Digestive Disease Interventions 2023; 07(01): 030-036
DOI: 10.1055/s-0042-1760371
Review Article

Neoadjuvant Treatment for Rectal Cancer and Nonoperative Management/Total Neoadjuvant Therapy

Amy Edwards-Murphy
1   Department of Academic Surgery, University Hospital Waterford, Waterford, Ireland
2   Department of Academic Surgery, University College Cork, Cork, Ireland
Peter Neary
1   Department of Academic Surgery, University Hospital Waterford, Waterford, Ireland
2   Department of Academic Surgery, University College Cork, Cork, Ireland
› Author Affiliations
Funding No funding or grant was received for this study.


Treatment of locally advanced rectal cancer remains one of the most challenging in colorectal surgery. It has had an evolving landscape over the past three decades. This review describes the introduction of total neoadjuvant therapy—a term aimed to describe an approach where both systemic chemotherapy and chemoradiation are administered in the preoperative setting. This novel strategy has come to the fore with the strength of well-documented results of recent trials. Its implementation has begun globally, but long-term outcomes and data analysis to identify optimal schedules are eagerly awaited.

Publication History

Received: 20 September 2022

Accepted: 05 December 2022

Article published online:
02 February 2023

© 2023. Thieme. All rights reserved.

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  • References

  • 1 Samee A, Selvasekar CR. Current trends in staging rectal cancer. World J Gastroenterol 2011; 17 (07) 828-834
  • 2 Patel UB, Taylor F, Blomqvist L. et al. Magnetic resonance imaging-detected tumor response for locally advanced rectal cancer predicts survival outcomes: MERCURY experience. J Clin Oncol 2011; 29 (28) 3753-3760
  • 3 Yang N. Rectal cancer - T3 N2 | Radiology Case | Radiopaedia.org. Accessed December 20, 2022 at: https://radiopaedia.org/cases/rectal-cancer-t3-n2-3
  • 4 Stewart DB, Dietz DW. Total mesorectal excision: what are we doing?. Clin Colon Rectal Surg 2007; 20 (03) 190-202
  • 5 Dimitrov D, Ivanov T, Deliyski T. et al. Macroscopic assessment of total mesorectal excision quality after robotic assisted rectal resection for rectal cancer in Bulgaria: a prospective trial. J Biomed Clin Res 2017; 10 (02) 130-134
  • 6 Petersen SH, Harling H, Kirkeby LT, Wille-Jørgensen P, Mocellin S. Postoperative adjuvant chemotherapy in rectal cancer operated for cure. Cochrane Database Syst Rev 2012; 2012 (03) CD004078
  • 7 Sauer R, Becker H, Hohenberger W. et al; German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351 (17) 1731-1740
  • 8 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
  • 9 Ngan SY, Burmeister B, Fisher RJ. et al. Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04. J Clin Oncol 2012; 30 (31) 3827-3833
  • 10 Gérard JP, Azria D, Gourgou-Bourgade S. et al. Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-PRODIGE 2. J Clin Oncol 2010; 28 (10) 1638-1644
  • 11 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
  • 12 Fernandez-Martos C, Garcia-Albeniz X, Pericay 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 trial. Ann Oncol 2015; 26 (08) 1722-1728
  • 13 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
  • 14 Radu C, Berglund A, Påhlman L, Glimelius B. Short-course preoperative radiotherapy with delayed surgery in rectal cancer - a retrospective study. Radiother Oncol 2008; 87 (03) 343-349
  • 15 van der Valk MJM, Hilling DE, Bastiaannet E. et al; IWWD Consortium. Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study. Lancet 2018; 391 (10139): 2537-2545
  • 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 Conroy T, Lamfichekh N, Etienne P. et al. Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiation in patients with locally advanced rectal cancer: final results of PRODIGE 23 phase III trial, a UNICANCER GI trial. J Clin Oncol 2020; 38 (15, Suppl): 4007-4007
  • 18 Giunta EF, Bregni G, Pretta A. et al. Total neoadjuvant therapy for rectal cancer: making sense of the results from the RAPIDO and PRODIGE 23 trials. Cancer Treat Rev 2021; 96: 102177
  • 19 Petrelli F, Trevisan F, Cabiddu M. et al. Total neoadjuvant therapy in rectal cancer: a systematic review and meta-analysis of treatment outcomes. Ann Surg 2020; 271 (03) 440-448
  • 20 Cercek A, Roxburgh CSD, Strombom P. et al. Adoption of total neoadjuvant therapy for locally advanced rectal cancer. JAMA Oncol 2018; 4 (06) e180071
  • 21 Fokas E, Allgäuer M, Polat B. et al; German Rectal Cancer Study Group. 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) 3212-3222
  • 22 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
  • 23 Glynne-Jones R, Grainger J, Harrison M, Ostler P, Makris A. Neoadjuvant chemotherapy prior to preoperative chemoradiation or radiation in rectal cancer: should we be more cautious?. Br J Cancer 2006; 94 (03) 363-371
  • 24 Quah HM, Chou JF, Gonen M. et al. Pathologic stage is most prognostic of disease-free survival in locally advanced rectal cancer patients after preoperative chemoradiation. Cancer 2008; 113 (01) 57-64
  • 25 Maas M, Nelemans PJ, Valentini V. et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol 2010; 11 (09) 835-844
  • 26 Nair RM, Siegel EM, Chen DT. et al. Long-term results of transanal excision after neoadjuvant chemoradiation for T2 and T3 adenocarcinomas of the rectum. J Gastrointest Surg 2008; 12 (10) 1797-1805 , discussion 1805–1806
  • 27 Walker AS, Zwintscher NP, Johnson EK. et al. Future directions for monitoring treatment response in colorectal cancer. J Cancer 2014; 5 (01) 44-57
  • 28 Habr-Gama A, Sabbaga J, Gama-Rodrigues J. et al. Watch and wait approach following extended neoadjuvant chemoradiation for distal rectal cancer. Diseases of the Colon &amp . Rectum 2013; 56 (10) 1109-1117