{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T23:07:26Z","timestamp":1783984046838,"version":"3.55.0"},"reference-count":45,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"vor","delay-in-days":57,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","award":["11320102410057"],"award-info":[{"award-number":["11320102410057"]}],"id":[{"id":"10.13039\/501100001826","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>Total neoadjuvant therapy (TNT) has emerged as a promising treatment strategy for locally advanced rectal cancer (LARC), demonstrating higher pathological complete response (pCR) rates and enhanced disease-free survival. However, evidence specifically addressing high-risk LARC and the potential for organ-preserving approaches remains limited. The potential benefit of TNT may be further optimised when administered to patients with specific high-risk characteristics, associated with poor prognosis. The optimal TNT regimen for achieving favourable organ preservation and survival outcomes has not yet been established, as no studies have directly compared triplet-based induction chemotherapy with doublet-based TNT strategies. Consequently, there is considerable heterogeneity in the administration of chemotherapy within TNT regimens in clinical practice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This multicentre, parallel-arms, open-label, randomised, controlled, phase III trial will include 394 patients with non-metastasised, high-risk LARC, with WHO-performance status 0\u20131 and fit for FOLFOXIRI. High-risk LARC is defined as the presence of at least one of the following tumour characteristics: invasion of the mesorectal fascia (MRF) (i.e. T4b or evident invasion), extramural venous invasion (EMVI) grade IV, tumour deposits (TD),\u2009\u2265\u20092 enlarged lateral lymph nodes (LLN) (\u2265\u20097\u00a0mm). Patients are informed about TNT versus chemoradiotherapy. Patients who will undergo TNT will be randomised 1:1 between 6 cycles of FOLFOXIRI, followed by chemoradiotherapy (25\u2009\u00d7\u20092 or 28\u2009\u00d7\u20091.8\u00a0Gy) or 4 cycles CAPOX\/6 cycles FOLFOX, followed by chemoradiotherapy. Patients either undergo surgery or enter a watch-and-wait approach after neoadjuvant treatment. A watch-and-wait approach is considered in case of a clinical complete response (cCR), determined maximal 26\u00a0weeks after start of treatment. The primary outcome is complete response rate (i.e. pCR or sustained cCR at 1\u00a0year). The main secondary outcomes are disease-free survival, overall survival, regrowth rate, radicality, toxicity and completion rate of neoadjuvant treatment, treatment related toxicity, quality of life, and post-operative morbidity. Patients who are eligible and undergo neoadjuvant chemoradiotherapy, will be asked to participate in the observational cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>This protocol describes the MEND-IT II study, which compares complete response rates (pCR and cCR) between FOLFOXIRI-based and CAPOX\/FOLFOX-based TNT in a homogeneous high-risk LARC population. The results of this study may contribute to optimise neoadjuvant treatment strategies and tailored treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>Overview of Medical-Scientific Research in the Netherlands (OMON): NL-011486. Clinicaltrials.gov: NCT07472868.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12885-026-16072-5","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T14:53:25Z","timestamp":1779116005000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A national, multicentre, randomised, controlled, parallel-arms, phase III clinical trial of neoadjuvant FOLFOXIRI and chemoradiotherapy versus neoadjuvant CAPOX\/FOLFOX and chemoradiotherapy in patients with high-risk locally advanced rectal cancer: study protocol of the MEND-IT II trial"],"prefix":"10.1186","volume":"26","author":[{"given":"E.","family":"Banken","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Borg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I. E. G.","family":"van