Total neoadjuvant therapy: A new standard of care for locally advanced rectal cancer?

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Sheila B Martins, MD, PhD student, FESCP Julio S Leite, MD, PhD, FACS


Delivering chemotherapy before surgery is a newer treatment approach called total neoadjuvant therapy (TNT), and the National Comprehensive Cancer Network guidelines recommend it for locally advanced rectal cancer (LARC) with cT3 / cN+ / cT4, in contrast with the European Society for Medical Oncology guidelines, in which most rectal cancers can be treated with surgery alone if good quality mesorectal resection is assured. Neoadjuvant or adjuvant treatments are reserved for patients with high-risk tumours, including cT3c/d or cT4, or that threaten the mesorectal fascia. The favourable outcomes in the RAPIDO trial for high-risk rectal cancers with a lower incidence of distant metastasis in the TNT group were observed but with an unexpected increase in the local recurrence with more extended follow-up. This suggests early surgery for nonresponding tumours. The TNT approach was also evaluated in the OPRA trial with long-course chemoradiotherapy and induction versus consolidation chemotherapy. Half the patients presented complete clinical responses and were enrolled in the watch-and-wait (WW) approach. Given the high number of trials and guidelines in this subject, the multidisciplinary team's decision-making process in rectal cancer management is complex. Looking at the actual data, it was concluded that TNT is not for all patients with LARC and is an option if organ preservation is a priority, although with a high regrowth rate in a WW strategy and increasing risk of distant metastasis, questioning the deleterious effect of deferral of surgery.

Keywords: locally advanced rectal cancer, total neoadjuvant therapy, organ preservation, watch and wait strategy, local regrowth.

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MARTINS, Sheila B; LEITE, Julio S. Total neoadjuvant therapy: A new standard of care for locally advanced rectal cancer?. Medical Research Archives, [S.l.], v. 12, n. 4, apr. 2024. ISSN 2375-1924. Available at: <>. Date accessed: 27 may 2024. doi:
Review Articles


1. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med. 2001;345(9):638-646. doi:10.1056/NEJMoa010580

2. Glynne-Jones R, Wyrwicz L, Tiret E, et al. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up [published correction appears in Ann Oncol. 2018 Oct 1;29(Suppl 4):iv263]. Ann Oncol. 2017;28 (suppl_4):iv22-iv40. doi:10.1093/annonc/mdx224

3. Evans J, Bhoday J, Sizer B et al. Results of a prospective randomised control 6 vs 12 trial: is greater tumour downstaging observed on post treatment MRI if surgery is delayed to 12-weeks versus 6-weeks after completion of neoadjuvant chemoradiotherapy?. Ann Oncol. 2016; 27 (Suppl 6): vi149 (abstract 4520). doi:10.1093/annonc/mdw370.1

4. Benson AB, Venook AP, Al-Hawary MM, et al. Rectal Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2022;20(10):1139-1167. doi:10.6004/jnccn.2022.0051

5. Cercek A, Roxburgh CSD, Strombom P, et al. Adoption of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer. JAMA Oncol. 2018;4(6):e180071. doi:10.1001/jamaoncol.2018.0071

6. Conroy T, Bosset JF, Etienne PL, et al. 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(5):702-715.

7. Bahadoer RR, Dijkstra EA, van Etten B, et al. 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 [published correction appears in Lancet Oncol. 2021 Feb;22(2):e42]. Lancet Oncol. 2021;22(1):29-42. doi:10.1016/S1470-2045(20)30555-6

8. Dijkstra EA, Nilsson PJ, Hospers GAP, et al. 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(4):e766-e772.

9. Garcia-Aguilar J, Patil S, Gollub MJ, et al. Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy. J Clin Oncol. 2022;40 (23):2546-2556. doi:10.1200/JCO.22.00032

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(5):500-506. doi:10.1200/JCO.23.01208

11. Habr-Gama A, Perez RO, Proscurshim I, et al. Interval between surgery and neoadjuvant chemoradiation therapy for distal rectal cancer: does delayed surgery have an impact on outcome?. Int J Radiat Oncol Biol Phys. 2008;71 (4):1181-1188. doi:10.1016/j.ijrobp.2007.11.035

12. van der Sande ME, Figueiredo N, Beets GL. Management and Outcome of Local Regrowths in a Watch-and-wait Prospective Cohort for Complete Responses in Rectal Cancer. Ann Surg. 2021;274(6):e1056-e1062. doi:10.1097/SLA.0000000000003738

13. Nagtegaal ID, Glynne-Jones R. How to measure tumour response in rectal cancer? An explanation of discrepancies and suggestions for improvement. Cancer Treat Rev. 2020;84: 101964. doi:10.1016/j.ctrv.2020.101964

14. Schrag D, Shi Q, Weiser MR, et al. Preoperative Treatment of Locally Advanced Rectal Cancer. N Engl J Med. 2023;389(4): 322-334. doi:10.1056/NEJMoa2303269

15. Basch E, Dueck AC, Mitchell SA, et al. Patient-Reported Outcomes During and After Treatment for Locally Advanced Rectal Cancer in the PROSPECT Trial (Alliance N1048). J Clin Oncol. 2023;41(21):3724-3734.

