Results of the Prodige 2-ACCORD 12/0405 Randomized trial comparing two neoadjuvant chemo-radiotherapy (Cape 45 vs Capox 50) in patients with T3-4 rectal cancer. Nice Jean-Pierre GERARD, D. Azria, S. Gourgou-Bourgade, I. Martel-Laffay, C. Hennequin, P.L. Etienne, V. Vendrely, T. Conroy, E. François, C. Montoto-Grillot, for the FNCLCC - FFCD No conflict of interest - Abstract # 31309 - ASCO – Orlando – 30 May 2009 30/05/2009

Background (1) ■ Surgery "TME" (sharp dissection) cornerstone of treatment of T3-4 M0 rectal cancer ■ German CAO/ARO Phase III trial (2004) Preop CT-RT > postop (standard) Local control - toxicity 30/05/2009

Background (2) Concurrent CT-RT > RT alone FFCD 92.03 - (EORTC) phase III RT CT - RT ypCR 4% 11% Loc rec 5 y 16% 7% No change : sphincter preservation – survival ASCO 2005 JCO 2006;24:4260 30/05/2009

2005 : How to optimize neoadjuvant treatment for T3-4 Nx M0 rectal cancer ? FFCD 92.03 : RT 45 Gy/5 weeks - 5 FU 225 mg/m² ACCORD 12/0405-Prodige 2 pragmatic approach : 2 modifications RT dose increase : 50 Gy/5 weeks (BED + 15%) CT intensification : Oxaliplatin (50 mg/m²) Capecitabine (1600 mg/m²/d) = 5FU - LV 30/05/2009

Accord 12 inclusion criteria As in FFCD 92.03 ■ Adenocarcinoma of rectum ■ Accessible to digital examination ■ T3-4 resectable N0-2 M0 T2 distal anterior rectum - Workup = EUS – MRI – CT (Th. Abd) 30/05/2009

Primary end point : Complete sterilization of operative specimen ypCR Dworak- Quirke 0 = no regression 1 = moderate pathological tumor response 2 = very few residual tumor cells 3 = no visible tumor cell (ypCR) Dworak Int J Colorect Dis 1997;12:19 Quirke Lancet Oncol 2007;8:651 30/05/2009

Secondary end points ■ circumferential rectal margin (CRM) - 0 to < 1 mm (R0) - 0 to < 2 mm ■ - Toxicity – sphincter preservation (AR) - Local control – DFS - ov. Survival - Bowel – sexual functions 30/05/2009

Hypothesis – sample size ypCR : 11% 20% N = 590 for statistical power 85% (2 sided a = 0.05) - 3 years enrollment - Database locked march 2009 Stratification : center – T stage – T site 30/05/2009

ACCORD 12/0405-Prodige 2-Design of trial T3 (4) M0 - Accessible DRE < 80 y (low ant T2) 45 Gy/5 w + Cap 50 Gy/5 w + Capox R 6 weeks TME Adjuvant chemo left each institution (constant) Hypothesis : ypCR = 11% 20% (590 pts) 30/05/2009

Capox 50 50 Gy/25F/5 weeks • Radiotherapy • Capecitabine 800/m²x2/Day 1 2 3 4 5 ● • Capecitabine 800/m²x2/Day (1600mg/m²) except WE • Oxaliplatin IV 50 mg/m²(2h) 30/05/2009

Pathology ypT0 N0 – R0 Quirke - Dworak 30/05/2009

November 2005 - July 2008 598 pts / 2,9 years 56 centers Age : 63 y M/F : 2/1 T3 : 87% T2 : 8% T4 : 5% 30/05/2009

Flow-Chart 598 584 574 563 598 randomized patients RT45-Cap N= 299 RT50-CapOx N= 299 598 Eligible n= 293 584 Eligible n= 291 Surgery n= 287 574 Surgery n= 287 Operative specimen n= 285 563 Operative specimen n= 278 Adj. Chemotherapy 42% Adj. Chemotherapy 30% 30/05/2009

Early toxicity G2-3-4 (CTC –NCI V3) Adverse event Cape 45 (293) Capox 50 (291) p-value All toxicity G3-4 11% (32) 25% (74) <0.0001 Diarrhea G3-4 3% 13% < 0.0001 Haematol G3-4 4% 5% Hand. foot G2 < 1% 0% Periph. neurop. G2 0.4% 5% <0.002 RXT full dose 99% 90% * Surgery 98% (287) 99% (287) * < 44 Gy : 2% Asco 2008 30/05/2009

