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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,

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  1. Results of the Prodige 2-ACCORD 12/0405Randomized 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

  2. 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

  3. 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 2005JCO 2006;24:4260 30/05/2009

  4. 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

  5. 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

  6. Primary end point :Complete sterilization of operative specimenypCR 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

  7. 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

  8. 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

  9. R 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 6 weeks TME Adjuvant chemo left each institution (constant) • Hypothesis : ypCR = 11% 20% (590 pts) 30/05/2009

  10. 50 Gy/25F/5 weeks Capox 50 44 Gy • Radiotherapy ● • Capecitabine 800/m²x2/Day (1600mg/m²) except WE • Oxaliplatin IV 50 mg/m²(2h) 30/05/2009

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

  12. 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

  13. Flow-Chart 598 randomized patients RT45-Cap N= 299 RT50-CapOx N= 299 598 Eligible n= 293 Eligible n= 291 584 Surgery n= 287 Surgery n= 287 574 Operative specimen n= 285 Operative specimenn= 278 563 Adj. Chemotherapy42% Adj. Chemotherapy30% 30/05/2009

  14. Early toxicity G2-3-4 (CTC –NCI V3) Adverse event Cape 45 (293) Capox 50 (291) p-value All toxicity G3-411%(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

  15. 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

  16. Primary end point – operative specimenSterilization 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

  17. 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

  18. 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

  19. 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

  20. 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

  21. 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

  22. 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

  23. 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

  24. (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

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

  26. 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) - Capecitabine1600 mg/m²(RT days) ■ How to fight distant metastases ? (oxaliplatin) 30/05/2009

  27. 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

  28. 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 30/05/2009

  29. 30/05/2009

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

  31. GRECCAR 1 - Results 30/05/2009

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