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  • **Pooled analyses in metastatic setting showed improved or similar survival benefit for older pts receiving combination vs IV FU/LV **Suggests older patients derive benefit from adjuvant therapy after surgery **Formed basis of ACCENT data group
  • † Compared to control arm of intravenous 5-flourouracil (IV 5-FU) and leucovorin (LV) ‡ Remaining patients were stage II or unknown Recently added data from 6 newer studies evaluating the survival benefit of either intravenous (IV) FU combination chemotherapy or oral FU chemotherapy compared to standard IV FU/LV monotherapy in stage II and III CRC Abbreviations: MOSAIC, Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer; XACT, Xeloda in Adjuvant Colon Cancer Therapy; NSABP, National Surgical Adjuvant Breast and Bowel Project; CALGB, Cancer and Leukemia Group B; PETACC, Pan-European Trials in Adjuvant Colon Cancer; FOLFOX, infusional 5-FU/LV + oxaliplatin; FLOX, bolus IV 5-fluorouracil (FU)/ leucovorin (LV) + oxaliplatin; IFL, bolus IV 5-FU/LV + irinotecan; FOLFIRI, infusional 5-FU/LV + irinotecan
  • To reiterate graphically, these forest plots depict no alteration of treatment effect by age. **These associations are further illustrated by forest plots organized by drug class (Figure 1).

MON 2011 - Slide 19 - P. Rougier - Adjuvant treatment (stage 2 and 3) Presentation Transcript

  • 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
  • 2. Colorectal cancer -1
    • Third most common tumour type world wide, representing 9% of cancer
    • Two third colon, one third rectum
    • More frequent in developed countries
    • Environnemental factors (diet, activity, overweight) vs Genetic factors (APC: 1%, HNPCC: 2%, familiar predisposition: 15%)
    • MSS (pMMR): 85% ; MSI (dMMR): 15%
  • 3. Colorectal cancer - 2
    • In Europe: # 250 000 new cases / year
    • 70% are > 65 years of age.
    • Overall survival in Europe:
      • 72% at 1 year ;
      • 54% at 5 years.
    • Prognosis mainly dependent on stage
  • 4. TNM and Stage II & III heterogeneity (6th AJC classification)
    • Stage II & III CC splited according to T & N involvement
        • Stage nb T & N Survival (5y)
        • II 34 261 T3-T4 N0 82.5 %
          • IIa 28 635 T3-N0 84.7 %
          • IIb 5 826 T4 N0 72.2 %
        • III 26 249 Tx, N1 ,2 59,5 %
          • IIIa 1 989 T1-2, N1 83.4 %
          • IIIb 15 940 T3-4, N1 64.1 %
          • IIIc 8 600 Tx, N2 44.3 %
      • SEER 119 363 pts ; JB O ’Connell J Nat Cancer Inst 2004 ; 19: 1420-25.
    • (AJC ; 6- August - 2004 ; www.cancerstaging.org .)
  • 5. => concept of high and low risk CC
    • Stage II & III according to T & N involvement
        • Stade nb T & N Survie 5 ans
        • II 34 261 T3-T4 N0 82.5 %
          • IIa 28 635 T3-N0 84.7 %
          • IIb 5 826 T4 N0 72.2 %
        • III 26 249 Tx, N1 ,2 59,5 %
          • IIIa 1 989 T1-2, N1 83.4 %
          • IIIb 15 940 T3-4, N1 64.1 %
          • IIIc 8 600 Tx, N2 44.3 %
      • SEER 119 363 pts ; JB O ’Connell J Nat Cancer Inst 2004 ; 19: 1420-25.
    • (AJC ; 6- August - 2004 ; www.cancerstaging.org .)
