{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T18:49:59Z","timestamp":1784141399573,"version":"3.55.0"},"reference-count":46,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Background: Total neoadjuvant therapy (TNT) is increasingly administered in rectal cancer, but compared with concurrent chemoradiotherapy (CRT), data regarding the gastrointestinal (GI) toxicity profile and clinical predictors remain limited. Objectives: To evaluate GI toxicity associated with TNT compared with CRT and to explore clinical predictors of these adverse events (AEs). Methods: This retrospective study included 201 patients with rectal cancer treated with TNT (n = 157) and CRT (n = 44). GI AEs (nausea, vomiting, diarrhea) were graded according to CTCAE v5.0. In the analysis of factors associated with GI AEs, multiple clinical and pathological variables were included using multivariable logistic regression. Results: The composite endpoint \u201cany GI AEs grade \u2265 1\u201d was more frequent in the TNT group compared with the CRT group (33.1% vs. 15.9%; RR = 2.08; 95% CI 1.02\u20134.25; p = 0.038). Nausea was significantly more frequent in the TNT group (28.7% vs. 9.1%; RR = 3.15; 95% CI 1.20\u20138.30; p = 0.012), whereas vomiting (9.6% vs. 2.3%; p = 0.203) and diarrhea (17.8% vs. 9.1%; p = 0.242) did not reach statistical significance. In multivariable logistic regression, TNT (OR = 2.65; 95% CI 1.08\u20136.53; p = 0.032) and female sex (OR = 2.03; 95% CI 1.05\u20133.77; p = 0.033) were identified as independent predictors of grade \u2265 1 GI AEs. For nausea, TNT remained significant (OR = 4.37; 95% CI 1.45\u201313.20; p = 0.0089). Upper rectal tumor location was significantly associated with vomiting (p = 0.0054). No grade 3\u20134 GI AEs were observed in either treatment group. Conclusions: TNT was associated with a higher incidence of mild GI AEs, predominantly driven by nausea, without an increase in severe toxicities. TNT and female sex were identified as independent clinical predictors of an increased risk of GI AEs, while tumor location in the upper third of the rectum was associated with a higher occurrence of vomiting.<\/jats:p>","DOI":"10.3390\/life16030422","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T15:01:07Z","timestamp":1772636467000},"page":"422","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Gastrointestinal Toxicity and Clinical Predictors of Total Neoadjuvant Therapy in Rectal Cancer: A Real-World Retrospective Study"],"prefix":"10.3390","volume":"16","author":[{"given":"Lucian Drago\u0219","family":"Bratu","sequence":"first","affiliation":[{"name":"Doctoral School, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"},{"name":"Sf. Nectarie Oncology Center, 200347 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Puiu Olivian","family":"Stovicek","sequence":"additional","affiliation":[{"name":"Sf. Nectarie Oncology Center, 200347 Craiova, Romania"},{"name":"Department of Pharmacology, Faculty of Nursing, T\u00e2rgu Jiu Subsidiary, Titu Maiorescu University, 040441 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0910-475X","authenticated-orcid":false,"given":"Ana-Maria","family":"Ciurea","sequence":"additional","affiliation":[{"name":"Sf. Nectarie Oncology Center, 200347 Craiova, Romania"},{"name":"Department of Oncology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina Maria","family":"Mehedin\u021beanu","sequence":"additional","affiliation":[{"name":"Sf. Nectarie Oncology Center, 200347 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tradian Ciprian","family":"Berisha","sequence":"additional","affiliation":[{"name":"Doctoral School, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"},{"name":"Sf. Nectarie Oncology Center, 200347 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramona Adriana","family":"Schenker","sequence":"additional","affiliation":[{"name":"Sf. Nectarie Oncology Center, 200347 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei Mircea","family":"Dicianu","sequence":"additional","affiliation":[{"name":"Sf. Nectarie Oncology Center, 200347 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Stamulescu","sequence":"additional","affiliation":[{"name":"Sf. Nectarie Oncology Center, 200347 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7648-107X","authenticated-orcid":false,"given":"\u0218tefan","family":"Paitici","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stelian \u0218tef\u0103ni\u021b\u0103","family":"Mogoant\u0103","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"},{"name":"3rd General Surgery Clinic, Emergency County Hospital, 200642 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Schenker","sequence":"additional","affiliation":[{"name":"Sf. Nectarie Oncology Center, 200347 Craiova, Romania"},{"name":"Department of Oncology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,4]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1136\/gutjnl-2015-310912","article-title":"Global patterns and trends in colorectal cancer incidence and mortality","volume":"66","author":"Arnold","year":"2017","journal-title":"Gut"},{"key":"ref_3","first-page":"iv22","article-title":"Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"28","author":"Wyrwicz","year":"2017","journal-title":"Ann. Oncol."},{"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":"29","DOI":"10.1016\/S1470-2045(20)30555-6","article-title":"Short-course radiotherapy followed by chemotherapy before total mesorectal excision versus preoperative chemoradiotherapy 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_6","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1038\/nrc1950","article-title":"Preventing or reducing late side effects of radiation therapy: Radiobiology meets molecular pathology","volume":"6","author":"Bentzen","year":"2006","journal-title":"Nat. Rev. Cancer"},{"key":"ref_7","first-page":"145","article-title":"Colorectal cancer statistics, 2020","volume":"70","author":"Siegel","year":"2020","journal-title":"CA Cancer J. Clin."