Surgical toxicity Event Cape 45 (287) Capox 50 (287) p-value Ant. Resect. 73% (211) 76% (218) NS Fistula (sgy) (AR) 3% (7) 2% (5) 2nd surg. 15% 16% G2-3-4 med.compl. 21% (59) 18% (52) Hospital stay (days) 15 15 Death 60 days 0.3% (1) 0.3% (1) 30/05/2009

Primary end point – operative specimen Sterilization ypCR (Dworak-Quirke) Cape 45 (282) Capox 50 (276) p-value no visible cell (ypCR) 14% (40) 19% (53) 0.11 No + few residual cell 30% (85) 41% (113) 0.008 ypT0 14% 19% ns yp N0 69% 71% ns 30/05/2009

Circumferential rectal margin - CRM Margin Cape 45 (162) Capox 50 (147) p-value 0-1 mm 12% (19) 7% (11) 0 .21 0-2 mm 19% (31) 9% (14) 0.017 Pelvic local control ?? 30/05/2009

Subgroup analysis : ypCR Cape 45 Capox 50 T2 (42) 36% 50% T3 (509) 13% 17% T4 (32) 7% 13% Full dose RXT (558) 14% 20% Occult M1 (surg) 4% 3% 30/05/2009

Weaknesses and limitations of study Short Follow up (12m) no clinical end point (loc. DFS) Primary end point : not significant (ypCR) (0.11) ypCR : not a good surrogate end point Two modifications : RT dose – oxaliplatin BUT : good overview of French clinical practice 56 institutions (30 academic) 2006-2008 30/05/2009

Summary Main results "Capox 50" Early G3-4 toxicity : increased 25% Surgery performed : no detriment 99% Operative death (60 days) : low 0.3% Sphincter preservation : no increase 75% CRM "negative" trend ++ 93% ypCR trend ++ 19% 30/05/2009

Rectal Cancer T3-4 M0 STAR (747) ACCORD (598) RT50.4 + Oxali (60 mg) RT50 + Capox G3-4 toxicity 25% ypCR 19% (increase) 30/05/2009

Rectal Cancer T3-4 M0 STAR (747) ACCORD (598) RT 50.4 + Oxali (60 mg) RT50 + Capox G3-4 toxicity 24% (increase) 25% ypCR 16% (no difference) 19% (increase) 30/05/2009

When analysing the results of ACCORD 12 trial with reference to the STAR trial the following comments and suggestions can be made regarding : (1) Oxaliplatin (2) Dose of RT (3) Capecitabine 30/05/2009

(1) Oxaliplatin increases toxicity (diarrhea) without impact on ypCR (not radiosensitizer) (occult. M1 ?) (2) 50 Gy/5 weeks compatible with surgery and increase ypCR and CRM "negative" (RX dose effect) (3) Capecitabine has the same activity as 5FU 30/05/2009

Oxaliplatin not a good radiosensitizer Folkword – Radiat Oncol 2008;86:428 30/05/2009

Proposal : "Cape 50" regimen ■ For T3-4 Nx M0 rectal cancers (resectable) Good option for neoadjuvant treatment - RT 50 Gy/5 weeks (2 Gy/fraction/25 F) - Capecitabine 1600 mg/m² (RT days) ■ How to fight distant metastases ? (oxaliplatin) 30/05/2009

SPONSOR - PARTNER Monitoring : J. Genève, M. Torres, F. Do Nascimento, S.Levêque, F. Nait-Atmane, AC Le Gall (FNCLCC, BECT, Paris) FFCD : M. Moreau, C. Choine-Pourret, F. Guiliani-Kpodoh, A. Kodjo, S. Ngassam, H. Fattouh, N. Le Provost Data center : Huguet Helena Supported by a Clinical Research Hospital Program GRANT (PHRC 2004) from the French Ministry of Health Grants from Roche and sanofi-aventis 30/05/2009

