Total neoadjuvant therapy for locally advanced rectal cancer: a literature review

   The problem of locally advanced rectal cancer (LARC) treatment has not lost its importance and relevance over the past decades, due to the steady increase in the incidence. For a long time, neoadjuvant chemoradiotherapy (nCRT) before total mesorectal excision (TME) and followed systemic chemotherapy was widely accepted as the standard therapy for locally advanced rectal cancer. Although local control is more than satisfactory using this approach, the same cannot be said of distant metastases, which rate reaches 30 % or more and is mainly the cause of death of this category of patients. One of the reasons for this lack of improvement may be the rate of patients who complete the planned adjuvant chemotherapy, which is approximately 50 %. The reasons for that may be postoperative complications, long-term recovery after extensive surgical procedures, etc. Total Neoadjuvant Therapy (TNT) is an emerging approach for the treatment of LARC aimed at improving distant metastasis. This review will outline the main steps in the evolution of LARC treatment and the formation of the stages of total neoadjuvant therapy.

1. Malignant tumors in Russia in 2018 (morbidity and mortality). Eds.: А.D. Kaprin, V.V. Starinskiy, G.V. Petrovoi. Moscow: MNIOI im. P.A. Gertsena – filial FGBU “NMITS radiologii” Minzdrava Rossii, 2019.250 p. (In Russ.)

2. The Beyond TME Collaborative. Consensus statement on the multidisciplinary management of patients with recurrent and primary rectal cancer beyond total mesorectal excision planes. Br J Surg 2013;100(8):1009–1014. doi: 10.1002/bjs.9192

3. Zwart W.H., Hotca A., Hospers G.A.P., et al. The multimodal management of locally advanced rectal cancer: making sense of the new data. Am Soc Clin Oncol Educ Book 2022;42:1–14. doi: 10.1200/EDBK_351411

4. Mendis S., Hang To Y., Tie J. Biomarkers in locally advanced rectal cancer : a review. Clin Colorectal Cancer 2022;21(1):36–44. doi: 10.1016/j.clcc.2021.11.002

5. Van Gijn W., Marijnen C.A.M., Nagtegaal I.D., et al. 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(6):575–582. doi: 10.1016/S1470-2045(11)70097-3

6. 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(3):336–346. doi: 10.1016/S1470-2045(17)30086-4

7. Cionini L., Sainato A., De Paoli A., et al. Final results of randomized trial on adjuvant chemotherapy after preoperative chemoradiation in rectal cancer. Radiother Oncol 2010;96: S113-S114.

8. Breugom A.J., Swets M., Bosset J.F., et al. Adjuvant chemotherapy after preoperative (chemo) radiotherapy and surgery for patients with rectal cancer : a systematic review and meta-analysis of individual patient data. Lancet Oncol 2015;16(2):200–207. doi: 10.1016/S1470-2045(14)71199-4

9. Morris M.C., Winer L.K., Lee T.C., et al. Omission of adjuvant chemotherapy in rectal cancer patients with pathologic complete response: a national analysis. J Gastrointest Surg 2021;25(7):1857–1865. doi: 10.1007/s11605-020-04749-6

10. Bahadoer R.R., Dijkstra E.A., 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. Lancet Oncol 2020;22(1):29–42. doi: 10.1016/S1470-2045(20)30555-6

11. Conroy T., Bosset J.-F., Etienne P-L., 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. doi: /10.1016/S1470-2045(21)00079-6

12. Jin J., Tang Y., Hu C., et al. Multicenter, randomized, phase III trial of short-term radiotherapy plus chemotherapy versus long-term chemoradiotherapy in locally advanced rectal cancer (STELLAR). J Clin Oncol 2022;40(15):1681–1692. doi: 10.1200/JCO.21.01667

13. Liao C.-K., Kuo Y.-T., Lin Y.-C. et. al. Neoadjuvant short-course radiotherapy followed by consolidation chemotherapy before surgery for treating locally advanced rectal cancer : a systematic review and meta-analysis. Curr Oncol 2022;29(5):3708–3727. doi: 10.3390/curroncol29050297

14. 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. doi: 10.1200/JCO.2011.40.1836

