1. Adjuvant chemotherapy in CCR in 2011 Philippe Rougier , Digestive Oncology Hopital Européen Georges Pompidou, APHP 75015 Paris ; France UVSQ ; UFR Paris-ile de France Ouest

7. Risk of recurrence Risk of death 40% decrease in RR of recurrence 33% decrease in RR of recurrence 20% absolute decrease 20% absolute decrease P < 0.0001 (controle vs 5FU + Levamisole) P < 0.0007 (controle vs 5FU + Levamisole) 5FU + levamisole (n = 304) Levamisole (n = 310) Follow-up only (n = 315) 100 90 80 70 60 50 40 30 20 10 0 0 1 2 3 4 Years from Registration Moertel CG et al. Ann Intern Med. 1995;122:321-326 . Patients free from recurrence (%) Patients surviving (%) A risque 5FU + levamisole (n = 304) Levamisole (n = 310) Follow-up only (n = 315) 100 90 80 70 60 50 40 30 20 10 0 0 1 2 3 4 Years from Registration A 1990: the first step : 5FU + levamisole INT-0035 trial ( Moertel et al, New England Journal of Medicine, 1990)

8. Adjuvant therapy with 5FU increases the chance of survival and Cure patients: evidence in 20,898 CC Stage II CC Stage III CC Sargent D, et al. JCO 2009 1.0 0.8 0.6 0.4 0.2 0 OS estimate p=0.026 0 1 2 3 4 5 6 7 8 Follow-up time (years) Surgery alone 8-year OS rate (95% CI): 66.8% (63.7% to 70.0%) Surgery + FU-based chemotherapy 8-year OS rate (95% CI): 72.2% (69.3% to 75.2%) p<0.0001 Surgery alone 8-year OS rate (95% CI): 42.7% (39.9% to 45.7%) Surgery + FU-based chemotherapy 8-year OS rate (95% CI): 53.0% (50.2% to 55.9%) 0 1 2 3 4 5 6 7 8 Follow-up time (years) CC=colon cancer OS=overall survival OS estimate 1.0 0.8 0.6 0.4 0.2 0

10. DFS : Stage III (60% of pts) Probability DFS (months) Decrease: 24% RR of recurrence in stage III by FOLFOX4 Hazard ratio: 0.76 [0.62-0.92] FOLFOX4 (n=672) 72.2% 3 years André et al. NEJM 2004, 350; 2343-2351 +6,9 % at LV5FU2 (n=675) : 65.3% FOLFOX4 as adjuvant tt ; Stage II-III CC: MOSAIC FOLFOX4 vs LV5FU2 for 6 m Primary end point : DFS n=2246 Stage :II: 40% III: 60% Colon ADK

11. Years No benefit of chemotherapy Cured by chemotherapy Already Cured by Surgery Adjuvant Therapy for Colon Cancer Stage III What benefit ?? 0 20 40 60 80 100 0 1 2 3 4 5 exposed to toxicit y Surgery alone Surgery plus Chemotherapy 25% % Disease Free Survival 55% 20% 20% 25%

12. Years No benefit of chemotherapy Cured by chemotherapy Already Cured by Surgery Adjuvant Therapy for Colon Cancer Stage III What benefit ?? 0 20 40 60 80 100 0 1 2 3 4 5 exposed to toxicit y Surgery alone Surgery plus Chemotherapy 25% % Disease Free Survival 55% 20% 20% 25% 20% from 5FU & 5% by adding oxaliplatin ?? 1 out of 4 patient Benefit from adjuvant CT and 1 out of 20 from Adding OxaliP

13. 6 Year Overall Survival: Stage II and Stage III Data cut-off: January 2007 FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III 0.1% 4.2% p=0.996 p=0.029 André et al. J Clin Oncol. 2009 MOSAIC 2009 Overall survival (months) Probability 1.0 0.8 0.6 0.4 0.2 0 0.9 0.7 0.5 0.3 0.1 0 6 12 18 24 60 30 36 42 48 54 66 96 72 78 84 90 HR [95% CI] Stage II 1.00 [0.70–1.41] Stage III 0.80 [0.65–0.97]

14. 3 positive phases III in favor of Oxaliplatin Δ 3y DFS Δ 5y DFS Δ 5-6y 0S Mosaic FOLFOX4 + 5.3% + 5.9% + 2.5% HR 0.84 (median FU:82 months) C-07 NSAPB mFOLFOX + 4.3% + 5.2% + 4.2% HR 0.85 (median FU: 67 months) Xelox + 4.5% + 6.3% + 3.4% HR 0.85 (median FU ?)

