{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T02:04:10Z","timestamp":1784081050410,"version":"3.55.0"},"reference-count":49,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>Background: Total neoadjuvant therapy is becoming a preferred option for locally advanced rectal cancer, particularly in patients with high-risk baseline features. However, real-world evidence comparing tumor response, MRI-defined high-risk feature clearance, surgical outcomes, and survival after total neoadjuvant therapy versus conventional long-course chemoradiotherapy remains limited. This study aimed to compare outcomes between total neoadjuvant therapy and long-course chemoradiotherapy in patients with locally advanced rectal cancer treated in routine clinical practice. Methods: This is a retrospective, single-centre cohort study focused on patients with stage II\u2013III locally advanced rectal adenocarcinoma treated with curative-intent neoadjuvant therapy using either total neoadjuvant therapy or long-course chemoradiotherapy. Tumor response was assessed using restaging MRI, clinical complete response, and pathological complete response. Surgical outcomes and overall survival were evaluated. Results: A total of 110 patients were included. Patients treated with total neoadjuvant therapy had a higher baseline disease burden reflected by a greater proportion of cT4 tumors (40.6% vs. 19.2%; p = 0.014). Radiologic tumor-length response and clearance of MRI-defined high-risk features were comparable between treatment strategies. Clinical and pathological complete response rates were numerically higher in the total neoadjuvant therapy group, but the differences were not significant (cCR: 15.6% vs. 6.4%, p = 0.151; pCR: 18.5% vs. 9.7%, p = 0.301). Conclusions: In this real-world cohort, TNT was preferentially used in patients with more advanced baseline disease and showed numerically higher complete response rates, although differences were not statistically significant. Radiologic response, surgical outcomes, and short-term survival were comparable between treatment strategies. These findings support the feasibility of TNT in routine clinical practice but should be interpreted as exploratory and hypothesis-generating rather than evidence of treatment superiority.<\/jats:p>","DOI":"10.3390\/medsci14030393","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T01:05:58Z","timestamp":1784077558000},"page":"393","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Total Neoadjuvant Therapy Versus Long-Course Chemoradiotherapy in Locally Advanced Rectal Cancer: Real-World Tumor Response and Clinical Outcomes"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9749-0610","authenticated-orcid":false,"given":"Sorinel","family":"Lunca","sequence":"first","affiliation":[{"name":"Grigore T Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"2nd Department of Surgical Oncology, Regional Institute of Oncology, 700483 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wee Liam","family":"Ong","sequence":"additional","affiliation":[{"name":"Grigore T Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"2nd Department of Surgical Oncology, Regional Institute of Oncology, 700483 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7767-0975","authenticated-orcid":false,"given":"Stefan","family":"Morarasu","sequence":"additional","affiliation":[{"name":"Grigore T Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"2nd Department of Surgical Oncology, Regional Institute of Oncology, 700483 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Maria","family":"Musina","sequence":"additional","affiliation":[{"name":"Grigore T Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"2nd Department of Surgical Oncology, Regional Institute of Oncology, 700483 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristian Ene","family":"Roata","sequence":"additional","affiliation":[{"name":"Grigore T Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"2nd Department of Surgical Oncology, Regional Institute of Oncology, 700483 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raluca","family":"Zaharia","sequence":"additional","affiliation":[{"name":"Grigore T Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"2nd Department of Surgical Oncology, Regional Institute of Oncology, 700483 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel Mihail","family":"Dimofte","sequence":"additional","affiliation":[{"name":"Grigore T Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"2nd Department of Surgical Oncology, Regional Institute of Oncology, 700483 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1002\/bjs.1800691019","article-title":"The mesorectum in rectal cancer surgery\u2014The clue to pelvic