15. Gao Y.-H., Lin J.-Z., An X., et al. Neoadjuvant sandwich treatment with oxaliplatin and capecitabine administered prior to, concurrently with, and following radiation therapy in locally advanced rectal cancer: a prospective phase 2 trial. Int J Radiat Oncol Biol Phys 2014;90(5):1153–1160. doi: 10.1016/j.ijrobp.2014.07.021

16. 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(8):1722–1728. doi: 10.1093/annonc/mdv223

17. Bujko K., Wyrwicz L., Rutkowski A., et al. Long-course oxaliplatin-based preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study. Ann Oncol 2016;27(5):834–842. doi: 10.1093/annonc/mdw062

18. Fokas E., Allgäuer M., Polat B., et al. 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. doi: 10.1200/JCO.19.00308.

19. Dijkstra E.A., Nilsson P.J., Hospers G.A.P., 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. doi: 10.1097/SLA.0000000000005799

20. Romesser P.B., Park B.K., Nemirovsky D., et al. Organ preservation and total neoadjuvant therapy for rectal cancer: Investigating long course chemoradiation versus short course radiation therapy. Meeting Abstract 2023 ASCO Annual Meeting I GASTROINTESTINAL CANCER—COLORECTAL AND ANAL. doi: 10.1200/JCO.2023.41.4_suppl.10

21. Garcia-Aguilar J., Patil S., Gollub M.J., 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

22. 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(3):440–448. doi: 10.1097/SLA.0000000000003471

23. Liu S., Jiang T., Xiao L., et al. Total neoadjuvant therapy (TNT) versus standard neoadjuvant chemoradiotherapy for locally advanced rectal cancer : a systematic review and meta-analysis. Oncologist 2021;26(9):e1555-e1566. doi: 10.1002/onco.13824

24. Kong J.C., Soucisse M., Michael M., et al. Total neoadjuvant therapy in locally advanced rectal cancer : a systematic review and metaanalysis of oncological and operative outcomes. Ann Surg Oncol 2021;28(12):7476–7486. doi: 10.1245/s10434-021-09837-8

25. Wu Q., Zhou J., Huang J., et al. Total neoadjuvant therapy versus chemoradiotherapy for locally advanced rectal cancer: Bayesian network meta-analysis. Br J Surg 2023;110(7):784–796. doi: 10.1093/bjs/znad120

26. Habr-Gama A., Perez R.O., Nadalin W., et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg 2004;240(4):711–717. doi: 10.1097/01.sla.0000141194.27992.32

27. Garcia-Aguilar J., Chow O.S., Smith D.D., et al. Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial. Lancet Oncol 2015;16(8):957–966. doi: 10.1016/S1470-2045(15)00004-2

28. Markovina S., Youssef F., Roy A., et al. Improved metastasis- and disease-free survival with preoperative sequential short-course radiation therapy and FOLFOX chemotherapy for rectal cancer compared with neoadjuvant long-course chemoradiotherapy: results of a matched pair analysis. Int J Radiat Oncol Biol Phys 2017;99(2):417–426. doi: 10.1016/j.ijrobp.2017.05.048

29. Glynne-Jones R., Counsell N., Quirke P., et al. Chronicle: results of a randomised phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin (XELOX) versus control. Ann Oncol 2014;25(7):1356–62. doi: 10.1093/annonc/mdu147

30. Breugom A.J., van Gijn W., Muller E.W., et al. Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo) radiotherapy and total mesorectal excision: a Dutch Colorectal Cancer Group (DCCG) randomized phase III trial. Ann Oncol 2015;26(4):696–701. doi: 10.1093/annonc/mdu560

31. Hong Y.S., Kim S.Y., Lee J.S., et al. Oxaliplatin-based adjuvant chemotherapy for rectal cancer after preoperative chemoradiotherapy (ADORE): long-term results of a randomized controlled trial. J Clin Oncol 2019;37(33):3111–3123. doi: 10.1200/JCO.19.00016

32. Dijkstra E.A., Hospers G.A., Kranenbarg E.M.-K., et al. Quality of life and late toxicity after short-course radiotherapy followed by chemotherapy or chemoradiotherapy for locally advanced rectal cancer–The RAPIDO trial. Radiother Oncol 2022;171:69–76. doi: 10.1016/j.radonc.2022.04.013.