Neoadjuvant treatment of locally advanced rectal cancer – a consensus procedure Comprehensive Cancer Center Brno

Czech version

Authors: P. Pospíšil ¹ ; E. Dvořáková ¹; P. Šlampa ¹ ; I. Kiss ² ; J. Tomášek ² ; L. Ostřížková ³ ; M. Eid ³ ; Z. Kala ⁴ ; J. Katolická ⁵
Authors‘ workplace: Klinika radiační onkologie, LF MU a MOÚ, Brno ¹; Klinika komplexní, onkologické péče, LF MU a MOÚ, Brno ²; Interní hematologická, a onkologická klinika, LF MU a FN Brno ³; Chirurgická klinika, LF MU a FN Brno ⁴; Onkologicko-chirurgické, oddělení, FN u sv. Anny, v Brně ⁵
Published in: Rozhl. Chir., 2025, roč. 104, č. 3, s. 105-113.
Category: Review
doi: https://doi.org/10.48095/ccrvch2025105

Overview

Significant changes have recently occurred in the treatment of locally advanced rectal cancer. These include a complete administration of systemic therapy in the neoadjuvant phase of treatment, nonsurgical interventions in case of clinically complete response and using of immunotherapy in patients with the deficiency ofmismatch repair. Although there is no universally accepted treatment standard, the concept of total neoadjuvant therapy, immunotherapy and non-operative management is widely accepted in clinical practice. The care of patients with rectal cancer is multimodal, comprehensive and should be based on consensual recommendations. A uniform approach in diagnostic and therapeutic procedures within the individual departments of the oncology center is a condition for high quality standard care. At the same time, unusual clinical situations and the specific wishes of patients should be taken into account. The listed recommended treatment procedures are a reflection of the efforts to unify patient care with rectal cancer at individual workplaces of the comprehensive oncology center in Brno. Defining general recommendations is not the goal.

Keywords:

rectal cancer – immunotherapy – Chemoradiotherapy – total neoadjuvant therapy – organ-sparing

Sources

1. 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.

2. Sun R, Dai Z, Zhang Y et al. 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. doi: 10.1007/s00520-021-06326-2.

3. 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(4): 711–717. doi: 10.1097/01.sla.0000141194.27992.32.

4. Dossa F, Chesney TR, Acuna SA et al. A watch-and-wait approach for locally advanced rectal cancer after a clinical complete response following neoadjuvant chemoradiation: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2017; 2(7): 501–513. doi: 10.1016/S2468-1253(17)30074-2.

5. Roeder F, Meldolesi E, Gerum S et al. Recent advances in (chemo-)radiation therapy for rectal cancer: a comprehensive review. Radiat Oncol 2020; 15(1): 262. doi: 10.1186/s13014-020-01695-0.

6. Breugom AJ, Swets M, Bosset JF 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.

7. Bosset JF, Collette L, Calais G et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006; 355(11): 1114–1123. doi: 10.1056/NEJMoa060829.

8. Sauer R, Becker H, Hohenberger W et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351(17): 1731–1740. doi: 10.1056/NEJMoa040694.

9. 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. doi: 10.1016/S1470-2045(21)00079-6.

10. 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. Lancet Oncol 2021; 22(1): 29–42. doi: 10.1016/S1470-2045(20)30555-6.

11. Conroy T, Lamfichekh N, Etienne PL 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(Suppl 15): 4007. doi: 10.1200/JCO.2020.38.15_suppl.4007.

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. 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.

14. Kasi A, Abbasi S, Handa S et al. Total neoadjuvant therapy vs standard therapy in locally advanced rectal cancer: a systematic review and meta-analysis. JAMA Netw Open 2020; 3(12): e2030097. doi: 10.1001/jamanetworkopen.2020.30097.

15. 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.

16. Kong JC, 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.

17. Brown G, Richards CJ, Newcombe RG et al. Rectal carcinoma: thin-section MR imaging for staging in 28 patients. Radiology 1999; 211(1): 215–222. doi: 10.1148/radiology.211.1.r99ap35215.