15. Tolerance : Peripheral sensory neuropathy may be armful in some patients … Proportion of pts treated by FOLFOX4 André et al. J Clin Oncol. 2009 ; 27 :3109 -15 MOSAIC 2009 At 48 months Evaluable patients n=811 Grade 0 84.3% Grade 1 12.0% Grade 2 2.8% Grade 3 0.7%

19. Gray R et al, Lancet 2007;370:2020−9 5 Year Survival in Stage II Pts: the QUASAR Study Chemo vs Observation OS at 5 Year 80,3 % 77,4 % (+2.9%) Relative Ris 0,83 (IC 95 : 0,71-0,97) 100 80 60 40 20 0 0 2 4 8 Years OS stage II (Dukes B) p = 0,04 6 10 5-FU + AF (Mayo or Roswell Park 6 mth ) ± lévamisole (n = 1 622) Observation (n = 1 617) R patients Characteristics RR of death reduced by 17% + 2.9% Chemotherapy Observation Chimo Observation Stage II (Dukes B2) 92 % 92 % Colon 71 % 71 % Rectum 29 % 29 % FUFOL hebdo 49 % 49 % Médian FU 4,6 Y 4,6 Y

20. Minimal benefit from FOLFOX over LV5FU2 on 5 Year Disease-free S. in Stage II Data cut-off: June 2006 3.8% 7.5% p=0.258 p=0.005 André et al. J Clin Oncol. 2009 ; 27 :3109 -15. MOSAIC 2009 HR [95% CI] p-value Stage II 0.84 [0.62–1.14] 0.258 Stage III 0.80 [0.65–0.93] 0.005 FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III Months Probability 1.0 0.8 0.6 0.4 0.2 0 0.9 0.7 0.5 0.3 0.1 0 6 12 18 24 60 30 36 42 48 54 66 72

21. Absence of benefit from FOLFOX over LV5FU2 on 6 Year Overall Survival: Stage II and Stage III Data cut-off: January 2007 FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III 0.1% 4.2% p=0.996 p=0.029 André et al. J Clin Oncol. 2009 MOSAIC 2009 Overall survival (months) Probability 1.0 0.8 0.6 0.4 0.2 0 0.9 0.7 0.5 0.3 0.1 0 6 12 18 24 60 30 36 42 48 54 66 96 72 78 84 90 HR [95% CI] Stage II 1.00 [0.70–1.41] Stage III 0.80 [0.65–0.97]

22. Years Chemotherapy without benefit Cured by chemotherapy allready cured by surgery Adjuvant chemotherapy for CC Stage II A very small benefit ? => be cautious 0 20 40 60 80 100 0 1 2 3 4 5 T O X I C I T Y Surgery alone Surgery plus chemotherapy 3-5 % 80% 5% 15% Overall Survival

23. Patient Selection +++ => Factors influencing prognosis in stage II ? Lymphatic Venous Perineural invasion Poor Differentiation Tumor invasion (T4) No. of nodes examined Less to 8-10 Perforation Occlusion MSS-MSI T3N0 without unfavorable prognosis factors and or MSI : prognosis close to Stage I T 3-4 N0 with unfavorable prognosis factors : prognosis close to Stage III

24. 0.5 0.7 0.9 1.1 1.3 1.5 Hazard Ratio 1 Stage III High risk Stage II Stage II Stage III High risk Stage II Stage II Overall survival (OS) Disease-free survival (DFS) Hazard ratios for DFS and OS by sub group Favours FOLFOX4 Favours LV5FU2 André et al. J Clin Oncol. 2009 MOSAIC

28. Gene Expression Profiles in Dukes’B Colon Cancer Wang et al. JCO 2004,22:1564 17616 informative genes 2 dominant clusters (39 resp.14 genes)