16. van der Sande ME, Hupkens BJP, Berbée M, et al. Impact of radiotherapy on anorectal function in patients with rectal cancer following a watch and wait programme. Radiother Oncol. 2019;132:79-84.

17. Hupkens B, Lambregts D, Van der Sande M, et al. Anorectal function after watch and wait-policy in rectal cancer patients. Eur J Cancer. 2015;51:S327. doi:10.1016/S0959-8049(16)30927-3

18. Allievi N, Fabio F, Lord A, et al. Selective radiotherapy based on optimal MRI staging maximises outcomes in patients with rectal cancer. Colorectal Dis. 2022.24; Issue S3:54-55. doi:10.1111/codi.16276

19. Hazen S, Sluckin T, Horsthuis K, et al. Abandoning routine radiotherapy for non-locally advanced rectal cancer at a national level without compromising oncological outcome. Colorectal Dis. 2022; Issue S3:12-13. doi:10.1111/codi.16273

20. Glynne-Jones R, Hollingshead J. TNT and local recurrence in the RAPIDO trial - untangling the puzzle. Nat Rev Clin Oncol. 2023;20(6) :357-358. doi:10.1038/s41571-023-00751-4

21. Hayden DM, Jakate S, Pinzon MC, et al. Tumor scatter after neoadjuvant therapy for rectal cancer: are we dealing with an invisible margin? Dis Colon Rectum. 2012;55(12):1206-1212. doi:10.1097/DCR.0b013e318269fdb3

22. Wu Q, Zhou J, Huang J, et al. Total neoadjuvant therapy versus chemoradiotherapy for locally advanced rectal cancer: Bayesian network meta-analysis [published correction appears in Br J Surg. 2023 Nov 14;:]. Br J Surg. 2023;110(7):784-796. doi:10.1093/bjs/znad120

23. Zhu S, Brodin NP, English K, et al. Comparing outcomes following total neoadjuvant therapy and following neoadjuvant chemoradiation therapy in patients with locally advanced rectal cancer. EClinicalMedicine. 2019;16:23-29. Published 2019 Oct 22. doi:10.1016/j.eclinm.2019.09.009

24. Mohan H, Rabie M, Walsh C, et al. Patient and multidisciplinary team perspectives on watch and wait in rectal cancer. Colorectal Dis. 2023;25(7):1489-1497. doi:10.1111/codi.16592

25. Rydbeck D, Azhar N, Blomqvist L. Watch and wait for rectal cancer-The Swedish WoW study. Colorectal Dis. 2023;25; Issue S2:23-24. doi:10.1111/codi.16719

26. Malcomson L, Thapa S, Myint A, et al. Sustained complete response to neoadjuvant (chemo) radiotherapy in patients with rectal cancer: Before and after 2016 in the OnCoRe research database. Colorectal Dis. 2023;25; Issue S2:14-15. doi:10.1111/codi.16676

27. Smith JJ, Strombom P, Chow OS, et al. Assessment of a Watch-and-Wait Strategy for Rectal Cancer in Patients With a Complete Response After Neoadjuvant Therapy. JAMA Oncol. 2019;5(4):e185896.

28. Fernandez LM, São Julião GP, Renehan AG, et al. The Risk of Distant Metastases in Patients With Clinical Complete Response Managed by Watch and Wait After Neoadjuvant Therapy for Rectal Cancer: The Influence of Local Regrowth in the International Watch and Wait Database. Dis Colon Rectum. 2023;66(1): 41-49. doi:10.1097/DCR.0000000000002494

29. São Julião GP, Fernández LM, Vailati BB, et al. Local Regrowth and the Risk of Distant Metastases Among Patients Undergoing Watch-and-Wait for Rectal Cancer: What Is the Best Control Group? Multicenter Retrospective Study. Dis Colon Rectum. 2024;67(1):73-81. doi:10.1097/DCR.0000000000002930

30. Dayde D, Tanaka I, Jain R, Tai MC, Taguchi A. Predictive and Prognostic Molecular Biomarkers for Response to Neoadjuvant Chemoradiation in Rectal Cancer. Int J Mol Sci. 2017;18(3):573. Published 2017 Mar 7. doi:10.3390/ijms18030573