Final results of the GRECCAR-6 trial on waiting period following neoadjuvant radiochemotherapy for locally advanced rectal cancer

November's Paper of the Month aims to evaluate the impact of prolonging this waiting period on the 5-year oncological prognosis and 2-year functional result of locally advanced rectal adenocarcinoma.

Final results of the GRECCAR-6 trial on waiting period following neoadjuvant radiochemotherapy for locally advanced rectal cancer: 5 years of follow-up
Collard MK, Mineur L, Nekrouf C, Denost Q, Rouanet P, de Chaisemartin C, Merdrignac A, Jafari M, Cotte E, Desrame J, Manceau G, Benoist S, Buscail E, Karoui M, Panis Y, Piessen G, Saudemont A, Prudhomme M, Peschaud F, Dubois A, Loriau J, Tuech JJ, Duchalais E, Lupinacci R, Goasgen N, Simon T, Parc Y, Lefevre JH; French Research Group of Rectal Cancer Surgery (GRECCAR).
Dis Colon Rectum. 2024 Nov 7. doi: 10.1097/DCR.0000000000003477. Epub ahead of print. PMID: 39508462.

What is known about the subject?

Multimodal therapies are the gold standard for locally advanced rectal cancer to reduce the risk for local recurrence [1,2] and to achieve - in some cases - a pathologic complete response (ypT0N0) with excellent oncological outcomes [3-5]. Surgery after long course neoadjuvant radio chemotherapy (RCT) was initially indicated 6 to 8 weeks after the end of the treatment [7]. More recently, however, it has been hypothesised that a longer waiting period between the end of RCT and rectal resection may improve the rate of clinical complete response [8]; for those patients with a clinical complete response, this means that they can be managed with a 'watch and wait' strategy and do not require surgery [6].

However, the ideal waiting time remains controversial - especially its long-term effect - although several trials have investigated the potential oncological benefit of extending the waiting time between neoadjuvant RCT and surgical resection for rectal cancer [9-15].

The early oncological results of the GRECCAR-6 randomised trial did not show a difference in the 3-year oncological prognosis between a 7-week and an 11-week waiting period from RCT to the surgery [15]. This recent study aims to verify these results-in terms of overall survival (OS) and disease-free survival (DFS) - after a prolonged 5-year oncological follow-up and to assess the functional results with the low anterior resection syndrome (LARS) score in patients undergoing reconstructive surgery.

What the study adds?

This is a phase III, multicenter, randomised, open-label, parallel-group, controlled trial. Patients with non-metastatic mid or lower cT3-4 or TxN+ rectal adenocarcinoma who had received neoadjuvant RCT (45 to 50 Gy with fluorouracil or capecitabine) were randomly assigned to undergo total mesorectal excision either 7 weeks (W7) or 11 weeks (W11) after the end of the treatment.

Among 253 patients in the intent-to-treat analysis (125 in the W7 and 128 in the W11 group) 5-year OS and DFS (both in terms of local and distant recurrence) did not differ in the two groups. LARS score was similar between the two groups

Implications for colorectal practice

This randomised-controlled trial found that extending the waiting period between neoadjuvant RCT and surgery from 7 to 11 weeks for locally advanced rectal cancer did not improve 5-year OS neither DFS. The different waiting periods had no effect on the rate of pathologic complete responses (pCR) and no impact LARS at 2 years. These results align with another phase III trial, which -although reporting a higher pCR in the 8–12-week group (vs 4-8 weeks) - found no long-term survival advantage [16]. The findings of this trial indicate that a longer waiting period between RCT and surgery does not offer oncological or functional benefits, though further research is needed on the effects of extended intervals after new multimodal regimens such as total neoadjuvant therapies.