Hellemond","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. G.","family":"van Ravensteijn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. M. U.","family":"Peulen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. E.","family":"Verrijssen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Nederend","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. W.","family":"Daniels-Gooszen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. R.","family":"van Oudheusden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"van Lijnschoten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. G.","family":"Bloemen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. J. T.","family":"Rutten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. L.","family":"van Westreenen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. W. B.","family":"de Groot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Verhoef","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. J.","family":"Tanis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. A.","family":"Grotenhuis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. G. J.","family":"Aalbers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I. M.","family":"Werter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. D. den","family":"Hartogh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. A. J.","family":"Douma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. G. A.","family":"Calon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L. B. J. Valkenburg-van","family":"Iersel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. L.","family":"Beets","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. B.","family":"Tuynman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. P. W.","family":"Intven","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. M. J.","family":"van Kuijk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Berb\u00e9e","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. E.","family":"Buffart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. M. L.","family":"Roodhart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. W. A.","family":"Burger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Dutch Colorectal Cancer Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"issue":"16","key":"16072_CR1","doi-asserted-by":"publisher","first-page":"1926","DOI":"10.1200\/JCO.2011.40.1836","volume":"30","author":"R Sauer","year":"2012","unstructured":"Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO\/ARO\/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol. 2012;30(16):1926\u201333.","journal-title":"J Clin Oncol"},{"issue":"6","key":"16072_CR2","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1016\/S1470-2045(11)70097-3","volume":"12","author":"W van Gijn","year":"2011","unstructured":"van Gijn W, Marijnen CA, Nagtegaal ID, Kranenbarg EM, Putter H, Wiggers T, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. 2011;12(6):575\u201382.","journal-title":"Lancet Oncol"},{"issue":"2","key":"16072_CR3","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1097\/DCR.0000000000000547","volume":"59","author":"W van der Meij","year":"2016","unstructured":"van der Meij W, Rombouts AJ, Rutten H, Bremers AJ, de Wilt JH. Treatment of locally recurrent rectal carcinoma in previously (chemo)irradiated patients: a review. Dis Colon Rectum. 2016;59(2):148\u201356.","journal-title":"Dis Colon Rectum"},{"issue":"1","key":"16072_CR4","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/S1470-2045(20)30555-6","volume":"22","author":"RR Bahadoer","year":"2021","unstructured":"Bahadoer RR, Dijkstra EA, van Etten B, Marijnen CAM, Putter H, Kranenbarg EM, et al. 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. Lancet Oncol. 