30. p=0.004 QUASAR RESULTS : Colon Cancer Recurrence Score Predicts Recurrence Following Surgery STROMAL FAP INHBA BGN CELL CYCLE Ki-67 c-MYC MYBL2 REFERENCE ATP5E GPX1 PGK1 UBB VDAC2 GADD45B RECURRENCE SCORE Calculated from Tumor Gene Expression Prospectively-Defined Primary Analysis in Stage II Colon Cancer (n=711) D. Kerr et al., ASCO 2009, A 4000 Group Risk (by Kaplan-Meier) 12% 18% 22%

31. QUASAR RESULTS: Recurrence Score, T Stage, and MMR Deficiency are Key Independent Predictors of Recurrence in Stage II Colon Cancer Multivariate Analysis D. Kerr et al., ASCO 2009, A 4000

32. Colorectal Cancer : adjuvant ColoPrint ® : an independent prognostic factor ColoPrint ® : genomic Signature for prognosis prediction in CRC stade II, III RFS 5 y (all stages, n=206) : Low risk 87,6% High risk 67,2% (HR) 2,5 (95%CI : 1,33 – 4,73 ; p<0,005) RFS 5 y (stage II, n=114) : Low risk 90,9% High risk 73,9% (95%CI : 59,2% – 88,6% ; p=0,017) RFS 5 y (stade III, n=62) : Low risk 78,2% high risk 47,2% Salazar R. et al. JCO 2011

35. MOSAIC data in patients > 70 years OS unpublished

36. ACCENT update: 6 trials added † Compared to control arm of intravenous 5-flourouracil (IV 5-FU) and leucovorin (LV) ‡ Remaining patients were stage II or unknown N. Jackson McCleary ASCO 2009 NSABP C-06 1997-99 1557 23 Uracil/tegafur 53 CALGB 89803 1999-01 1263 24 IFL 98 MOSAIC 1998-01 2246 14 FOLFOX4 60 Trial Accrual Period # pts % pts ≥ 70 yrs Experimental treatment arm † % stage III ‡ NSABP C-07 2000-02 2434 16 FLOX 71 PETACC-3 2000-02 3186 13 FOLFIRI 71 X-ACT 1998-01 1983 20 Capecitabine 100

37. ACCENT Forest Plots of Hazard Ratios: Disease-Free Survival N. Jackson McCleary ASCO 2009 No benefit After 70 years

38. ACCENT Forest Plots of Hazard Ratios: Overall Survival N. Jackson McCleary ASCO 2009 No benefit After 70 years

39. b estimated from forest plot c stage III 190 patients a stage III Population > 70 and Hazard-Ratios N>70 % DFS HR OS HR reference ACCENT Oral FP 755 21.3 1.13 1.17 ASCO 2009 X-ACT a 397 20.0 0.93 b 0.93 b Twelves NEJM 2005, ASCO GI 2008 C-06 358 22.3 NA >1.13 NA >1.17 Lembersky JCO 2006 ACCENT Oxaliplatin 703 15.0 1.04 1.19 ASCO 2009 MOSAIC 315 c 14.0 0.91 1.10 unpublished C-07 388 16.9 NA >1.04 NA >1.19 Kuebler JCO 2007 NO16968 a 409 21.7 0.87 0.94 ASCO GI 2010

40. Capecitabine alone, in stage III pts, a reasonable option XELOX / FOLFOX minimal DFS advantage. OS might be improved with a more intensive management of relapse or second-cancer. ? A reduced duration of chemotherapy should be tested and could help ederly patients: IDEA (International Duration Evaluation of Adjt Chemo.) Colon Cancer Prospective Pooled Analysis Which adjuvant treatment in ederly pts? (4)

41. Treatment of Stage III ederly pts according to … Standard Treatment Best Supportive Care Adapted Treatment Geriatric Evaluation Cancer < Live Expentency < Cancer Harmonious Group The Oncologist 2000;5:224-237 Intermediate Group Frail Group FOLFOX ou XELOX LV5FU2, capecitabine, No CT ? No CT

