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Rectal Cancer: French Prodige Study: Best of ASCO, Beirut, July 2009

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

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Rectal Cancer: French Prodige Study: Best of ASCO, Beirut, July 2009

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

  2. 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

  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 30/05/2009

  4. 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

  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 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) 30/05/2009

  7. 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

  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 30/05/2009

  9. 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

  10. 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

  11. 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

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

  14. 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

  15. 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

  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) 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

  17. 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

  18. 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

  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

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