2021;22(1):29\u201342.","journal-title":"Lancet Oncol"},{"issue":"4","key":"16072_CR5","doi-asserted-by":"publisher","first-page":"e766","DOI":"10.1097\/SLA.0000000000005799","volume":"278","author":"EA Dijkstra","year":"2023","unstructured":"Dijkstra EA, Nilsson PJ, Hospers GAP, Bahadoer RR, Meershoek-Klein Kranenbarg E, Roodvoets AGH, et al. Locoregional failure during and after short-course radiotherapy followed by chemotherapy and surgery compared with long-course chemoradiotherapy and surgery: a 5-year follow-up of the RAPIDO trial. Ann Surg. 2023;278(4):e766\u201372.","journal-title":"Ann Surg"},{"issue":"10","key":"16072_CR6","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1016\/j.annonc.2024.06.019","volume":"35","author":"T Conroy","year":"2024","unstructured":"Conroy T, Castan F, Etienne PL, Rio E, Mesgouez-Nebout N, Evesque L, et al. Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiotherapy in patients with locally advanced rectal cancer: long-term results of the UNICANCER-PRODIGE 23 trial. Ann Oncol. 2024;35(10):873\u201381.","journal-title":"Ann Oncol"},{"issue":"4","key":"16072_CR7","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1111\/codi.16032","volume":"24","author":"A Chandramohan","year":"2022","unstructured":"Chandramohan A, Mittal R, Dsouza R, Yezzaji H, Eapen A, Simon B, et al. Prognostic significance of MR identified EMVI, tumour deposits, mesorectal nodes and pelvic side wall disease in locally advanced rectal cancer. Colorectal Dis. 2022;24(4):428\u201338.","journal-title":"Colorectal Dis"},{"issue":"4","key":"16072_CR8","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1097\/01.sla.0000205627.05769.08","volume":"243","author":"M Miyoshi","year":"2006","unstructured":"Miyoshi M, Ueno H, Hashiguchi Y, Mochizuki H, Talbot IC. Extent of mesorectal tumor invasion as a prognostic factor after curative surgery for T3 rectal cancer patients. Ann Surg. 2006;243(4):492\u20138.","journal-title":"Ann Surg"},{"issue":"2","key":"16072_CR9","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1097\/SLA.0000000000004499","volume":"276","author":"AC Lord","year":"2022","unstructured":"Lord AC, D\u2019Souza N, Shaw A, Rokan Z, Moran B, Abulafi M, et al. MRI-diagnosed tumor deposits and EMVI status have superior prognostic accuracy to current clinical TNM staging in rectal cancer. Ann Surg. 2022;276(2):334\u201344.","journal-title":"Ann Surg"},{"issue":"12","key":"16072_CR10","doi-asserted-by":"publisher","first-page":"1513","DOI":"10.1038\/bjc.2017.99","volume":"116","author":"MRS Siddiqui","year":"2017","unstructured":"Siddiqui MRS, Simillis C, Hunter C, Chand M, Bhoday J, Garant A, et al. A meta-analysis comparing the risk of metastases in patients with rectal cancer and MRI-detected extramural vascular invasion (mrEMVI) vs mrEMVI-negative cases. Br J Cancer. 2017;116(12):1513\u20139.","journal-title":"Br J Cancer"},{"issue":"3","key":"16072_CR11","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1016\/j.ijrobp.2021.06.013","volume":"111","author":"DP Schaap","year":"2021","unstructured":"Schaap DP, Voogt ELK, Burger JWA, Cnossen JS, Creemers GM, van Lijnschoten I, et al. Prognostic implications of MRI-detected EMVI and tumor deposits and their response to neoadjuvant therapy in cT3 and cT4 rectal cancer. Int J Radiat Oncol Biol Phys. 2021;111(3):816\u201325.","journal-title":"Int J Radiat Oncol Biol Phys"},{"issue":"3","key":"16072_CR12","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1097\/00000478-200203000-00009","volume":"26","author":"ID Nagtegaal","year":"2002","unstructured":"Nagtegaal ID, Marijnen CA, Kranenbarg EK, van de Velde CJ, van Krieken JH, Pathology Review C, Cooperative Clinical I. Circumferential margin involvement is still an important predictor of local recurrence in rectal carcinoma: not one millimeter but two millimeters is the limit. Am J Surg Pathol. 