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1820","DOI":"10.1136\/gutjnl-2018-317592","article-title":"Increasing incidence of colorectal cancer in young adults in Europe over the last 25 years","volume":"68","author":"Vuik","year":"2019","journal-title":"Gut"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1016\/j.ijrobp.2005.12.056","article-title":"Intensity-modulated radiotherapy in patients with locally advanced rectal cancer reduces bowel dose and acute gastrointestinal toxicity","volume":"65","author":"Henrys","year":"2006","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_10","first-page":"677","article-title":"Preoperative intensity-modulated and image-guided radiotherapy with a simultaneous integrated boost in locally advanced rectal cancer","volume":"75","author":"Engels","year":"2009","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_11","unstructured":"Lotfollahzadeh, S., Kashyap, S., Tsoris, A., Recio-Boiles, A., and Babiker, H.M. (2024). Rectal cancer. StatPearls, StatPearls Publishing."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1016\/S1470-2045(15)00004-2","article-title":"Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: A multicentre, phase 2 trial","volume":"16","author":"Chow","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_13","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_14","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1136\/gut.2004.062596","article-title":"Gastrointestinal complications of pelvic radiotherapy: Are they of any importance?","volume":"54","author":"Andreyev","year":"2005","journal-title":"Gut"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/S0167-8140(02)00060-9","article-title":"The radiotherapeutic injury\u2014A complex \u201cwound\u201d","volume":"63","author":"Denham","year":"2002","journal-title":"Radiother. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1136\/gutjnl-2011-300563","article-title":"Practice guidance on the management of acute and chronic gastrointestinal problems arising as a result of treatment for cancer","volume":"61","author":"Andreyev","year":"2012","journal-title":"Gut"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2212","DOI":"10.1016\/j.ejca.2008.07.018","article-title":"Small bowel bacterial overgrowth and lactose intolerance during radical pelvic radiotherapy: An observational study","volume":"44","author":"Wedlake","year":"2008","journal-title":"Eur. J. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5124","DOI":"10.1200\/JCO.2009.22.0467","article-title":"Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03","volume":"27","author":"Roh","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1056\/NEJMoa060829","article-title":"Chemotherapy with preoperative radiotherapy in rectal cancer","volume":"355","author":"Bosset","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3542","DOI":"10.1200\/JCO.2005.04.9544","article-title":"Phase III trial of fluorouracil-based chemotherapy regimens plus radiotherapy in postoperative adjuvant rectal cancer: GI INT 0144","volume":"24","author":"Smalley","year":"2006","journal-title":"J. Clin. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.ijrobp.2007.06.066","article-title":"The dose\u2013volume relationship of small bowel irradiation and acute grade 3 diarrhea during chemoradiotherapy for rectal cancer","volume":"70","author":"Robertson","year":"2008","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.ijrobp.2009.04.048","article-title":"Predicting grade 3 acute diarrhea during radiation therapy for rectal cancer using a cutoff-dose logistic regression normal tissue complication probability model","volume":"77","author":"Robertson","year":"2010","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1080\/02841860701317873","article-title":"Dose\u2013volume relationships between enteritis and irradiated bowel volumes during 5-fluorouracil- and oxaliplatin-based chemoradiotherapy in locally advanced rectal cancer","volume":"46","author":"Gunnlaugsson","year":"2007","journal-title":"Acta Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e513","DOI":"10.1016\/j.ijrobp.2012.01.013","article-title":"Dose\u2013volume effects on patient-reported acute gastrointestinal symptoms during chemoradiation therapy for rectal cancer","volume":"83","author":"Chen","year":"2012","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1016\/j.ijrobp.2011.01.051","article-title":"Reduced acute bowel toxicity in patients treated with intensity-modulated radiotherapy for rectal cancer","volume":"82","author":"Samuelian","year":"2012","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1016\/j.ijrobp.2011.06.008","article-title":"RTOG 0822: A phase II study of preoperative chemoradiotherapy utilizing IMRT in combination with capecitabine and oxaliplatin for patients with locally advanced rectal cancer","volume":"81","author":"Garofalo","year":"2011","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1748-717X-5-17","article-title":"Intensity-modulated radiation therapy versus 3D conformal radiotherapy in locally advanced rectal cancer: Dosimetric comparison and clinical implications","volume":"5","author":"Arbea","year":"2010","journal-title":"Radiat. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e81","DOI":"10.1016\/j.ijrobp.2011.12.012","article-title":"Normal tissue complication probability analysis of acute gastrointestinal toxicity in cervical cancer patients undergoing intensity-modulated radiation therapy and concurrent cisplatin","volume":"83","author":"Simpson","year":"2012","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.radonc.2003.05.001","article-title":"A dosimetric analysis of acute gastrointestinal toxicity in women receiving intensity-modulated whole-pelvic radiation therapy","volume":"69","author":"Roeske","year":"2003","journal-title":"Radiother. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.radonc.2009.07.006","article-title":"A multi-institutional acute gastrointestinal toxicity analysis of anal cancer patients treated with concurrent intensity-modulated radiation therapy and chemotherapy","volume":"93","author":"Devisetty","year":"2009","journal-title":"Radiother. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"102195","DOI":"10.1016\/j.esmoop.2023.102195","article-title":"2023 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting","volume":"9","author":"Herrstedt","year":"2024","journal-title":"ESMO Open"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2782","DOI":"10.1200\/JCO.20.01296","article-title":"Antiemetics: ASCO Guideline Update","volume":"38","author":"Hesketh","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1136\/gutjnl-2024-333812","article-title":"British Society of Gastroenterology practice guidance on the management of acute and chronic gastrointestinal symptoms and complications as a result of treatment for cancer","volume":"74","author":"Andreyev","year":"2025","journal-title":"Gut"},{"key":"ref_34","unstructured":"National Cancer Institute (2017). Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Bratu, L.D., Schenker, M., Stovicek, P.O., Schenker, R.A., Mehedin\u021beanu, A.M., Berisha, T.C., Donoiu, A., and Mogoant\u0103, S.\u0218. (2024). Retrospective Evaluation of the Efficacy of Total Neoadjuvant Therapy and Chemoradiotherapy Neoadjuvant Treatment in Relation to Surgery in Patients with Rectal Cancer. Medicina, 60.","DOI":"10.3390\/medicina60040656"},{"key":"ref_36","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.-Q.N., and Skibber, J.M. (2024). Total Neoadjuvant Therapy for Rectal Cancer: Which Regimens to Use?. Cancers, 16.","DOI":"10.3390\/cancers16112093"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Iwamoto, M., Ueda, K., and Kawamura, J. (2025). Neoadjuvant Treatment for Locally Advanced Rectal Cancer: Current Status and Future Directions. Cancers, 17.","DOI":"10.3390\/cancers17152540"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"100170","DOI":"10.1016\/j.esmogo.2025.100170","article-title":"Total neoadjuvant therapy in early-onset versus average-onset locally advanced rectal cancer: Patient characteristics and tolerance of therapy","volume":"8","author":"Conces","year":"2025","journal-title":"ESMO Gastrointest. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6728","DOI":"10.1245\/s10434-025-17421-7","article-title":"Compliance and toxicity of total neoadjuvant therapy in locally advanced rectal cancer: A systematic review and network meta-analysis","volume":"32","author":"Seow","year":"2025","journal-title":"Ann. Surg. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Schenker, M., Bi\u021b\u00een\u0103, L.C., Schenker, R.A., Ciurea, A.M., Mehedin\u021beanu, A.M., Berisha, T.C., Bratu, L.D., Cara, M.L., Dicianu, A.M., and Stovicek, P.O. (2025). Prospective Evaluation of the Influence of Chemoradiotherapy and Stoma on Functional and Symptomatic Outcomes in Rectal Cancer Patients. Cancers, 17.","DOI":"10.3390\/cancers17122052"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Barba, M.C., De Franco, P., Russo, D., Cavalera, E., Ciurlia, E., De Matteis, S., Di Paola, G., Federico, C., Leone, A., and Papaleo, A. (2025). Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: Evaluation of Sequencing, Response, and Toxicity in a Single-Institution Cohort. Cancers, 17.","DOI":"10.3390\/cancers17152416"},{"key":"ref_42","first-page":"129","article-title":"Predictors of Acute Gastrointestinal Toxicity during Pelvic Chemoradiotherapy in Patients with Rectal Cancer","volume":"6","author":"Yang","year":"2013","journal-title":"Gastrointest. Cancer Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4850","DOI":"10.3748\/wjg.v25.i33.4850","article-title":"Neoadjuvant Radiotherapy for Rectal Cancer Management","volume":"25","author":"Feeney","year":"2019","journal-title":"World J. Gastroenterol."},{"key":"ref_44","first-page":"137","article-title":"Acute Gastrointestinal Toxicity and Tumor Response with Preoperative Intensity-Modulated Radiation Therapy for Rectal Cancer","volume":"6","author":"Parekh","year":"2013","journal-title":"Gastrointest. Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Ching, J.C., Liu, K.C., Pang, I.K., Nicol, A.J., Leung, V.W., Cai, J., and Lee, S.W. (2025). Predictive Factors for Gastrointestinal and Genitourinary Toxicity Following Radiotherapy in Pelvic Tumors: A Scoping Review. Diagnostics, 15.","DOI":"10.3390\/diagnostics15111331"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1186\/s13014-015-0566-6","article-title":"Is the Irradiated Small Bowel Volume Still a Predictor for Acute Lower Gastrointestinal Toxicity during Preoperative Concurrent Chemo-Radiotherapy for Rectal Cancer?","volume":"10","author":"Xu","year":"2015","journal-title":"Radiat. Oncol."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/3\/422\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T12:11:45Z","timestamp":1772712705000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/3\/422"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,4]]},"references-count":46,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["life16030422"],"URL":"https:\/\/doi.org\/10.3390\/life16030422","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,4]]}}}