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DOI: 10.1055/a-2771-6871
Why Is There a Demand for Organ-Sparing Approaches in the Era of TNT and TME?
Authors
Abstract
Total neoadjuvant therapy (TNT) has emerged as a transformative approach in the management of locally advanced rectal cancer, shifting radiation and chemotherapy to the preoperative setting to optimize local and distant disease control. Landmark trials have demonstrated improved compliance, tumor downstaging, and disease-free survival with TNT, increasing options for nonoperative strategies such as watch-and-wait. This paradigm allows patients who achieve a clinical complete response (cCR) to avoid surgery and its associated morbidity, including ostomy formation and low anterior resection syndrome (LARS). The Organ Preservation in Patients with Rectal Adenocarcinoma (OPRA) trial and other prospective studies have validated the oncologic safety of watch-and-wait, showing comparable disease-free and overall survival to traditional approaches, with salvage surgery effective in cases of regrowth. However, not all patients are ideal candidates for TNT and watch-and-wait protocols. Tumor location, anatomy, comorbidities, and patient preferences influence treatment selection. For mid-to-upper rectal tumors, TNT may be over-treatment, as suggested in the Preoperative Treatment of Locally Advanced Rectal Cancer (PROSPECT) Trial, which supports selective use of chemoradiation. This is an important option for patients wishing to preserve fertility. Additionally, predicting cCR and regrowth remain challenging, and intensive surveillance is required. This article reviews the evolution of TNT and watch-and-wait strategies, highlighting key trials such as OPRA, the Rectal Cancer and Preoperative Induction Therapy followed by Dedicated Operation (RAPIDO) Trial, the Partenariat de Recherche en Oncologie Digestive 23 (PRODIGE 23) Trial, the Organ Preservation after TNT for Locally Advanced Rectal Cancer (CAO/ARO/AIO-16) Trial, and PROSPECT. We examine the oncologic safety, organ preservation rates, and quality-of-life implications of nonoperative management, including the risks of LARS and ostomy formation. With multiple validated strategies, surgeons must balance oncologic outcomes with quality of life for each individual patient. Ongoing trials continue to refine these approaches, aiming to optimize tumor downstaging, integrate immunotherapy, and expand organ-preserving options.
Keywords
rectal cancer - total mesorectal excision - total neoadjuvant therapy - nonoperative management - watch-and-waitPublication History
Article published online:
30 December 2025
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References
- 1 Cedermark B, Dahlberg M, Glimelius B, Påhlman L, Rutqvist LE, Wilking N. Swedish Rectal Cancer Trial. Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 1997; 336 (14) 980-987
- 2 Kapiteijn E, Marijnen CA, Nagtegaal ID. et al; Dutch Colorectal Cancer Group. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001; 345 (09) 638-646
- 3 van Gijn W, Marijnen CA, Nagtegaal ID. et al; Dutch Colorectal Cancer Group. 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 (06) 575-582
- 4 Sauer R, Fietkau R, Wittekind C. et al; German Rectal Cancer Group. Adjuvant vs. neoadjuvant radiochemotherapy for locally advanced rectal cancer: the German trial CAO/ARO/AIO-94. Colorectal Dis 2003; 5 (05) 406-415
- 5 Sauer R, Liersch T, Merkel S. 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) 1926-1933
- 6 Heald RJ, Ryall RD. Recurrence and survival after total mesorectal excision for rectal cancer. Lancet 1986; 1 (8496): 1479-1482
- 7 Erlandsson J, Holm T, Pettersson D. et al. Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial. Lancet Oncol 2017; 18 (03) 336-346
- 8 Habr-Gama A, Perez RO, Nadalin W. et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg 2004; 240 (04) 711-717 , discussion 717–718
- 9 Garcia-Aguilar J, Patil S, Kim J. et al. Preliminary results of the organ preservation of rectal adenocarcinoma (OPRA) trial. J Clin Oncol 2020; 38 (15, suppl): 4008-4008
- 10 Verheij FS, Omer DM, Williams H. 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 (05) 500-506
- 11 National Comprehensive Cancer Network. NCCN Guidelines Rectal Cancer (Version 2.2025). Accessed August 6, 2025 at: https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf
- 12 Erlandsson J, Lörinc E, Ahlberg M. et al. Tumour regression after radiotherapy for rectal cancer - Results from the randomised Stockholm III trial. Radiother Oncol 2019; 135: 178-186
- 13 de Campos-Lobato LF, Stocchi L, da Luz Moreira A. et al. Pathologic complete response after neoadjuvant treatment for rectal cancer decreases distant recurrence and could eradicate local recurrence. Ann Surg Oncol 2011; 18 (06) 1590-1598