2002;26(3):350\u20137.","journal-title":"Am J Surg Pathol"},{"issue":"9","key":"16072_CR13","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1056\/NEJMoa010580","volume":"345","author":"E Kapiteijn","year":"2001","unstructured":"Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH, Wiggers T, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med. 2001;345(9):638\u201346.","journal-title":"N Engl J Med"},{"issue":"13","key":"16072_CR14","doi-asserted-by":"publisher","first-page":"1844","DOI":"10.1002\/bjs.10949","volume":"105","author":"DP Schaap","year":"2018","unstructured":"Schaap DP, Ogura A, Nederend J, Maas M, Cnossen JS, Creemers GJ, et al. Prognostic implications of MRI-detected lateral nodal disease and extramural vascular invasion in rectal cancer. Br J Surg. 2018;105(13):1844\u201352.","journal-title":"Br J Surg"},{"issue":"1","key":"16072_CR15","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1200\/JCO.18.00032","volume":"37","author":"A Ogura","year":"2019","unstructured":"Ogura A, Konishi T, Cunningham C, Garcia-Aguilar J, Iversen H, Toda S, et al. Neoadjuvant (Chemo)radiotherapy with total mesorectal excision only is not sufficient to prevent lateral local recurrence in enlarged nodes: results of the multicenter lateral node study of patients with low ct3\/4 rectal cancer. J Clin Oncol. 2019;37(1):33\u201343.","journal-title":"J Clin Oncol"},{"issue":"1","key":"16072_CR16","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1200\/JCO.2012.45.3258","volume":"32","author":"FG Taylor","year":"2014","unstructured":"Taylor FG, Quirke P, Heald RJ, Moran BJ, Blomqvist L, Swift IR, et al. Preoperative magnetic resonance imaging assessment of circumferential resection margin predicts disease-free survival and local recurrence: 5-year follow-up results of the MERCURY study. J Clin Oncol. 2014;32(1):34\u201343.","journal-title":"J Clin Oncol"},{"issue":"10","key":"16072_CR17","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.1200\/JCO.2016.68.9091","volume":"35","author":"ID Nagtegaal","year":"2017","unstructured":"Nagtegaal ID, Knijn N, Hugen N, Marshall HC, Sugihara K, Tot T, et al. Tumor deposits in colorectal cancer: improving the value of modern staging-a systematic review and meta-analysis. J Clin Oncol. 2017;35(10):1119\u201327.","journal-title":"J Clin Oncol"},{"issue":"6","key":"16072_CR18","doi-asserted-by":"publisher","first-page":"108307","DOI":"10.1016\/j.ejso.2024.108307","volume":"50","author":"E Geffen","year":"2024","unstructured":"Geffen E, Nederend J, Sluckin TC, Hazen SJA, Horsthuis K, Beets-Tan RGH, et al. Prognostic significance of MRI-detected extramural venous invasion according to grade and response to neo-adjuvant treatment in locally advanced rectal cancer A national cohort study after radiologic training and reassessment. Eur J Surg Oncol. 2024;50(6):108307.","journal-title":"Eur J Surg Oncol"},{"issue":"3","key":"16072_CR19","doi-asserted-by":"publisher","first-page":"e526","DOI":"10.1097\/SLA.0000000000005755","volume":"278","author":"E Agger","year":"2023","unstructured":"Agger E, Jorgren F, Joud A, Lydrup ML, Buchwald P. Negative prognostic impact of tumor deposits in rectal cancer: a national study cohort. Ann Surg. 2023;278(3):e526\u201333.","journal-title":"Ann Surg"},{"issue":"1","key":"16072_CR20","doi-asserted-by":"publisher","first-page":"17","DOI":"10.6004\/jnccn.2023.7081","volume":"22","author":"EGM van Geffen","year":"2024","unstructured":"van Geffen EGM, Sluckin TC, Hazen SJA, Horsthuis K, Beets-Tan RGH, van Dieren S, et al. Value of size and malignant features of lateral lymph nodes in risk stratification at lateral local recurrence of rectal cancer: a national cohort study. J Natl Compr Canc Netw. 2024;22(1):17\u201325.","journal-title":"J Natl Compr Canc Netw"},{"issue":"5","key":"16072_CR21","doi-asserted-by":"publisher","first-page":"109699","DOI":"10.1016\/j.ejso.2025.109699","volume":"51","author":"K van den Berg","year":"2025","unstructured":"van den Berg K, Banken E, van Rees JM, Coolen LM, de Vries M, Voogt ELK, et al. Neoadjuvant chemotherapy and chemoradiotherapy versus chemoradiotherapy alone in high-risk locally advanced rectal cancer: A retrospective comparison of two Dutch tertiary referral centres. Eur J Surg Oncol. 