42. Targeted therapy in adjuvant therapy ?

45. DFS (ITT Stage III) Data cut-off date: 30 June 2010 (3-year minimum follow-up) 955 960 952 890 921 900 823 868 865 779 791 784 740 728 722 708 695 688 451 436 415 FOLFOX4 FOLFOX4 + Bev XELOX + Bev Number at risk 609 586 580 282 280 268 FOLFOX4 FOLFOX4 + Bev XELOX + Bev Event-free rate 121 123 110 0 1 0 32 33 28 0 0 0 A de gramont, ASCO GI 2011 FOLFOX (N=955) FOLFOX4 + Bev (N=960) XELOX + Bev (N=952) HR (95% CI) 1.17 (0.98, 1.39) 1.07 ( 0.90, 1.28 ) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 6 18 30 36 42 48 0 12 24 Time (months) 54 60 66 72

46. Interim OS (ITT Stage III) 955 960 952 914 942 920 899 925 908 884 900 894 863 869 861 844 835 840 573 573 546 FOLFOX4 FOLFOX4 + Bev XELOX + Bev Number at risk 776 763 765 461 449 445 288 269 290 0 1 0 63 70 64 0 0 0 Event-free rate FOLFOX4 FOLFOX4 + Bev XELOX + Bev A de gramont, ASCO GI 2011 No benefit at all ! Bevacizumab has no role in adjuvant FOLFOX (N=955) FOLFOX4 + Bev (N=960) XELOX + Bev (N=952) HR (95% CI) 1.31 (1.03, 1.67) 1.27 (0.99, 1.62) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 6 18 30 36 42 48 0 12 24 Time (months) 54 60 66 72

48. Stage III CC FOLFOX4 vs FOLFOX4 + cetuximab 2,450* PETACC-8 Stage III CC mFOLFOX6 vs mFOLFOX6 + cetuximab 2,300 Intergroup 0147 (ECOG/NCCTG) Disease Treatment n Trial *Protocol amended in 2008 for KRAS status Anti-EGFR adjuvant therapy

51. Adjuvant CT & rectal cancer

54. Meta-analysis IV Chemo vs surveillance Colon Rectum Odds ratio 0.81 0.64 95% C.I. 0.69 – 0.94 0.48 – 0.85 29 RCT; 12079 pts; no IDP Dubé S. Dis Colon Rectum 40, 1997 Overall Survival

56. Gray R et al, Lancet 2007;370:2020−9 5 Year Survival in Stage II Pts: the QUASAR Study Chemo vs Observation OS at 5 Year 80,3 % 77,4 % (+2.9%) Relative Ris 0,83 (IC 95 : 0,71-0,97) 100 80 60 40 20 0 0 2 4 8 Years OS stage II (Dukes B) p = 0,04 6 10 5-FU + AF (Mayo or Roswell Park 6 mth ) ± lévamisole (n = 1 622) Observation (n = 1 617) R patients Characteristics RR of death reduced by 17% + 2.9% Chemotherapy Observation Chimo Observation Stage II (Dukes B2) 92 % 92 % Colon 71 % 71 % Rectum 29 % 29 % FUFOL hebdo 49 % 49 % Médian FU 4,6 Y 4,6 Y

57. Bosset JF et al. NEJM 355, 2006 Non significative amelioration of OS… but only 43% of patients have received the whole planed chemotherapy treatment.

59. Rectal Cancer Exemple of Recommendations for adjuvant Tt (tncd.org) (Thessaurus de bonne pratique en cancéro digestive) Preop stagging : clinical, NMR, CT, +/- EUS T1-2N0 T3N0 & NMR margin > 1 mm T1-4 N+ T3T4N0 & MRC < 1 mm MRC : circunferential resection margin RT : radiotherapy TME: total mesorectum excision RCT (5FU) : radio-chimiothérapie avec 5FU ou capécitabine Surgery + TME–R0 resection RT 25 Gy or RCT (5FU) RCT (5FU +/- LOHP) pT1-2N0 ypT0-2N0 ypT3-4N0 pT1-2N+ ypT1-4 N+ Follow-up Follow-up ? Adjuvant CT (5FU, X or FOLFOX) « Expert » advise (www.tncd.org)