ACKNOWLEDGEMENTS "Patients and families" Co-investigators : Pr CONROY Centre Alexis Vautrin (NANCY) ; Dr BOUCHE Centre Hospitalier R. Debré (REIMS) ; Dr DENIS Hôpital Pasteur (COLMAR) ; Dr MIRABEL Centre Oscar Lambret (LILLE) ; Dr BERDAH Clinique Ste Marguerite (HYERES) ; Dr LLEDO Clinique St Jean (LYON) ; Pr MAHE Centre René Gauducheau (NANTES - St HERBLAIN) ; Pr BECOUARN Institut Bergonié (BORDEAUX) ; Dr ROMESTAING Centre Hospitalier Lyon Sud (LYON) ; Dr BOIGE Institut Gustave Roussy (VILLEJUIF) ; Dr MOUREAU - ZABOTTO Institut Paoli Calmettes (MARSEILLE) ; Dr GALAIS Centre François Baclesse (CAEN) ; Dr DUPUIS Clinique Victor Hugo (LE MANS) ; Dr GUICHARD Polyclinique Nord Aquitaine (BORDEAUX) ; Dr SEITZ Centre hospitalier La Timone (MARSEILLE) ; Dr OLLIER Centre Paul Strauss (STRASBOURG) ; Dr RIVES Institut Claudius Regaud (TOULOUSE) ; Dr CHARNEAU Centre hospitalier (BOULOGNE SUR MER) ; Dr DEBRIGODE Centre Hospitalier Carémeau (NIMES) ; Pr. MICHEL Centre hospitalier Ch. Nicolle (ROUEN) ; Dr TAIEB Centre hospitalier La Pitié (PARIS) ; Dr ZAWADI Centre Hospitalier Les Oudairies (LA ROCHE SUR YON) ; Dr JOUVE CHU La Bocage (DIJON) ; Dr GUICHARD Polyclinique des 4 pavillons (LORMONT) ; Dr MARTIN Centre Bourgogne (LILLE) ; Dr GASMI Hôpital Nord (MARSEILLE) ; Dr VIE Centre Maurice Tubiana (CAEN) ; Dr BONNICHON-LAMICHHANE Clinique Tivoli (BORDEAUX) ; Dr LELOUP Centre Hospitalier "La Source" (ORLEANS) ; Dr NOIRCLERC Centre Hospitalier (MULHOUSE) ; Dr CVITKOVIC Centre René Huguenin (ST CLOUD) ; Dr AZZEDINE Centre Hospitalier (AVIGNON) ; Dr STREMSDOERFER Hôpital Pierre Oudot (BOURGOIN JALLIEU) ; Dr CLIPPE Centre hospitalier (VALENCE) ; Dr MORAILLON Clinique Générale (VALENCE) ; Dr KLEIN Centre d'Oncologie St Yves (VANNES) ; DR GARGOT Centre hospitalier (BLOIS) ; Dr AUBY Centre Hospitalier R. Boulin (LIBOURNE) ; Dr ROCHER Clinique Ste Marie (CHALON SUR SAONE) ; Dr APARICIO Centre hospitalier –Bichat (PARIS) ; Pr LAGRANGE Hôpital Henri Mondor (CRETEIL) ; Dr MONNIER Centre Hospitalier A. Boulloche (MONTBELLIARD) ; Dr NGUYEN Centre Hospitalier (BEAUVAIS) ; Dr PLATINI Hôpital du Bon Secours (METZ) ; Pr NGUYEN Institut Jean Godinot (REIMS) ; Pr PEZET CHU Hôtel Dieu (CLERMONT-FERRAND) ; Dr PAPADOPOULOU Centre Hospitalier (ANNECY) - FRANCE Taux de succès attendus (% pièces stérilisées) : Bras A (50 Gy + capecitabine/oxaliplatine) = 20% Bras B (45 Gy + capecitabine) = 11% Mettre en évidence une différence d’au- moins 9% avec un risque alpha bi-latéral de 5% et une puissance de 85% (béta = 15%), il faut inclure 590 patients. Une analyse intermédiaire est prévue après l’évaluation de 354 patients. 590 patients were needed Secondary endpoints included toxicity, conservative surgery, local relapse and survival. This report presents early toxicities in the first 150 patients 30/05/2009

30/05/2009

GRECCAR 1 - Ph. Rouanet et al. Low rectal cancer (APR ?) u T2-3 RXT 63 Gy RXT 45 Gy + 5FU (CI) R Rest 4-6 w surgery - CT if ypN1-2 End point : conservative surgery 2001- 2005 : 207 pts (13 centers) 30/05/2009

GRECCAR 1 - Results RT63 (100) RT45 + FU (95) CR resp. DRE 80% 87% APR 18% ypT0 8% 15% ypN0 60% 66% 3y Loc Rec. 2y Met 20% 21% 3y ov. Surv. 91% 90% 30/05/2009