1. 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

2. Complete response after radiochemo
16% ypT0N % LARS
in T3T4 after TME
Lefevre J, J Clin Oncol 2016 (GRECCAR 6)
Croeze A, Int J Surg 2018 (Meta-analysis LARS)

3. 23 series
19 retrospectives
15 had < 30 patients
67% T3

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

5. GRECCAR 2 1
mrT 2
ymrT
ypT 3

6. End points and Sample size calculation
TME Local excision
Operative death % 0
Local recurrence % 5%
Metastatic recurrence 10% 10%
Major morbidity 20% 5%
Severe after-effects % 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)

8. Complications and side-effects according to type of surgery

9. 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%

10. 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

11. 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.

12. 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

13. 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)

15. 5-year results local recurrence (10/145)
Occurrence of LR: 70% at 2 years, 90% at 3 years

16. 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%]

17. 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%]

18. 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

19. 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

20. 5-year Metastatic recurrenceLE
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

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

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

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

24. 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

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

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%

27. 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)

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