Efficacy of total neoadjuvant therapy for rectal cancer: results of a randomized trial

AIM: to compare the treatment outcomes of rectal cancer patients using two regimens of total neoadjuvant therapy (TNT): short-course radiotherapy with three cycles of consolidating chemotherapy and long-course chemoradiotherapy with three cycles of consolidating chemotherapy.

PATIENTS AND METHODS: a prospective, Single-Center, Randomized Study. From September 2022 to February 2025, 125 patients were enrolled in the study. Of these, 64 were assigned to Group A and 61 to Group B. In Group A, patients received a short-course radiotherapy (RT) regimen followed by three cycles of consolidating chemotherapy with the XELOX regimen. Treatment response was assessed 10–18 weeks after the completion of radiotherapy. In Group B, patients received a long-course chemoradiotherapy (CRT) regimen followed by three cycles of consolidating chemotherapy with the XELOX regimen. Treatment response was assessed 10–18 weeks after the completion of chemoradiotherapy. The primary endpoint of the study is the rate of complete tumor response (pathological complete response, pCR).

RESULTS: the median tumor size was 50 mm (interquartile range, IQR: 24–123 mm) in Group A and 47 mm (IQR: 27–76 mm) in Group B (p = 0.3). There were no significant differences in the presence or absence of involved circular resection margin (p = 0.9) or extramural vascular invasion (p = 0.8) before treatment initiation. Both groups showed comparable results in terms of compliance (p = 1.0), tolerability (p = 0.7), and toxicity (p = 0.8) of radiotherapy. No statistically significant differences were found in the compliance (p = 1.0), tolerability (p = 0.8), and toxicity (p = 0.2) of chemotherapy. Surgical outcomes were also comparable regarding the rate of negative resection margins (p = 1.0), quality of mesorectal excision (p = 0.5), degree of tumor response to neoadjuvant treatment (p = 0.6), and postoperative complications (p = 0.8). The rate of complete tumor responses (both clinical and pathological) did not differ significantly between the groups. With a follow-up ranging from 3 to 35 months (median 18 months), the clinical complete response rate was 5/61 (8.2%) in Group A and 11/64 (17.2%) in Group B (p = 0.18). The pathological complete response rate was 9/53 (14.7%) vs. 6/51 (9.3%), respectively (p = 0.6). The overall complete response rate was 14/61 (22.9%) in the short-course RT and 17/64 (26.5%) in the long-course CRT group (p = 0.6).

CONCLUSION: the compared TNT regimens are comparable in compliance, tolerability, and toxicity. The combination of SCRT with consolidation chemotherapy in a neoadjuvant regimen is comparable in the frequency of complete responses compared with a CRT with consolidation chemotherapy.

1. Ludmir EB, Palta M, Willett CG, et al. Total neoadjuvant therapy for rectal cancer: An emerging option. Cancer. 2017 May 1;123(9):1497-1506. doi: 10.1002/cncr.30600. Epub 2017 Mar 10. PMID: 28295220.

2. 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 Dec 1;3(12):e2030097. doi: 10.1001/jamanetworkopen.2020.30097. PMID: 33326026; PMCID: PMC7745099.

3. 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 Dec 1;37(34):3212-3222. doi: 10.1200/JCO.19.00308. Epub 2019 May 31. PMID: 31150315.

4. 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 Jan;22(1):29-42. doi: 10.1016/S1470-2045(20)30555-6. Epub 2020 Dec 7. Erratum in: Lancet Oncol. 2021 Feb;22(2):e42. doi: 10.1016/S1470-2045(20)30781-6. PMID: 33301740.

5. Clavien PA, Barkun J, de Oliveira ML, et al. The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg. 2009 Aug;250(2):187-96. doi: 10.1097/SLA.0b013e3181b13ca2. PMID: 19638912.

6. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys. 1995 Mar 30;31(5):1341-6. doi: 10.1016/0360-3016(95)00060-C. PMID: 7713792.

7. Freites-Martinez A, Santana N, Arias-Santiago S, et al. Using the Common Terminology Criteria for Adverse Events (CTCAE - Version 5.0) to Evaluate the Severity of Adverse Events of Anticancer Therapies. Actas Dermosifiliogr (Engl Ed). 2021 Jan;112(1):90-92. English, Spanish. doi: 10.1016/j.ad.2019.05.009. Epub 2020 Sep 3. PMID: 32891586.

8. Forrest JA, Finlayson ND, Shearman DJ. Endoscopy in gastrointestinal bleeding. Lancet. 1974 Aug 17;2(7877):394-7. doi: 10.1016/s0140-6736(74)91770-x. PMID: 4136718.

9. 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 Oct;240(4):711-7; discussion 717-8. doi: 10.1097/01.sla.0000141194.27992.32. PMID: 15383798; PMCID: PMC1356472.

10. 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 May 20;40(15):1681-1692. doi: 10.1200/JCO.21.01667. Epub 2022 Mar 9. PMID: 35263150; PMCID: PMC9113208.

11. Emmertsen KJ, Laurberg S. Rectal Cancer Function Study Group. Impact of bowel dysfunction on quality of life after sphincter-preserving resection for rectal cancer. Br J Surg. 2013 Sep;100(10):1377-87. doi: 10.1002/bjs.9223. PMID: 23939851.

12. Habr-Gama A, Perez RO, Wynn G, et al. Complete clinical response after neoadjuvant chemoradiation therapy for distal rectal cancer: characterization of clinical and endoscopic findings for standardization. Dis Colon Rectum. 2010 Dec;53(12):1692-8. doi: 10.1007/DCR.0b013e3181f42b89. PMID: 21178866.

13. Goffredo P, Quezada-Diaz FF, Garcia-Aguilar J, et al. Non-Operative Management of Patients with Rectal Cancer: Lessons Learnt from the OPRA Trial. Cancers (Basel). 2022 Jun 30;14(13):3204. doi: 10.3390/cancers14133204. PMID: 35804975; PMCID: PMC9264788.

14. 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 Jun 23;391(10139):2537-2545. doi: 10.1016/S0140-6736(18)31078-X. PMID: 29976470.

15. 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.

16. Guida AM, Sensi B, Formica V, et al. Total neoadjuvant therapy for the treatment of locally advanced rectal cancer: a systematic minireview. Biol Direct. 2022 Jun 13;17(1):16. doi: 10.1186/s13062-022-00329-7. PMID: 35698084; PMCID: PMC9195214.

17. Bujko K, Wyrwicz L, Rutkowski A, et al. Polish Colorectal Study Group. 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 May;27(5):834-42. doi: 10.1093/annonc/mdw062. Epub 2016 Feb 15. PMID: 26884592.

18. Kim SY, Joo J, Kim TW, et al. A Randomized Phase 2 Trial of Consolidation Chemotherapy After Preoperative Chemoradiation Therapy Versus Chemoradiation Therapy Alone for Locally Advanced Rectal Cancer: KCSG CO 14-03. Int J Radiat Oncol Biol Phys. 2018 Jul 15;101(4):889-899. doi: 10.1016/j.ijrobp.2018.04.013. Epub 2018 Apr 12. PMID: 29976501.

19. Moore J, Price T, Carruthers S, et al. Prospective randomized trial of neoadjuvant chemotherapy during the 'wait period' following preoperative chemoradiotherapy for rectal cancer: results of the WAIT trial. Colorectal Dis. 2017 Nov;19(11):973-979. doi: 10.1111/codi.13724. PMID: 28503826.

20. 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 May;22(5):702-715. doi: 10.1016/S1470-2045(21)00079-6. Epub 2021 Apr 13. PMID: 33862000.