18. Brown G, Radcliffe AG, Newcombe RG et al. Preoperative assessment of prognostic factors in rectal cancer using high-resolution magnetic resonance imaging. Br J Surg 2003; 90(3): 355–364. doi: 10.1002/bjs.4034.

19. MERCURY Study Group. Diagnostic accuracy of preoperative magnetic resonance imaging in predicting curative resection of rectal cancer: prospective observational study. BMJ 2006; 333(7572): 779. doi: 10.1136/bmj.38937.646400.55.

20. Taylor FG, Quirke P, Heald RJ et al. Preoperative high-resolution magnetic resonance imaging can identify good prognosis stage I, II, and III rectal cancer best managed by surgery alone: a prospective, multicenter, European study. Ann Surg 2011; 253(4): 711–719. doi: 10.1097/SLA.0b013e31820b8d52.

21. Taylor FG, Quirke P, Heald RJ et al. Preoperative magnetic resonance imaging assessment of circumferential resection margin predicts disease-free survival and local recurrence: 5-year follow-up results of the MERCURY study. J Clin Oncol 2014; 32(1): 34–43. doi: 10.1200/JCO.2012.45.3258.

22. Fowler KJ, Kaur H, Cash BD et al. ACR Appropriateness criteria® pretreatment staging of colorectal cancer. J Am Coll Radiol 2017; 14(5S): S234–S244. doi: 10.1016/j.jacr.2017.02.012.

23. Boot J, Gomez-Munoz F, Beets-Tan RG. Imaging of rectal cancer. Radiologe 2019; 59(Suppl 1): 46–50. doi: 10.1007/s00117-019-0579-5.

24. Beets-Tan RGH, Lambregts DMJ, Maas M et al. Magnetic resonance imaging for clinical management of rectal cancer: updated recommendations from the 2016 European Society of Gastrointestinal and Abdominal Radiology (ESGAR) consensus meeting. Eur Radiol 2018; 28(4): 1465–1475. doi: 10.1007/s00330-017-5026-2.

25. Tudyka V, Blomqvist L, Beets-Tan RG et al. EURECCA consensus conference highlights about colon & rectal cancer multidisciplinary management: the radiology experts review. Eur J Surg Oncol 2014; 40(4): 469–475. doi: 10.1016/j.ejso.2013.10.029.

26. Siddiqui MRS, Simillis C, Hunter C et al. A meta-analysis comparing the risk of metastases in patients with rectal cancer and MRI-detected extramural vascular invasion (mrEMVI) vs mrEMVI-negative cases. Br J Cancer 2017; 116(12): 1513–1519. doi: 10.1038/bjc.2017.99.

27. Schaap DP, Ogura A, Nederend J et al. Prognostic implications of MRI-detected lateral nodal disease and extramural vascular invasion in rectal cancer. Br J Surg 2018; 105(13): 1844–1852. doi: 10.1002/bjs.10949.

28. Ryan JE, Warrier SK, Lynch AC et al. Assessing pathological complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer: a systematic review. Colrectal Dis 2015; 17(10): 849–861. doi: 10.1111/codi.13081.

29. Krishnamoorthy M, Lenehan JG, Maleki Vareki S. Neoadjuvant immunotherapy for high-risk, resectable malignancies: scientific rationale and clinical challenges. J Natl Cancer Inst 2021; 113(7): 823–832. doi: 10.1093/jnci/djaa216.

30. Henricks LM, Lunenburg CATC, de Man FM et al. A cost analysis of upfront DPYD genotype-guided dose individualisation in fluoropyrimidine-based anticancer therapy. Eur J Cancer 2019; 107: 60–67. doi: 10.1016/j.ejca.2018.11.010.

31. Garcia-Aguilar J, Renfro LA, Chow OS et al. Organ preservation for clinical T2N0 distal rectal cancer using neoadjuvant chemoradiotherapy and local excision (ACOSOG Z6041): results of an open-label, single-arm, multi-institutional, phase 2 trial. Lancet Oncol 2015; 16(15): 1537–1546. doi: 10.1016/S1470-2045(15)00215-6.

32. Gérard JP, André T, Bibeau F et al. Rectal cancer: French Intergroup clinical practice guidelines for diagnosis, treatments and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO). Dig Liver Dis 2017; 49(4): 359–367. doi: 10.1016/j.dld.2017.01.152.