References

  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;30:1926–1933.
  2. van Gijn W, Marijnen CA, Nagtegaal ID, et al; Dutch Colorectal Cancer Group. 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;12:575–582.
  3.  Capirci C, Valentini V, Cionini L, et al. Prognostic value of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: long-term analysis of 566 ypCR patients. Int J Radiat Oncol Biol Phys. 2008;72:99–107
  4. 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 Sep;11(9):835-44.
  5. Collard MK, Rullier E, Panis Y et al; GRECCAR Group. Nonmetastatic ypt0 rectal cancer after neoadjuvant treatment and total mesorectal excision: Lessons from a retrospective multicentric cohort of 383 patients. Surgery. 2022 May;171(5):1193-1199.
  6. Loria A, Tejani MA, Temple LK, et al. Practice Patterns for Organ Preservation in US Patients With Rectal Cancer, 2006-2020. JAMA Oncol. 2024 Jan 1;10(1):79-86.
  7. Lakkis Z, Manceau G, Bridoux V, et al; French Research Group of Rectal Cancer Surgery (GRECCAR) and the French National Society of Coloproctology (SNFCP). Management of rectal cancer: the 2016 French guidelines. Colorectal Dis. 2017 Feb;19(2):115-122.
  8. Habr-Gama A, São Julião GP, Fernandez LM, et al. Achieving a complete clinical response after neoadjuvant chemoradiation that does not require surgical resection: it may take longer than you think! Dis Colon Rectum. 2019;62:802–808.
  9. Ryan ÉJ, O'Sullivan DP, Kelly ME, et al. Meta-analysis of the effect of extending the interval after long-course chemoradiotherapy before surgery in locally advanced rectal cancer. Br J Surg. 2019 Sep;106(10):1298-1310.
  10. Petrelli F, Sgroi G, Sarti E, Barni S. Increasing the interval between neoadjuvant chemoradiotherapy and surgery in rectal cancer: a meta-analysis of published studies. Ann Surg. 2016;263:458–464.
  11. Lefevre JH, Rousseau A, Svrcek M, et al; French Research Group of Rectal Cancer Surgery (GRECCAR). A multicentric randomized controlled trial on the impact of lengthening the interval between neoadjuvant radiochemotherapy and surgery on complete pathological response in rectal cancer (GRECCAR-6 trial): rationale and design. BMC Cancer. 2013 Sep 12;13:417. doi: 10.1186/1471-2407-13-417. PMID: 24028546; PMCID: PMC3848646.
  12. Lefevre JH, Mineur L, Kotti S, et al. Effect of Interval (7 or 11 weeks) Between Neoadjuvant Radiochemotherapy and Surgery on Complete Pathologic Response in Rectal Cancer: A Multicenter, Randomized, Controlled Trial (GRECCAR-6). J Clin Oncol. 2016 Nov 1;34(31):3773-3780. doi: 10.1200/JCO.2016.67.6049. PMID: 27432930.
  13. Yu M, Wang DC, Li S, et al. Does a long interval between neoadjuvant chemoradiotherapy and surgery benefit the clinical outcomes of locally advanced rectal cancer? A systematic review and meta-analyses. Int J Colorectal Dis. 2022 Apr;37(4):855-868.
  14. Cheng YK, Qin QY, Huang XY, et al. Effect of interval between preoperative radiotherapy and surgery on clinical outcome and radiation proctitis in rectal cancer from FOWARC trial. Cancer Med. 2020 Feb;9(3):912-919
  15. Lefèvre JH, Mineur L, Cachanado M, et al; The French Research Group of Rectal Cancer Surgery (GRECCAR). Does A Longer Waiting Period After Neoadjuvant Radio-chemotherapy Improve the Oncological Prognosis of Rectal Cancer?: Three Years' Follow-up Results of the Greccar-6 Randomized Multicenter Trial. Ann Surg. 2019 Nov;270(5):747-754.
  16. Akgun E, Caliskan C, Bozbiyik O, et al. Randomized clinical trial of short or long interval between neoadjuvant chemoradiotherapy and surgery for rectal cancer. Br J Surg. 2018 Oct;105(11):1417-1425.