2025;51(5):109699.","journal-title":"Eur J Surg Oncol"},{"issue":"15","key":"16072_CR22","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 LM, 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 Oncol. 2022;40(15):1681\u201392.","journal-title":"J Clin Oncol"},{"issue":"8","key":"16072_CR23","doi-asserted-by":"publisher","first-page":"1298","DOI":"10.1093\/annonc\/mdz186","volume":"30","author":"B Cisel","year":"2019","unstructured":"Cisel B, Pietrzak L, Michalski W, Wyrwicz L, Rutkowski A, Kosakowska E, et al. Long-course preoperative chemoradiation versus 5 x 5 Gy and consolidation chemotherapy for clinical T4 and fixed clinical T3 rectal cancer: long-term results of the randomized Polish II study. Ann Oncol. 2019;30(8):1298\u2013303.","journal-title":"Ann Oncol"},{"issue":"5","key":"16072_CR24","doi-asserted-by":"publisher","first-page":"834","DOI":"10.1093\/annonc\/mdw062","volume":"27","author":"K Bujko","year":"2016","unstructured":"Bujko K, Wyrwicz L, Rutkowski A, Malinowska M, Pietrzak L, Krynski J, et al. Long-course oxaliplatin-based preoperative chemoradiation versus 5 x 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study. Ann Oncol. 2016;27(5):834\u201342.","journal-title":"Ann Oncol"},{"issue":"5","key":"16072_CR25","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 JF, Etienne PL, Rio E, Francois E, 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(5):702\u201315.","journal-title":"Lancet Oncol"},{"issue":"6","key":"16072_CR26","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1056\/NEJM199002083220602","volume":"322","author":"CG Moertel","year":"1990","unstructured":"Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Goodman PJ, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med. 1990;322(6):352\u20138.","journal-title":"N Engl J Med"},{"key":"16072_CR27","unstructured":"Specialisten FM. Colorectaal Carcinoom - 6.4 Neoadjuvante of inductietherapie bij het lokaal gevorderd rectumcarcinoom 2025. https:\/\/richtlijnendatabase.nl\/richtlijn\/colorectaal_carcinoom_crc\/primaire_behandeling_rectumcarcinoom_bij_crc\/neoadjuvante_of_inductietherapie_bij_het_lokaal_gevorderd_rectumcarcinoom.html.\u00a0Updated 2025 Sept 1. Cited 2026 Feb 9."},{"issue":"4","key":"16072_CR28","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/S1470-2045(19)30862-9","volume":"21","author":"C Cremolini","year":"2020","unstructured":"Cremolini C, Antoniotti C, Rossini D, Lonardi S, Loupakis F, Pietrantonio F, et al. Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2020;21(4):497\u2013507.","journal-title":"Lancet Oncol"},{"issue":"2","key":"16072_CR29","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1097\/01.sla.0000171299.43954.ce","volume":"242","author":"SK Hendren","year":"2005","unstructured":"Hendren SK, O\u2019Connor BI, Liu M, Asano T, Cohen Z, Swallow CJ, et al. Prevalence of male and female sexual dysfunction is high following surgery for rectal cancer. Ann Surg. 2005;242(2):212\u201323.","journal-title":"Ann Surg"},{"key":"16072_CR30","doi-asserted-by":"publisher","first-page":"944843","DOI":"10.3389\/fonc.2022.944843","volume":"12","author":"EP Pappou","year":"2022","unstructured":"Pappou EP, Temple LK, Patil S, Smith JJ, Wei IH, Nash GM, et al. Quality of life and function after rectal cancer surgery with and without sphincter preservation. Front Oncol. 