33. Glynne-Jones R, Wyrwicz L, Tiret E et al. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018; 29(Suppl 4): iv263. doi: 10.1093/annonc/mdy161.

34. 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.

35. Jia XX, Wang Y, Cheng J et al. Low-versus high-risk rectal cancer based on MRI features: outcomes in patients treated without neoadjuvant chemoradiotherapy. AJR Am J Roentgenol 2018; 211(2): 327–334. doi: 10.2214/AJR.17.18980.

36. Dijkstra EA, Nilsson PJ, Hospers GA 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.

37. 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.

38. Fokas E, Schlenska-Lange A, Polat B et al. Chemoradiotherapy plus induction or consolidation chemotherapy as total neoadjuvant therapy for patients with locally advanced rectal cancer: long-term results of the CAO/ARO/AIO-12 randomized clinical trial. JAMA Oncol 2022; 8(1): e215445. doi: 10.1001/jamaoncol.2021.5445.

39. Sclafani F, Corrò C, Koessler T. Debating pros and cons of total neoadjuvant therapy in rectal cancer. Cancers (Basel) 2021; 13(24): 6361. doi: 10.3390/cancers13246361.

40. Maas M, Beets-Tan RG, Lambregts DM et al. Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer. J Clin Oncol 2011; 29(35): 4633–4640. doi: 10.1200/JCO.2011.37.7176.

41. den Dulk M, Putter H, Collette L et al. The abdominoperineal resection itself is associated with an adverse outcome: the European experience based on a pooled analysis of five European randomised clinical trials on rectal cancer. Eur J Cancer 2009; 45(7): 1175–1183. doi: 10.1016/j.ejca.2008.11.039.

42. 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.

43. Sebag-Montefiore D, Stephens RJ, Steele R et al. Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet 2009; 373(9666): 811–820. doi: 10.1016/S0140-6736(09)60484-0.

44. Jörgren F, Johansson R, Damber L et al. Risk factors of rectal cancer local recurrence: population-based survey and validation of the Swedish rectal cancer registry. Colorectal Dis 2010; 12(10): 977–986. doi: 10.1111/j.1463-1318.2009.01930.x.

45. NCCN. Rectal cancer, version 2. 2024. [online]. Dostupné z: https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf.

46. Shin R, Jeong SY, Yoo HY et al. Depth of mesorectal extension has prognostic significance in patients with T3 rectal cancer. Dis Colon Rectum 2012; 55(12): 1220–1228. doi: 10.1097/DCR.0b013e31826fea6a.

47. Akagi Y, Hisaka T, Mizobe T et al. Histopathological predictors for local recurrence in patients with T3 and T4 rectal cancers without preoperative chemoradiotherapy. J Surg Oncol 2014; 110(6): 739–744. doi: 10.1002/jso.23678.

48. 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.

49. Overman MJ, McDermott R, Leach JL et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 2017; 18(9): 1182–1191. doi: 10.1016/S1470-2045(17)30422-9.

50. Overman MJ, Lonardi S, Wong KY et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol 2018; 36(8): 773–779. doi: 10.1200/JCO.2017.76.9901.

51. Cercek A, Lumish M, Sinopoli J et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med 2022; 386(25): 2363–2376. doi: 10.1056/NEJMoa2201445.

52. Sebag-Montefiore D, Stephens RJ, Steele R et al. Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet 2009; 373(9666): 811–820. doi: 10.1016/S0140-6736(09)60484-0.

53. Maas M, Lambregts DM, Nelemans PJ et al. Assessment of clinical complete response after chemoradiation for rectal cancer with digital rectal examination, endoscopy, and MRI: selection for organ-saving treatment. Ann Surg Oncol 2015; 22(12): 3873–3880. doi: 10.1245/s10434-015-4687-9.

54. Breugom AJ, Swets M, Bosset JF 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.

MUDr. Petr Pospíšil, Ph.D.

Klinika radiační onkologie

LF MU a MOÚ

Žlutý kopec 7

656 53 Brno

petr.pospisil@mou.cz