{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:59:44Z","timestamp":1792789184516,"version":"4.5.0"},"reference-count":42,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Tumor Center Dresden","award":["15_05_2014"],"award-info":[{"award-number":["15_05_2014"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Persistent lymph node metastases after neoadjuvant radiochemotherapy (RCT) for locally advanced rectal cancer indicate poor response to treatment. This study evaluated the long-term prognosis of patients with residual nodal disease following neoadjuvant RCT and total mesorectal excision (TME) in comparison with patients who underwent upfront TME without adjuvant radiotherapy. Methods: Consecutive patients with rectal adenocarcinoma and histopathologically confirmed lymph node metastases after TME were identified from the prospectively maintained database of the colorectal unit at Dresden-Friedrichstadt General Hospital. Patients with distant metastases, in-hospital mortality, or postoperative radiotherapy were excluded. The two groups were comprehensively compared regarding patient-, tumor-, and treatment-related characteristics. Cumulative local recurrence, time to recurrence, cancer-specific survival, and overall survival were analyzed using the Kaplan\u2013Meier method. Results: Between 1996 and 2021, 155 eligible patients were identified, including 101 patients in the RCT group and 54 in the upfront surgery group. Baseline characteristics were largely comparable, except for a higher median age (70.5 vs. 64 years, p &lt; 0.001) and a higher proportion of lymphovascular invasion (36.0% vs. 15.2%, p = 0.004) in the upfront surgery group. Ten-year local recurrence rates were similar between groups (21.0% [95% CI: 10.4\u201331.6] vs. 20.8% [95% CI: 8.5\u201333.1], p = 0.609). No significant differences were observed in time to recurrence or cancer-specific survival. Overall survival was lower in the upfront surgery group, most likely reflecting the substantially higher age of these patients. Conclusions: Despite more intensive treatment, patients with a persistent ypN-positive category have outcomes no better than untreated patients with node-positive disease after TME, indicating a biologically high-risk subgroup. Non-response is therefore a sign of a negative selection. These patients may lose the opportunity for optimal local tumor control during prolonged neoadjuvant treatment, underscoring the urgent need for reliable predictive markers to identify non-responders and guide individualized treatment strategies.<\/jats:p>","DOI":"10.3390\/cancers18111686","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T10:07:47Z","timestamp":1779444467000},"page":"1686","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Ten-Year Outcomes of Patients with Rectal Cancer Remaining Lymph Node Positive After Preoperative Radiochemotherapy"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7804-196X","authenticated-orcid":false,"given":"Sigmar","family":"Stelzner","sequence":"first","affiliation":[{"name":"Department of Visceral, Transplant, Thoracic, and Vascular Surgery, University Hospital of Leipzig, Liebigstr. 20, D-04103 Leipzig, Germany"},{"name":"Department of General and Visceral Surgery, Dresden-Friedrichstadt General Hospital, Teaching Hospital of the Technische Universit\u00e4t Dresden, Friedrichstr. 41, D-01067 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Niebisch","sequence":"additional","affiliation":[{"name":"Department of Visceral, Transplant, Thoracic, and Vascular Surgery, University Hospital of Leipzig, Liebigstr. 20, D-04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Puffer","sequence":"additional","affiliation":[{"name":"Institut of Pathology, Dresden-Friedrichstadt General Hospital, Teaching Hospital of the Technische Universit\u00e4t Dresden, Friedrichstr. 41, D-01067 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joerg","family":"Zimmer","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Dresden-Friedrichstadt General Hospital, Teaching Hospital of the Technische Universit\u00e4t Dresden, Friedrichstr. 41, D-01067 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorothea","family":"Bleyl","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dresden-Friedrichstadt General Hospital, Teaching Hospital of the Technische Universit\u00e4t Dresden, Friedrichstr. 41, D-01067 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Willing","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, Dresden-Friedrichstadt General Hospital, Teaching Hospital of the Technische Universit\u00e4t Dresden, Friedrichstr. 41, D-01067 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Kittner","sequence":"additional","affiliation":[{"name":"Department of Radiology, Dresden-Friedrichstadt General Hospital, Teaching Hospital of the Technische Universit\u00e4t Dresden, Friedrichstr. 41, D-01067 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Rhode","sequence":"additional","affiliation":[{"name":"Department of Visceral, Transplant, Thoracic, and Vascular Surgery, University Hospital of Leipzig, Liebigstr. 20, D-04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Mehdorn","sequence":"additional","affiliation":[{"name":"Department of Visceral, Transplant, Thoracic, and Vascular Surgery, University Hospital of Leipzig, Liebigstr. 20, D-04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soeren Torge","family":"Mees","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, Dresden-Friedrichstadt General Hospital, Teaching Hospital of the Technische Universit\u00e4t Dresden, Friedrichstr. 