recurrence?","volume":"69","author":"Heald","year":"1982","journal-title":"Br. J. Surg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1097\/00000478-200203000-00009","article-title":"Circumferential margin involvement is still an important predictor of local recurrence in rectal carcinoma: Not one millimeter but two millimeters is the limit","volume":"26","author":"Nagtegaal","year":"2002","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/S0140-6736(09)60485-2","article-title":"Effect of the plane of surgery achieved on local recurrence in patients with operable rectal cancer: A prospective study using data from the MRC CR07 and NCIC-CTG CO16 randomised clinical trial","volume":"373","author":"Quirke","year":"2009","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1056\/NEJMoa040694","article-title":"Preoperative versus postoperative chemoradiotherapy for rectal cancer","volume":"351","author":"Sauer","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.soc.2023.02.003","article-title":"Advances in radiotherapy for rectal cancer","volume":"32","author":"Lin","year":"2023","journal-title":"Surg. Oncol. Clin. N. Am."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1200\/JCO.2011.40.1836","article-title":"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","volume":"30","author":"Sauer","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/S1470-2045(11)70097-3","article-title":"Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial","volume":"12","author":"Marijnen","year":"2011","journal-title":"Lancet Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S1470-2045(20)30555-6","article-title":"Short-course radiotherapy followed by chemotherapy before total mesorectal excision versus preoperative chemoradiotherapy, total mesorectal excision, and optional adjuvant chemotherapy in locally advanced rectal cancer: The RAPIDO randomised, open-label, phase 3 trial","volume":"22","author":"Bahadoer","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/S1470-2045(21)00079-6","article-title":"Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer: The UNICANCER-PRODIGE 23 multicentre, randomised, open-label, phase 3 trial","volume":"22","author":"Conroy","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3212","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. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e2030097","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":"ref_12","doi-asserted-by":"crossref","first-page":"e1555","DOI":"10.1002\/onco.13824","article-title":"Total neoadjuvant therapy versus standard neoadjuvant chemoradiotherapy for locally advanced rectal cancer: A systematic review and meta-analysis","volume":"26","author":"Liu","year":"2021","journal-title":"Oncologist"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ma, Z., Tan, L., Liu, Z.L., and Xiao, J.W. (2022). Total neoadjuvant therapy or standard chemoradiotherapy for locally advanced rectal cancer: A systematic review and meta-analysis. Front. Surg., 9.","DOI":"10.3389\/fsurg.2022.911538"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1007\/s00384-023-04376-y","article-title":"Efficacy and safety of total neoadjuvant therapy in locally advanced rectal cancer: A meta-analysis","volume":"38","author":"Xiong","year":"2023","journal-title":"Int. J. Colorectal Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1159\/000534815","article-title":"Is total neoadjuvant treatment beneficial for locally advanced rectal cancer? A meta-analysis of randomized controlled trials","volume":"102","author":"Wu","year":"2024","journal-title":"Oncology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2546","DOI":"10.1200\/JCO.22.00032","article-title":"Organ preservation in patients with rectal adenocarcinoma treated with total neoadjuvant therapy","volume":"40","author":"Patil","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4633","DOI":"10.1200\/JCO.2011.37.7176","article-title":"Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer","volume":"29","author":"Maas","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1200\/JCO.23.01208","article-title":"Long-term results of organ preservation in patients with rectal adenocarcinoma treated with total neoadjuvant therapy: The randomized phase II OPRA trial","volume":"42","author":"Verheij","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1016\/S0140-6736(18)31078-X","article-title":"Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database: An international multicentre registry study","volume":"391","author":"Hilling","year":"2018","journal-title":"Lancet"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/s00330-006-0388-x","article-title":"Local staging of rectal cancer: The current role of MRI","volume":"17","author":"Klessen","year":"2007","journal-title":"Eur. Radiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.2214\/AJR.08.1298","article-title":"MRI for detection of extramural vascular invasion in rectal cancer","volume":"191","author":"Smith","year":"2008","journal-title":"Am. J. Roentgenol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1097\/SLA.0000000000001193","article-title":"Prospective validation of a low rectal cancer magnetic resonance imaging staging system and development of a local recurrence risk stratification model: The MERCURY II study","volume":"263","author":"Battersby","year":"2016","journal-title":"Ann. Surg."