2022;12:944843.","journal-title":"Front Oncol"},{"issue":"5","key":"16072_CR31","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1002\/bjs5.75","volume":"2","author":"D Steffens","year":"2018","unstructured":"Steffens D, Solomon MJ, Young JM, Koh C, Venchiarutti RL, Lee P, et al. Cohort study of long-term survival and quality of life following pelvic exenteration. BJS Open. 2018;2(5):328\u201335.","journal-title":"BJS Open"},{"issue":"6","key":"16072_CR32","doi-asserted-by":"publisher","first-page":"zraf136","DOI":"10.1093\/bjsopen\/zraf136","volume":"9","author":"E Banken","year":"2025","unstructured":"Banken E, Geubels BM, VandeKerckhove FEC, Creemers DMJ, Ketelaers SHJ, Nederend J, et al. Watch-and-wait approach in high-risk locally advanced rectal cancer: outcomes after complete response to total neoadjuvant therapy. BJS Open. 2025;9(6):zraf136.","journal-title":"BJS Open"},{"issue":"1","key":"16072_CR33","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1186\/s12885-022-09947-w","volume":"22","author":"K van den Berg","year":"2022","unstructured":"van den Berg K, Schaap DP, Voogt ELK, Buffart TE, Verheul HMW, de Groot JWB, et al. Neoadjuvant FOLFOXIRI prior to chemoradiotherapy for high-risk (\u201cugly\u201d) locally advanced rectal cancer: study protocol of a single-arm, multicentre, open-label, phase II trial (MEND-IT). BMC Cancer. 2022;22(1):957.","journal-title":"BMC Cancer"},{"key":"16072_CR34","unstructured":"Specialisten FM. Colorectaal Carcinoom. Locoregionale stadi\u00ebring rectumcarcinoom. https:\/\/richtlijnendatabase.nl\/richtlijn\/colorectaal_carcinoom_crc\/diagnostiek_bij_crc\/locoregionale_stadi_ring_rectumcarcinoom.html.\u00a0Updated 2025 Sept 1. Cited 2026 9 Feb."},{"issue":"4","key":"16072_CR35","doi-asserted-by":"publisher","first-page":"1465","DOI":"10.1007\/s00330-017-5026-2","volume":"28","author":"RGH Beets-Tan","year":"2018","unstructured":"Beets-Tan RGH, Lambregts DMJ, Maas M, Bipat S, Barbaro B, Curvo-Semedo L, et al. Magnetic resonance imaging for clinical management of rectal cancer: Updated recommendations from the 2016 European Society of Gastrointestinal and Abdominal Radiology (ESGAR) consensus meeting. Eur Radiol. 2018;28(4):1465\u201375.","journal-title":"Eur Radiol"},{"key":"16072_CR36","doi-asserted-by":"crossref","unstructured":"Brierley JD, Gospodarowicz MK, Wittekind C. TNM Classification of Malignant Tumours, 8th edition. Wiley; 2017. http:\/\/mom.gov.az\/resources\/content_files\/ebook\/TNM-Classification-of-Malignant-Tumours-8th-edition.pdf.","DOI":"10.1002\/9780471420194.tnmc26.pub3"},{"key":"16072_CR37","doi-asserted-by":"publisher","unstructured":"UbinkM, Verheul HMW, Verhoef C, Tanis PJ. Critical Evaluation of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer. JCO Oncol Pract. 2025:OP2500530. https:\/\/doi.org\/10.1200\/OP-25-00530.","DOI":"10.1200\/OP-25-00530"},{"issue":"5","key":"16072_CR38","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1200\/JCO.23.01208","volume":"42","author":"FS Verheij","year":"2024","unstructured":"Verheij FS, Omer DM, Williams H, Lin ST, Qin LX, Buckley JT, et al. Long-term results of organ preservation in patients with rectal adenocarcinoma treated with total neoadjuvant therapy: the randomized phase II OPRA trial. J Clin Oncol. 2024;42(5):500\u20136.","journal-title":"J Clin Oncol"},{"issue":"34","key":"16072_CR39","doi-asserted-by":"publisher","first-page":"3212","DOI":"10.1200\/JCO.19.00308","volume":"37","author":"E Fokas","year":"2019","unstructured":"Fokas E, Allgauer M, Polat B, Klautke G, Grabenbauer GG, Fietkau R, et al. Randomized phase II trial of chemoradiotherapy plus induction or consolidation chemotherapy as total neoadjuvant therapy for locally advanced rectal cancer: CAO\/ARO\/AIO-12. J Clin Oncol. 2019;37(34):3212\u201322.","journal-title":"J Clin Oncol"},{"issue":"23","key":"16072_CR40","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 Oncol. 2022;40(23):2546\u201356.","journal-title":"J Clin Oncol"},{"issue":"2","key":"16072_CR41","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1016\/j.jamcollsurg.2015.04.010","volume":"221","author":"CP Probst","year":"2015","unstructured":"Probst CP, Becerra AZ, Aquina CT, Tejani MA, Wexner SD, Garcia-Aguilar J, et al. Extended intervals after neoadjuvant therapy in locally advanced rectal cancer: the key to improved tumor response and potential organ preservation. J Am Coll Surg. 2015;221(2):430\u201340.","journal-title":"J Am Coll Surg"},{"issue":"8","key":"16072_CR42","doi-asserted-by":"publisher","first-page":"1722","DOI":"10.1093\/annonc\/mdv223","volume":"26","author":"C Fernandez-Martos","year":"2015","unstructured":"Fernandez-Martos C, Garcia-Albeniz X, Pericay C, Maurel J, Aparicio J, Montagut C, et al. Chemoradiation, surgery and adjuvant chemotherapy versus induction chemotherapy followed by chemoradiation and surgery: long-term results of the Spanish GCR-3 phase II randomized trialdagger. Ann Oncol. 