41, D-01067 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"ref_1","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, randomized controlled TME trial","volume":"12","author":"Marijnen","year":"2011","journal-title":"Lancet Oncol."},{"key":"ref_2","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_3","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.annonc.2024.06.019","article-title":"Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiotherapy in patients with locally advanced rectal cancer: Long-term results of the UNICANCER-PRODIGE 23 trial","volume":"35","author":"Conroy","year":"2024","journal-title":"Ann. Oncol."},{"key":"ref_4","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 (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":"ref_5","doi-asserted-by":"crossref","first-page":"e766","DOI":"10.1097\/SLA.0000000000005799","article-title":"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","volume":"278","author":"Dijkstra","year":"2023","journal-title":"Ann. Surg."},{"key":"ref_6","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_7","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.cancergencyto.2008.11.011","article-title":"Preoperative chemoradiotherapy in locally advanced rectal cancer: Correlation of a gene expression-based response signature with recurrence","volume":"190","author":"Liersch","year":"2009","journal-title":"Cancer Genet. Cytogenet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1007\/DCR.0b013e3182070efb","article-title":"Prognostic value of tumor response to neoadjuvant therapy in rectal carcinoma","volume":"54","author":"Topova","year":"2011","journal-title":"Dis. Colon Rectum"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1245\/s10434-016-5736-8","article-title":"Prognostic Value of Sterilized Lymph Nodes After Preoperative Chemoradiotherapy for Patients with ypN0 Rectal Cancer","volume":"24","author":"Vychnevskaia","year":"2017","journal-title":"Ann. Surg. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.surg.2016.08.013","article-title":"The impact of the radiation-induced regression of positive nodes on survival in patients with rectal cancer treated with chemoradiotherapy","volume":"161","author":"Beppu","year":"2017","journal-title":"Surgery"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Calvo, F.A., Tudela, M., Serrano, J., Mu\u00f1oz-Fern\u00e1ndez, M., Peligros, M.I., Garcia-Alfonso, P., and Del Valle, E. (2023). Post-Chemoradiation Metastatic, Persistent and resistant nodes in locally advanced rectal cancer: Metrics and their impact on long-term outcome. Cancers, 15.","DOI":"10.3390\/cancers15184591"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1002\/bjs.10867","article-title":"Prognostic value of pathological node status after neoadjuvant radiotherapy for rectal cancer","volume":"105","author":"Duchalais","year":"2018","journal-title":"Br. J. Surg."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e70257","DOI":"10.1111\/codi.70257","article-title":"Clinical nodal staging to assess the risk of local recurrence after rectal cancer resection: A nationwide cross-sectional study","volume":"27","author":"Ubink","year":"2025","journal-title":"Color. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1007\/s00384-015-2219-5","article-title":"Outcome for stage II and III rectal and colon cancer equally good after treatment improvement over three decades","volume":"30","author":"Fischer","year":"2015","journal-title":"Int. J. Color. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1055\/s-2004-813699","article-title":"S3-guideline conference \u201cColorectal Cancer 2004\u201d","volume":"42","author":"Schmiegel","year":"2004","journal-title":"Z. Gastroenterol."},{"key":"ref_16","unstructured":"Guideline Programme Oncology (2013, August 14). S3-Guideline Colorectal Cancer, Version 1.0. Available online: http:\/\/leitlinenprogramm-onkologie.de\/leitlinien.7.0.html."},{"key":"ref_17","unstructured":"Guideline Programme Oncology (2025, July 17). S3-Guideline Colorectal Cancer, Version 2.1. Available online: http:\/\/www.leitlinienprogramm-onkologie.de\/leitlinen\/kolorektales-karzinom\/."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1148\/radiol.2272011747","article-title":"Morphologic predictors of lymph node status in rectal cancer with use of high-spatial-resolution MR imaging with histopathologic comparison","volume":"227","author":"Brown","year":"2003","journal-title":"Radiology"},{"key":"ref_19","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_20","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1200\/JCO.2006.08.3675","article-title":"Multicenter phase II trial of chemoradiation with oxaliplatin for rectal cancer","volume":"25","author":"Liersch","year":"2007","journal-title":"J. Clin. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1177\/014107688808100904","article-title":"The \u2018Holy Plane\u2018 of rectal surgery","volume":"81","author":"Heald","year":"1988","journal-title":"J. Roy. Soc. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1002\/bjs.5489","article-title":"Extended abdominoperineal resection with gluteus maximus flap reconstruction of the pelvic floor for rectal cancer","volume":"94","author":"Holm","year":"2007","journal-title":"Br. J. Surg."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s00053-019-00425-9","article-title":"Extralevator abdominoperineal excision","volume":"42","author":"Stelzner","year":"2020","journal-title":"Coloproctology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/s003840050072","article-title":"Pathological features of rectal cancer after preoperative radiochemotherapy","volume":"12","author":"Dworak","year":"1997","journal-title":"Int. J. Color. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Sobin, L.H., Gospodarowicz, M.K., and Wittekind, C. (2010). TNM Classification of Malignant Tumours, J. Wiley & Sons. [7th ed.].","DOI":"10.1002\/9780471420194.tnmc26.pub2"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Brierley, J.D., Gospodarowicz, M.K., and Wittekind, C. (2017). TNM Classification of Malignant Tumours, J. Wiley & Sons. [8th ed.].","DOI":"10.1002\/9780471420194.tnmc26.pub3"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1002\/bjs.9811","article-title":"Tumour regression in the randomized Stockholm III trial of radiotherapy regimens for rectal cancer","volume":"102","author":"Pettersson","year":"2015","journal-title":"Br. J. Surg."},{"key":"ref_28","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 (UNICANCER-PRODIGE 23): A multicentre, randomised, open-label, phase 3 trial","volume":"22","author":"Conroy","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"zrae118","DOI":"10.1093\/bjsopen\/zrae118","article-title":"Number of lymph nodes retrieved in patients with locally advanced rectal cancer after total neoadjuvant therapy: Post-hoc analysis from the STELLAR trial","volume":"8","author":"Zhang","year":"2024","journal-title":"BJS Open"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Greco, M.C.L., Acquaviva, G., Milazzotto, R., Liardo, R.L.E., La Rocca, M., Marano, G., Ferrantelli, G., Basile, A., Foti, P.V., and Palmucci, S. (2026). From radical resection to organ preservation: The evolution of neoadjuvant therapies in rectal cancer. Oncologie.","DOI":"10.1515\/oncologie-2025-0526"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e2432927","DOI":"10.1001\/jamanetworkopen.2024.32927","article-title":"Persistent Lymph Node Metastases After Neoadjuvant Chemoradiotherapy for Rectal Cancer","volume":"7","author":"Diefenhardt","year":"2024","journal-title":"JAMA Netw. Open"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.1002\/cncr.29260","article-title":"Downstage migration after neoadjuvant chemoradiotherapy for rectal cancer: The reverse of the Will Rogers phenomenon?","volume":"121","author":"Fokas","year":"2015","journal-title":"Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1111\/j.1463-1318.2009.02110.x","article-title":"Time to locoregional recurrence after curative resection of rectal carcinoma is influenced by neoadjuvant treatment. Implications for follow-up time needed for reliable treatment results statistics","volume":"13","author":"Merkel","year":"2010","journal-title":"Color. Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"102796","DOI":"10.1016\/j.ctrv.2024.102796","article-title":"Oncological risks associated with the planned watch-and-wait strategy using total neoadjuvant treatment for rectal cancer: A narrative review","volume":"129","author":"Socha","year":"2024","journal-title":"Cancer Treat. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1097\/DCR.0000000000000638","article-title":"A nomogram to predict lymph node positivity following neoadjuvant chemoradiation in locally advanced rectal cancer","volume":"59","author":"Newton","year":"2016","journal-title":"Dis. Colon Rectum"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1016\/j.radonc.2018.06.008","article-title":"Can clinicopathological parameters predict for lymph node metastases in ypT0-2 rectal carcinoma? Results of the CAO\/ARO\/AIO-94 and CAO\/ARO\/AIO-04 phase 3 trials","volume":"128","author":"Hartmann","year":"2018","journal-title":"Radiother. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1097\/DCR.0000000000000947","article-title":"Nodal disease in rectal cancer patients with complete tumor response after neoadjuvant chemoradiation: Danger below calm waters","volume":"60","author":"Baucom","year":"2017","journal-title":"Dis. Colon Rectum"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1016\/j.surg.2017.10.021","article-title":"Outcomes of persistent lymph node involvement after neoadjuvant therapy for stage III rectal cancer","volume":"163","author":"Dinaux","year":"2018","journal-title":"Surgery"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"110113","DOI":"10.1016\/j.ejrad.2021.110113","article-title":"Selection of patients with rectal cancer for neoadjuvant therapy using pre-therapeutic MRI\u2014Results from OCUM trial","volume":"147","author":"Stelzner","year":"2022","journal-title":"Eur. J. Radiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1016\/j.surg.2019.06.009","article-title":"Prognostic value of metastatic lymph node regression grade after neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer","volume":"166","author":"Tominaga","year":"2019","journal-title":"Surgery"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1007\/s00428-015-1901-x","article-title":"Prognostic significance of tumor regression in lymph nodes after neoadjuvant therapy for rectal carcinoma","volume":"468","author":"Granja","year":"2016","journal-title":"Virchows Arch."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.dld.2019.07.013","article-title":"ypN0 rectal cancer patients with sterilized lymph nodes after neoadjuvant chemoradiotherapy are of greater risk of recurrence","volume":"52","author":"Manceau","year":"2020","journal-title":"Dig. Liver Dis."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/11\/1686\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T10:18:39Z","timestamp":1779445119000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/11\/1686"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,22]]},"references-count":42,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["cancers18111686"],"URL":"https:\/\/doi.org\/10.3390\/cancers18111686","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,22]]}}}