Am Soc Clin Oncol"},{"key":"11829_CR10","doi-asserted-by":"publisher","first-page":"e215445","DOI":"10.1001\/jamaoncol.2021.5445","volume":"8","author":"E Fokas","year":"2022","unstructured":"Fokas E, Schlenska-Lange A, Polat B, Klautke G, Grabenbauer GG, Fietkau R, et al. Chemoradiotherapy Plus induction or Consolidation Chemotherapy as total neoadjuvant therapy for patients with locally advanced rectal Cancer: long-term results of the CAO\/ARO\/AIO-12 Randomized Clinical Trial. JAMA Oncol. 2022;8:e215445.","journal-title":"JAMA Oncol"},{"key":"11829_CR11","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1016\/S1470-2045(21)00079-6","volume":"22","author":"T Conroy","year":"2021","unstructured":"Conroy T, Bosset J-F, Etienne P-L, Rio E, Fran\u00e7ois \u00c9, Mesgouez-Nebout N, et al. 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. Lancet Oncol. 2021;22:702\u201315.","journal-title":"Lancet Oncol"},{"key":"11829_CR12","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1038\/s41591-020-0805-8","volume":"26","author":"M Chalabi","year":"2020","unstructured":"Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, Aalbers AG, Sikorska K, et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med. 2020;26:566\u201376.","journal-title":"Nat Med"},{"key":"11829_CR13","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/S2468-1253(21)00348-4","volume":"7","author":"H Hu","year":"2022","unstructured":"Hu H, Kang L, Zhang J, Wu Z, Wang H, Huang M, et al. Neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, in mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (PICC): a single-centre, parallel-group, non-comparative, randomised, phase 2 trial. Lancet Gastroenterol Hepatol. 2022;7:38\u201348.","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"11829_CR14","doi-asserted-by":"publisher","first-page":"2363","DOI":"10.1056\/NEJMoa2201445","volume":"386","author":"A Cercek","year":"2022","unstructured":"Cercek A, Lumish M, Sinopoli J, Weiss J, Shia J, Lamendola-Essel M, et al. PD-1 blockade in Mismatch Repair-Deficient, locally advanced rectal Cancer. N Engl J Med. 2022;386:2363\u201376.","journal-title":"N Engl J Med"},{"key":"11829_CR15","doi-asserted-by":"publisher","first-page":"2207","DOI":"10.1056\/NEJMoa2017699","volume":"383","author":"T Andr\u00e9","year":"2020","unstructured":"Andr\u00e9 T, Shiu K-K, Kim TW, Jensen BV, Jensen LH, Punt C, et al. Pembrolizumab in microsatellite-instability-high Advanced Colorectal Cancer. N Engl J Med. 2020;383:2207\u201318.","journal-title":"N Engl J Med"},{"key":"11829_CR16","doi-asserted-by":"publisher","first-page":"1709","DOI":"10.1158\/1078-0432.CCR-18-2581","volume":"25","author":"Y Wang","year":"2019","unstructured":"Wang Y, Liu Z-G, Yuan H, Deng W, Li J, Huang Y, et al. The reciprocity between Radiotherapy and Cancer Immunotherapy. Clin Cancer Research: Official J Am Association Cancer Res. 2019;25:1709\u201317.","journal-title":"Clin Cancer Research: Official J Am Association Cancer Res"},{"key":"11829_CR17","doi-asserted-by":"publisher","first-page":"1681","DOI":"10.1200\/JCO.21.01667","volume":"40","author":"J Jin","year":"2022","unstructured":"Jin J, Tang Y, Hu C, Jiang L-M, Jiang J, Li N, et al. Multicenter, Randomized, Phase III Trial of short-term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy in locally advanced rectal Cancer (STELLAR). J Clin Oncology: Official J Am Soc Clin Oncol. 2022;40:1681\u201392.","journal-title":"J Clin Oncology: Official J Am Soc Clin Oncol"},{"key":"11829_CR18","doi-asserted-by":"publisher","first-page":"4633","DOI":"10.1200\/JCO.2011.37.7176","volume":"29","author":"M Maas","year":"2011","unstructured":"Maas M, Beets-Tan RGH, Lambregts DMJ, Lammering G, Nelemans PJ, Engelen SME, et al. Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer. J Clin Oncology: Official J Am Soc Clin Oncol. 2011;29:4633\u201340.","journal-title":"J Clin Oncology: Official J Am Soc Clin Oncol"},{"key":"11829_CR19","doi-asserted-by":"crossref","unstructured":"Martens MH, Maas M, Heijnen LA, Lambregts DMJ, Leijtens JWA, Stassen LPS et al. Long-term outcome of an Organ Preservation Program after Neoadjuvant treatment for rectal Cancer. J Natl Cancer Inst. 2016;108.","DOI":"10.1093\/jnci\/djw171"}],"container-title":["BMC Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12885-024-11829-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12885-024-11829-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12885-024-11829-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T09:05:16Z","timestamp":1704877516000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmccancer.biomedcentral.com\/articles\/10.1186\/s12885-024-11829-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,10]]},"references-count":19,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["11829"],"URL":"https:\/\/doi.org\/10.1186\/s12885-024-11829-2","relation":{},"ISSN":["1471-2407"],"issn-type":[{"value":"1471-2407","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,10]]},"assertion":[{"value":"11 August 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 January 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 January 2024","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 is approved by the Medical Ethics Committee of Zhejiang Cancer Hospital in China. We will fully inform eligible patients about the purpose and procedures of this study. They will sign a written informed consent after deciding to participate in the study. The study complies with the principles of the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable. No patients level information in this manuscript.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"57"}}