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"20523","DOI":"10.1002\/cam4.6625","article-title":"Survival outcomes of different neoadjuvant treatment regimens in patients with locally advanced rectal cancer and MRI-detected extramural venous invasion","volume":"12","author":"Chen","year":"2023","journal-title":"Cancer Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1097\/SLA.0b013e31820b8d52","article-title":"Preoperative high-resolution magnetic resonance imaging can identify good-prognosis stage I, II, and III rectal cancer best managed by surgery alone: A prospective, multicenter, European study","volume":"253","author":"Taylor","year":"2011","journal-title":"Ann. Surg."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"110181","DOI":"10.1016\/j.ejso.2025.110181","article-title":"Real-world clinical outcomes of total neoadjuvant therapy followed by total mesorectal excision for locally advanced rectal cancer at a high-volume institution","volume":"51","author":"Ng","year":"2025","journal-title":"Eur. J. Surg. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Bandidwattanawong, C. (2024). Total neoadjuvant therapy for locally advanced rectal cancer: How to select the most suitable?. J. Clin. Med., 13.","DOI":"10.3390\/jcm13175061"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ochiai, K., Bhutiani, N., Ikeda, A., Uppal, A., White, M.G., Peacock, O., Messick, C.A., Bednarski, B.K., You, Y.N., and Skibber, J.M. (2024). Total neoadjuvant therapy for rectal cancer: Which regimens to use?. Cancers, 16.","DOI":"10.3390\/cancers16112093"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"7476","DOI":"10.1245\/s10434-021-09837-8","article-title":"Total neoadjuvant therapy in locally advanced rectal cancer: A systematic review and meta-analysis of oncological and operative outcomes","volume":"28","author":"Kong","year":"2021","journal-title":"Ann. Surg. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1093\/bjs\/znad177","article-title":"Total neoadjuvant therapy versus standard neoadjuvant treatment strategies for the management of locally advanced rectal cancer: Network meta-analysis of randomized clinical trials","volume":"110","author":"Donnelly","year":"2023","journal-title":"Br. J. Surg."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1097\/SLA.0000000000006161","article-title":"Surgical outcomes in total neoadjuvant therapy for rectal cancer versus standard long-course chemoradiation: A systematic review and meta-analysis of randomized controlled trials","volume":"279","author":"Lin","year":"2024","journal-title":"Ann. Surg."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1007\/s12029-022-00864-6","article-title":"A meta-analysis of total neoadjuvant therapies combining chemoradiotherapy with induction or consolidated chemotherapy for locally advanced rectal cancer","volume":"54","author":"Nov","year":"2023","journal-title":"J. Gastrointest. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e2414702","DOI":"10.1001\/jamanetworkopen.2024.14702","article-title":"Treatment of locally advanced rectal cancer in the era of total neoadjuvant therapy: A systematic review and network meta-analysis","volume":"7","author":"Turri","year":"2024","journal-title":"JAMA Netw. Open"},{"key":"ref_33","first-page":"326","article-title":"Oncological outcomes and response rate after total neoadjuvant therapy for locally advanced rectal cancer: A network meta-analysis comparing induction versus consolidation chemotherapy versus standard chemoradiation","volume":"23","author":"Bedrikovetski","year":"2024","journal-title":"Clin. Colorectal Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"\u015eenocak Ta\u015f\u00e7\u0131, E., Mutlu, A.U., Sayl\u0131k, O., \u00d6lmez, \u00d6.F., Bilici, A., S\u00fcnger, E., S\u00fct\u00e7\u00fco\u011flu, O., \u00c7akmak \u00d6ks\u00fczo\u011flu, \u00d6.B., \u00d6zdemir, N., and Akdo\u011fan, O. (2024). Total neoadjuvant therapy versus neoadjuvant chemoradiation for locally advanced rectal cancer: A multi-institutional real-world study. Cancers, 16.","DOI":"10.3390\/cancers16183213"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1007\/s00384-024-04610-1","article-title":"Total neoadjuvant therapy for locally advanced rectal cancer: A three-group propensity score matched study","volume":"39","author":"Zhou","year":"2024","journal-title":"Int. J. Colorectal Dis."