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

30/05/ 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 # ASCO – Orlando – 30 May 2009

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

30/05/ : How to optimize neoadjuvant treatment for T3-4 Nx M0 rectal cancer ? FFCD : 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/ Accord 12 inclusion criteria As in FFCD ■ 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/ 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/ 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/ 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

30/05/ 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)

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

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

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

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

30/05/ 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) < Diarrhea G3-4 3% 13% < 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%

30/05/ 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) Death 60 days 0.3% (1) 0.3% (1)

30/05/ 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) ypT0 14% 19% ns yp N0 69% 71% ns

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

30/05/ 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)

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

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

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

30/05/ 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)