LOCAL EXCISION IN DOWNSTAGED T2T3 LOW RECTAL CANCER 5-year results of the GRECCAR 2 trial E Rullier, V Vendrely, P Rouanet, JJ Tuech, A Valverde, B Lelong, M Rivoire, JL Faucheron, J Mehrdad, G Portier, E Frison, J Asselineau, Q Denost and the GRECCAR Group

Complete response after radiochemo 16% ypT0N0 41% LARS in T3T4 after TME Lefevre J, J Clin Oncol 2016 (GRECCAR 6) Croeze A, Int J Surg 2018 (Meta-analysis LARS)

23 series 19 retrospectives 15 had < 30 patients 67% T3

Local recurrence after cCR = 1/3 patients APR Renehan A, lancet Oncol 2015 Jones H, EJSO 2018

GRECCAR 2 1 mrT 2 ymrT ypT 3

End points and Sample size calculation TME Local excision Operative death 2% 0 Local recurrence 5% 5% Metastatic recurrence 10% 10% Major morbidity 20% 5% Severe after-effects 25-50% 5% Patients with at least 60% 25% one component at 2 years Hypothesis: LE is superior to TME Delta outcome risk 35%, randomisation 120 patients (60 x 2) Re-estimation after first 60 patients: randomisation 148 (74 x 2)

Complications and side-effects according to type of surgery

Pathologic response LE TME All Tumour response (n=74) (n=68) (n=142)* ypT0 26 31 57 40% ypT1 15 14 29 21% ypT2 27 17 44 31% ypT3 6 12 8% Nodal response (n=27) (n=62) (n=89) ypN0 23 59 82 92% ypN1 4 3 7 ypN1 % ypN1 ypT0 0/30 ypT1 0/13 ypT2 3/36 8% ypT3 4/10 40%

Pathologic response LE TME All Tumour response (n=74) (n=68) (n=142)* ypT0 26 31 57 40% ypT1 15 14 29 21% ypT2 27 17 44 31% ypT3 6 12 8% Nodal response (n=27) (n=62) (n=89) ypN0 23 59 82 92% ypN1 4 3 7 ypN1 % ypN1 ypT0 0/30 ypT1 0/13 ypT2 3/36 8% ypT3 4/10 40% 2% in cN0

FIRST Conclusion GRECCAR 2 trial The oncologic safety of the strategy is suggested by the similar LR and survival at 2 years between the 2 groups Globally, LE was not superior to TME due to a high rate of completion TME that increased morbidity and after-effects A better patient selection avoiding un necessary completion TME for ypT2/cN0 will give advantage of LE This is the first randomised multicentre study in the setting of organ preservation. It showed the oncologic efficacy of the strategy. The lack of superiority is due to the high rate of complletion TME that increases complications. However, due to the pathologic data of this trial we know how to improve the strategy. NB: this strategy is only for expert centres.

Questions at 5 years? Long term safety of the strategy Local recurrence Distant recurence Overall and DFS Causes of death Outcome of pT2 treated by LE alone

RESULTS AT 5 YEARS Mars 2007 to Sept 2012 186 patients 15 French Hospitals Analysis February 15, 2018 Follow-up LE TME Median, range (months) 61 (11-74) 60 (14-105) Mean (SD) 57 (13) End of follow-up End of study 80% 82% Death 15% 17% Lost of follow-up 5% (57,49,55,38) 1% (42)

5-year results local recurrence (10/145) Occurrence of LR: 70% at 2 years, 90% at 3 years

Local recurrence (Intention-to-treat) 7% vs 7% at 5 years P=0.599 Group LE : Cumulated incidence of local recurrence at 5 years : 7% [CI95%, 3%-16%] Group TME : Cumulated incidence of local recurrence at 5 years : 7% [CI95%, 3%-16%]

Local recurrence (As-to-treat analysis) 8% vs 3% at 5 years P=0.454 LE performed: Cumulated incidence of local recurrence at 5 years : 7.7% [CI95%, 3%-17%] TME performed: Cumulated incidence of local recurrence at 5 years : 3.3% [CI95%, 1%-13%]

local recurrence and pathologic stage (n=145) Surgery performed ypT0 2 LE, LE ypT1 3 LE, LE, TME ypT2 LE, TME ypT3 1 TME Watch and Wait No

Salvage TME FOR local recurrence Patient Stage Initial Surgery Recurrence Salvage TME Resection 1 T2 LE Local LAR R0 2 T3 3 Local + liver 4 W&W 5 APR 6 TME R1 7 R2 8 Local + lung No - 9 Local + méta 10 In curative intent: overall 100% salvage after LE 100% R0 and 75% SSR

5-year Metastatic recurrence   LE N=74 TME N=71 All patients N=145 Lung 13 9 22 Liver 5 12 17 Lymphatic 3 8 Peritoneum 1 2 Bone Brain 4 Number of patients 26 Number of sites of metastasis 28 29 57 88% of patients with metastatic recurrence have lung metastases

Metastatic recurrence 18% vs 19% at 5 years P=734 LE group 18% (95%CI: 11%-30%) TME group 19% (95%CI: 11%-31%)

Overall Survival 84% vs 82% at 5 years P=0.845

Disease-Free Survival 70% vs 72% at 5 years P=0.682

Causes of death LE N=11 TME N=12 Total N=23 Rectal cancer 4 6 10 (43%) 2nd Cancer 3 1 4 (17%) Cardiovascular 2 5 (22%) Infection 1 (4%) Crash Suicide Unknown Causes of death are related to other cause of rectal cancer in 57% of cases and did not differ between groups

Factors of recurrence Local Recurrence No predictive factor Metastatic recurrence Pathologic response ypT2-3 vs. ypT0-1 RR 2.88 (95%CI 1.16-7.16), p=0.023 Local recurrence Metastases ypT0-1 6% 11% ypT2-3 5% 26%

Outcome of pT2 patients treated by local excision alone (n=8) Events Local recurrence Metastasis 2nd Cancer Cardio vascular Rectal cancerdeath Not cancer death Alive 1 2 3 4 5 6 7 8 Total 25% 12% 37% 50% Uncontrolled isolated local recurrence 0%

Conclusion The 5-year results of the GRECCAR 2 trial confirm the oncologic safety of LE in downstaged T2T3 small rectal cancers after RCT Most deaths are due to other causes of rectal cancer suggesting to push to less aggressive surgery in such patients Advantages of LE requires avoiding completion TME, which was probably inadequate in most ypT2, due to the low rate of positive LN in ypT2 (overall 8% and 2% in cN0)

GRECCAR 12: Induction chemotherapy before radiochemotherapy Hypothesis: 60% to 80% organ preservation 218 patients (α 5% β 90%)