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Lo Greco, M.C., La Rocca, M., Marano, G., Finocchiaro, I., Liardo, R.L.E., Milazzotto, R., Acquaviva, G., Basile, A., Palmucci, S., and Foti, P.V. (2023). Integrated intensified chemoradiation in the setting of total neoadjuvant therapy (TNT) in patients with locally advanced rectal cancer: A retrospective single-arm study on feasibility and efficacy. Cancers, 15.","DOI":"10.3390\/cancers15030921"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1007\/s10151-024-02993-5","article-title":"Tumor response rates based on initial TNM stage and tumor size in locally advanced rectal cancer: A useful tool for shared decision-making","volume":"28","author":"Boubaddi","year":"2024","journal-title":"Tech. Coloproctol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1007\/s00384-013-1821-7","article-title":"Clinical tumour size and nodal status predict pathologic complete response following neoadjuvant chemoradiotherapy for rectal cancer","volume":"29","author":"Garland","year":"2014","journal-title":"Int. J. Colorectal Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1245\/s10434-015-5017-y","article-title":"Predictors of pathologic complete response following neoadjuvant chemoradiotherapy for rectal cancer","volume":"23","author":"Attwood","year":"2016","journal-title":"Ann. Surg. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s13244-019-0706-x","article-title":"Response evaluation after neoadjuvant treatment for rectal cancer using modern MR imaging: A pictorial review","volume":"10","author":"Lambregts","year":"2019","journal-title":"Insights Imaging"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1002\/jmri.28426","article-title":"Rectal MRI interpretation after neoadjuvant therapy","volume":"57","author":"Horvat","year":"2023","journal-title":"J. Magn. Reson. Imaging"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"15353508261462778","DOI":"10.1177\/15353508261462778","article-title":"Radiomic Analysis of MRI for Assessing Response to Neoadjuvant Chemoradiotherapy in Rectal Adenocarcinoma: A Systematic Review and Metaanalysis","volume":"25","author":"Jakipov","year":"2026","journal-title":"Mol. Imaging"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1515\/oncologie-2025-0526","article-title":"From radical resection to organ preservation: The evolution of neoadjuvant therapies in rectal cancer","volume":"28","author":"Acquaviva","year":"2026","journal-title":"Oncologie"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e2350903","DOI":"10.1001\/jamanetworkopen.2023.50903","article-title":"Organ preservation and survival by clinical response grade in patients with rectal cancer treated with total neoadjuvant therapy: A secondary analysis of the OPRA randomized clinical trial","volume":"7","author":"Thompson","year":"2024","journal-title":"JAMA Netw. Open"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1097\/01.sla.0000141194.27992.32","article-title":"Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: Long-term results","volume":"240","author":"Perez","year":"2004","journal-title":"Ann. Surg."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1016\/j.gassur.2006.09.005","article-title":"Patterns of failure and survival for nonoperative treatment of stage c0 distal rectal cancer following neoadjuvant chemoradiation therapy","volume":"10","author":"Perez","year":"2006","journal-title":"J. Gastrointest. Surg."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.radonc.2015.04.003","article-title":"Clinical complete response after neoadjuvant chemoradiotherapy and conservative treatment in rectal cancer: Findings from the ACCORD 12\/PRODIGE 2 randomized trial","volume":"115","author":"Chamorey","year":"2015","journal-title":"Radiother. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1880","DOI":"10.1007\/s11605-020-04583-w","article-title":"Organ preservation in rectal cancer","volume":"24","author":"Yuval","year":"2020","journal-title":"J. Gastrointest. Surg."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Williams, H., Lee, C., and Garcia-Aguilar, J. (2024). Nonoperative management of rectal cancer. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1477510"}],"container-title":["Medical Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3271\/14\/3\/393\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T01:17:40Z","timestamp":1784078260000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3271\/14\/3\/393"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,14]]},"references-count":49,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["medsci14030393"],"URL":"https:\/\/doi.org\/10.3390\/medsci14030393","relation":{},"ISSN":["2076-3271"],"issn-type":[{"value":"2076-3271","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,14]]}}}