- 14 Garcia-Aguilar J, Chow OS, Smith DD. et al; Timing of Rectal Cancer Response to Chemoradiation Consortium. Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial. Lancet Oncol 2015; 16 (08) 957-966
- 15 Marco MR, Zhou L, Patil S. et al; Timing of Rectal Cancer Response to Chemoradiation Consortium. Consolidation mFOLFOX6 chemotherapy after chemoradiotherapy improves survival in patients with locally advanced rectal cancer: final results of a multicenter phase II trial. Dis Colon Rectum 2018; 61 (10) 1146-1155
- 16 Bahadoer RR, Dijkstra EA, van Etten B. et al; RAPIDO collaborative investigators. 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 (01) 29-42
- 17 Dijkstra EA, Nilsson PJ, Hospers GAP. et al; Collaborative Investigators. 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 (04) e766-e772
- 18 Conroy T, Bosset JF, Etienne PL. et al; Unicancer Gastrointestinal Group and Partenariat de Recherche en Oncologie Digestive (PRODIGE) Group. 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 (05) 702-715
- 19 Habr-Gama A, Gama-Rodrigues J, São Julião GP. et al. Local recurrence after complete clinical response and watch and wait in rectal cancer after neoadjuvant chemoradiation: impact of salvage therapy on local disease control. Int J Radiat Oncol Biol Phys 2014; 88 (04) 822-828
- 20 Gani C, Fokas E, Polat B. et al. Organ preservation after total neoadjuvant therapy for locally advanced rectal cancer (CAO/ARO/AIO-16): an open-label, multicentre, single-arm, phase 2 trial. Lancet Gastroenterol Hepatol 2025; 10 (06) 562-572
- 21 Wang L, Zhang XY, Zhao YM. et al; Rectal Cancer Cooperative Group of Peking University Cancer Hospital. Intentional watch and wait or organ preservation surgery following neoadjuvant chemoradiotherapy plus consolidation CAPEOX for MRI-defined low-risk rectal cancer: findings from a prospective phase 2 trial (PKUCH-R01 trial, NCT02860234). Ann Surg 2023; 277 (04) 647-654
- 22 van der Valk MJM, Marijnen CAM, van Etten B. et al; Collaborative investigators. Compliance and tolerability of short-course radiotherapy followed by preoperative chemotherapy and surgery for high-risk rectal cancer - results of the international randomized RAPIDO-trial. Radiother Oncol 2020; 147: 75-83
- 23 Keane C, Fearnhead NS, Bordeianou LG. et al; LARS International Collaborative Group. International consensus definition of low anterior resection syndrome. Dis Colon Rectum 2020; 63 (03) 274-284
- 24 Tagkalidis PP, Tjandra JJ. Chronic radiation proctitis. ANZ J Surg 2001; 71 (04) 230-237
- 25 Bregendahl S, Emmertsen KJ, Lous J, Laurberg S. Bowel dysfunction after low anterior resection with and without neoadjuvant therapy for rectal cancer: a population-based cross-sectional study. Colorectal Dis 2013; 15 (09) 1130-1139
- 26 Sun W, Dou R, Chen J. et al. Impact of long-course neoadjuvant radiation on postoperative low anterior resection syndrome and quality of life in rectal cancer: post hoc analysis of a randomized controlled trial. Ann Surg Oncol 2019; 26 (03) 746-755
- 27 Sun R, Dai Z, Zhang Y, Lu J, Zhang Y, Xiao Y. The incidence and risk factors of low anterior resection syndrome (LARS) after sphincter-preserving surgery of rectal cancer: a systematic review and meta-analysis. Support Care Cancer 2021; 29 (12) 7249-7258
- 28 Ihnát P, Slívová I, Tulinsky L, Ihnát Rudinská L, Máca J, Penka I. Anorectal dysfunction after laparoscopic low anterior rectal resection for rectal cancer with and without radiotherapy (manometry study). J Surg Oncol 2018; 117 (04) 710-716
- 29 Conroy T, Castan F, Etienne PL. 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) 873-881
- 30 Williams H, Fokas E, Diefenhardt M. et al; German Rectal Cancer Study Group, OPRA Consortium. Survival among patients treated with total mesorectal excision or selective watch-and-wait after total neoadjuvant therapy: a pooled analysis of the CAO/ARO/AIO-12 and OPRA randomized phase II trials. Ann Oncol 2025; 36 (05) 543-547
- 31 São Julião GP, Karagkounis G, Fernandez LM. et al. Conditional survival in patients with rectal cancer and complete clinical response managed by watch and wait after chemoradiation: recurrence risk over time. Ann Surg 2020; 272 (01) 138-144
- 32 Schrag D, Shi Q, Weiser MR. et al. Preoperative treatment of locally advanced rectal cancer. N Engl J Med 2023; 389 (04) 322-334
- 33 Hill M, Schatoff E, Tawantanakorn T. et al. Neoadjuvant chemotherapy and surgery for rectal cancer: omission of radiation in clinical practice. J Clin Oncol 2025; 43 (16) 35-95
- 34 Wallace WH, Thomson AB, Saran F, Kelsey TW. Predicting age of ovarian failure after radiation to a field that includes the ovaries. Int J Radiat Oncol Biol Phys 2005; 62 (03) 738-744
- 35 Su HI, Lacchetti C, Letourneau J. et al. Fertility preservation in people with cancer: ASCO guideline update. J Clin Oncol 2025; 43 (12) 1488-1515