2015;26(8):1722\u20138.","journal-title":"Ann Oncol"},{"issue":"6","key":"16072_CR43","doi-asserted-by":"publisher","first-page":"1525","DOI":"10.1093\/annonc\/mdr473","volume":"23","author":"R Marechal","year":"2012","unstructured":"Marechal R, Vos B, Polus M, Delaunoit T, Peeters M, Demetter P, et al. Short course chemotherapy followed by concomitant chemoradiotherapy and surgery in locally advanced rectal cancer: a randomized multicentric phase II study. Ann Oncol. 2012;23(6):1525\u201330.","journal-title":"Ann Oncol"},{"issue":"2","key":"16072_CR44","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1007\/s00066-013-0469-0","volume":"190","author":"FA Calvo","year":"2014","unstructured":"Calvo FA, Sole CV, Serrano J, Del Valle E, Rodriguez M, Munoz-Calero A, et al. Preoperative chemoradiation with or without induction oxaliplatin plus 5-fluorouracil in locally advanced rectal cancer. Long-term outcome analysis. Strahlenther Onkol. 2014;190(2):149\u201357.","journal-title":"Strahlenther Onkol"},{"key":"16072_CR45","unstructured":"Specialisten FM. Richtlijnen Database - Colorectaal Carcinoom. 6.11 - IORT primair lokaal gevorderd rectumcarcinoom. 2024. https:\/\/richtlijnendatabase.nl\/richtlijn\/colorectaal_carcinoom_crc\/primaire_behandeling_rectumcarcinoom_bij_crc\/iort_primair_lokaal_gevorderd_rectumcarcinoom.html.\u00a0Updated 2024 Apr 8. Cited 2026 Feb 9."}],"container-title":["BMC Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12885-026-16072-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12885-026-16072-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12885-026-16072-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T23:00:34Z","timestamp":1783983634000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12885-026-16072-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,18]]},"references-count":45,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["16072"],"URL":"https:\/\/doi.org\/10.1186\/s12885-026-16072-5","relation":{},"ISSN":["1471-2407"],"issn-type":[{"value":"1471-2407","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,18]]},"assertion":[{"value":"16 March 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 April 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 May 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 research is centrally approved by the Dutch Competent Authority (CCMO, The Hague, the Netherlands) and the Medical Research Ethics Committees United (MEC-U, Nieuwegein, the Netherlands), on the fourth of February 2026, with EU-CT number 2025\u2013523692-00.All significant protocol amendments will be submitted to the competent authority, the medical research ethics committee, the institutional review boards of all participating study centres, the (principal) investigators, and the trial registries.Informed consent will be obtained before any study-related procedures during screening. The consent will be written, dated, and signed by both the interviewer and the participant. The investigator or a representative will explain the study and address any questions. The participant's understanding will be verified during the interview. A copy of the signed consent document will be provided to the participant, and consent will be properly documented. Sufficient time will be allowed for the participant to consider their decision to participate.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","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":"838"}}