Sphincter preserving surgery after preoperative treatment for ultra-low rectal carcinoma. A French multicenter prospective trial: GRECCAR 1 P Rouanet, M Rivoire, B Lelong, E Rullier, L Vanseymortier, L Mineur, P Lasser, M Pocard, JC Ollier, JL Faucheron, F Dravet, D Pezet, JM Fabre, J Balosso, C Lemanski, S Gourgou, B Saint Aubert. GRECCAR (French surgical research group of rectal carcinoma).

HDR (45 Gy + 18 Gy) LRC R Surg CT if pN+ RCT (45 Gy + 5FU continuous) GRECCAR 1 prospective muticentric randomised trial Inclusion: LRC which requires APR TIP - LA < 2 cm / UT2-T3 PA : Incidence of conservative surgery SA : - Oncological and functional results - Down staging impact on survival - Quality of life

Classification of Anoproctectomy Based on : - mucosal resection - endoanal resection ISR partial PISR ISR complete CISR Mucosectomy M Intersphincteric Resection

Ano-Proctectomy Mucosectomy Partial ISR Complete ISR

GRECCAR 1 : inclusion curves 4/2001 – 4/2005 : 207 patients in 13 centers VACLBIPCStACOLCSCIGRCRGCPSGrenCF Mtpl CAV HDR RCT

Effectives RANDOMISATION n: 207 HDR n: 106 Excluded n: 3 Non oper n: 3 RCT n: 101 Excluded n: 3 Non oper n: 2 n: 100n: 96

Patient characteristics Rt High Dose n = 100 Rt Chemo n = 96 X 2 / p Sex M/F66/3564/ OMS 092% 0.81 Age*60 (28-83) 64 (21-80) weight* (kg) height* (cm) BMI* (Kg/m 2 ) *median Results at 23 months Data base ended Feb 06

Tumor characteristics HDR n = 100 RCT n = 96 X 2 / p Distance ITP-LA* 0.5 (0-3) 0.5 (0-5) 0.35 Fixity 29%45% Circumference > ½ 40%42% 0.85 Distance ITP-PL* 1.1 (0-3.8) 1.2 (0-5.5) 0.72 Tumor height * T3 66%75% 0.47 N + 57%59% 0.75 ITP-LA* 0.5 (0-3) 0.5 (0-6) 0.37 Tumor height* *Median in centimetres RE Colo USR

Evaluation of neoadjuvant treatments HDR n = 100 RCT n = 96 X 2 / p Delay Random / Rt 13 (0-37) 13 (8-111) 0.59 Total irrad anal canal 68%69% 0.16 Symptomatic improvement 55%61% 0.67 TR: tumour regression 80%87% 0.26 Distance IP-LA* Fixity 23%14% 0.14 Circumference 45%40% 0.55 U IP-LA* 1 (0-4.5) 1 (0-6) 0.43 U Height T* *Median in centimetres RE USR

Treatment toxicities Grade 3-4 HDRRCT Peri anal Dermititis 75% 44% p : 0.21 Diarrhea 53% 40% p : 0.51 Prostatitis 25%20% p : 0.74 Nausea 4%8% p : 0.49 Cystitis 18%28% p : 0.34 Failure to continue TTT7%0 average 5 d (2-15)

Surgery: Conservative rate 85% HDR n = 100 RCT n = 96 X 2 / p Delay Rt / Surgery37 (7-88) 44 (13-136) Delay > 4 weeks76%89% Protection of pelvic Nerves 88% 1 APR %14 – 14.6% 0.69 APR in second time 4 (1R1/3C) 3 (2R1/1C) AP - Mucosectomy12 AP – ISR partial AP – ISR complete3643 CAA J pouch76%77% CAA coloplasty8%12% CAA direct13%7% 72%

Incidence of Conservation in relation to Topography TIP-LA Cons rate 0 very low 76 84% ≤ 2 cm low %

Incidence and distribution of APR by center

Operative morbidity According to pre op TTT HDR RCT Fistula 9% 3%p : 0.13 Pelvic abscess 2% 4 %p : 0.40 Colonic necrosis 3% 3%p : 0.99 Anastomotic stenosis 5% 4%p : 0.75 According to type of surgery APR M P ISR C ISR Fistula1 (3%) 4 (19%) 4 (6.9%) 2 (2.6%) p:0.06 Pelvic abscess 1 (3%) 2 (9.5%) 1 (1.7%) 2 (2.6%) p:0.36 Colonic necrosis 1 (3%) 0 2 (3.5%) 1 (1.3%) p:0.09 Anastomotic stenosis 0 2 (9.5%) 6 (10.3%) 1 (1.3%) p:0.06

Anatomical pathology HDR n = 100 RCT n = 96 X 2 / p Tumor height* (cm) Distal margin* (cm) 1 (0.1-6) 1.5 (0-8) 0.71 Lateral clearance* (mm) 5 (0-15) 4 (0-28) 0.80 pT08%14.6% 0.45 pT1 / pT2 /pT3-4 8% - 39%- 45%8%- 30%- 47% 0.45 pN0 / N1 / N2 61%-30%-9%66%-25%-9% 0.72 pM13%6% 0.27 R093%94% 0.74 *median

RO Patients : 78% Classical R1 patients n: 44 22% CRM  = 0n: 4 3 APR 1 st, 1 APR 2 nd  <1n: 9 9 AP 1 st, 1 APR 2 nd  = 1n : 29  DM  = 0n : 2 2 AP 1 st, 1 APR 2 nd "Real" R1 patients n: 157.6% ?

Relation between pT and pN staging pTpN0pN1pN2pN3Total Total pN+ => pT0-pT1 : 2/38 – 5.2%, pT2: 19/67 – 28%, pT3-4: 53/91 – 59%

Oncologic results HDRRCT 2-year OS 93%95% p: year DFS 78%76% p: year LR 6% 5% p: year Mt 17%21% p: 0.53 Stoma closure 90% 94% p: 0.40 Median FU : 23 months

Overall survival

Survival according to the type of surgery

Survival without local relapse

Preliminary conclusions of GRECCAR 1 85% of sphincter conservation in respect with the oncological quality criteria. No significant statistical difference between HDR and RCT arms Possible standardization of the surgery: the crucial impact of the surgical technique (72% of ISR). Tumoral Down staging is an excellent prognostic factor : It can modify an initial surgical indication of APR into conservative surgery. More follow-up is needed in order to analyse the oncological safety and the functional reliability of this treatment.