1. Rectal Cancer: French Prodige Study: Best of ASCO, Beirut, July 2009 Prof Eric Van Cutsem, MD, PhD Digestive Oncology Leuven, Belgium

2. 30/05/2009 2 Nice 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. 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

3. 30/05/2009 3 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

4. 30/05/2009 4 Background (2) Concurrent CT-RT > RT alone FFCD 92.03 - (EORTC) phase III RTCT - RT ypCR 4%11% Loc rec 5 y16%7% No change : sphincter preservation – survival ASCO 2005 JCO 2006;24:4260

5. 30/05/2009 5 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

6. 30/05/2009 6 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)

7. 30/05/2009 7 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

8. 30/05/2009 8 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

9. 30/05/2009 9 Hypothesis – sample size ypCR : 11% 20% N = 590 for statistical power 85% (2 sided  = 0.05) - 3 years enrollment - Database locked march 2009 Stratification : center – T stage – T site

10. 30/05/2009 10 ACCORD 12/0405-Prodige 2-Design of trial T3 (4) M0 - Accessible DRE < 80 y (low ant T2) R 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)

11. 30/05/2009 11 12345 Radiotherapy 44 Gy 50 Gy/25F/5 weeks Capecitabine 800/m²x2/Day (1600mg/m²) except WE Oxaliplatin IV 50 mg/m²(2h) Capox 50 ●

12. 30/05/2009 12 Pathology ypT0 N0 – R0 Quirke - Dworak

13. 30/05/2009 13 November 2005 - July 2008 598 pts / 2,9 years 56 centers Age : 63 y M/F : 2/1 T3 : 87% T2 : 8% T4 : 5%

14. 30/05/2009 14 RT45-Cap N= 299 RT50-CapOx N= 299 Eligible n= 293Eligible n= 291 Surgery n= 287 Operative specimen n= 285 Operative specimen n= 278 563 574 584 598 randomized patients Adj. Chemotherapy 42% Adj. Chemotherapy 30% Flow-Chart 598

15. 30/05/2009 15 Early toxicity G2-3-4 (CTC –NCI V3) Adverse eventCape 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) Asco 2008 * < 44 Gy : 2%

16. 30/05/2009 16 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) 2 nd 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)

17. 30/05/2009 17 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

18. 30/05/2009 18 Circumferential rectal margin - CRM Margin Cape 45 (162) Capox 50 (147) p-value 0-1 mm12% (19) 7% (11) 0.21 0-2 mm19% (31) 9% (14) 0.017 Pelvic local control ??

19. 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

20. 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%

21. 30/05/2009 21 STAR (747) ACCORD (598) RT50.4 + Oxali (60 mg) RT50 + Capox G3-4 toxicity 25% ypCR 19% (increase) Rectal Cancer T3-4 M0

22. 30/05/2009 22 STAR (747) ACCORD (598) RT 50.4 + Oxali (60 mg) RT50 + Capox G3-4 toxicity 24% (increase) 25% ypCR 16% (no difference) 19% (increase) Rectal Cancer T3-4 M0

23. 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

24. 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

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

26. 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) - Capecitabine 1600 mg/m² (RT days) ■ How to fight distant metastases ? (oxaliplatin)