    Low Risk IIa IIIa high Risk IIb IIIb IIIc
  • 6. DFS (3-year) vs OS (5-year) : Endpoint for Adjuvant Colon Cancer Studies:
    • 3-year DFS is an excellent predictor of 5-year OS
    • These data support use of 3-year DFS as primary endpoint in trials testing adjuvant therapy in colon cancer
    HR: 3-Year DFS vs 5-Year OS Sargent D, et al. . J Clin Oncol. 2005 ; 23 :8664 -70. Data from Randomized Trials
  • 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
  • 9. Oral Fluoropyrimidines in Adjuvant Setting
    • X-ACT (n=1987)
    • NSABP C06 (n= 1953)
    Primary Endpoint Met Trend to Superior DFS (ITT) DFS capecitabine 64.2% FU-LV 60.6% 68,3% 66,9% 100 80 60 40 20 0 0 1 2 Year % DFS 3 p=0.0528 100 80 60 40 20 0 0 1 2 3 4 n Death FU-LV 771 173 UFT-LV 782 180 Year OS % OS 78,7% 5 6 78,7% p = 0,88 DFS HR = 0.87 (95% CI: 0.75–1.00 ) Twelves,C et al. N. Engl. J. Med. 2005 ;352, 2696-2704 Wolmark N, et al . J Clin Oncol 2005 ; 23 : 1092s : a 3500 A valid option
  • 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%
  • 16. Conclusion on Adjuvant Therapy For Colon Cancer Stage III in 2010
    • STANDARD : 6 months of FU-FA + OX but Stopping oxali in case of neuropathy grade 2 or 3 and continuing sLV5FU2
    • Prefered regimen: FOLFOX4 rather than Roswell Park regimen + oxaliplatin: => less diarrhea (16.8 % vs 38 %) & vomiting (5.9 vs 12.9%) & mortality (0.5% vs 1.2%)
    • XELOX after ASCO in 2010 is also a standard in Europe
    • Capecitabine alone is considered if patients refused IV chemo or in case of neuropathy
    1 André, et al. N Engl J Med 2004;350:2343–2351 2 Kuebler JP et al. J Clin Oncol 2007 ; 25 ;2198-2204 3 D Haller et al, Berlin ECCO/ESMO, September 2009, ASCO 2010
  • 17. Questions for the future: duration ?
    • Do we need 12 cycles of FOLFOX ?
      • median of 10 cycles was used in MOSAIC study
      • dose intensity of oxaliplatin was lower in NSABP C-07 compared with MOSAIC trial
      • => 6 or 8 cycles be enough?
    • => IDEA (International Duration Evaluation of Adjuvant Chemotherapy) A Grottey and D Sargent ;
      • Meta-Analysis of prospective studies ( # 2000 pts included)
      • Comparing 12 vs 6 cycles of FOLFOX
      • Non inferiority trial comparing 3 to 6 months
      • Sample size of 10,500 patients provides 90% power
  • 18. Adjuvant Therapy for Colon Cancer S tage II
    • What benefit ??
    • An hetoregeneous group of patients: pT3N0 vs pT4N0
    • Relative vs absolute survival benefit ?
    • How many patients treated for one more cured patients ?
  • 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
  • 25. Stage II : Conclusions
    • Adjt tt for stage II pts is controversial ; identification of co-morbidity and reliable prognostic factors is crucial.
    • Trends in favour of adjuvant chemotherapy (QUASAR)
    • “ low risk” stage II (T3N0) and tumor MSI: no chemotherapy.
    • “ High risk” Stage II: MSS tumors + poor prognosis factors
        • fluoropyrimidine (oral) as adjuvant tt ;
        • FOLFOX4 for selected patients (T4, <10 examined LN)
    • In the future: selection by molecular signature ?
    André T, Sargent D et al. Current Issues in Adjuvant Treatment of Stage II Colon Cancer. Ann Surg Oncol. 2006 Apr
  • 26.
    • MSI statut = dMMR or MSS = pMMR associated to different evolutive profiles & sensitivity to 5FU
    • 1915 pts stage II ; 11.5% dMMR in QUASAR (G. Hutchins et al ., ASCO 2010, A 3517)
    • 2141 pts st II/III ; 16% dMMR (F Sinicrope et al .,A 3519)
    • 562 pts st II/III NSABP trials (GP Kim et al ., A 3518)
    •  recurrence risk in dMMR patients treated by surgery alone with more localrecurrences and better overall suvival:
    • dMMR : 11 - 21,6% vs pMMR : 26% - 38%
    Genetic factors in resected colon cancer impact of MSI (dMMR) status on recurrence rate
  • 27. Colic cancers stage II vs III are they different or not ?
    • Roth et al. ASCO 2009 suggested that stage II & III may be different diseases, ?
    • From NSABP C01/02-04-06 trial Identification (RT-PCR) of 375 genes in 634 st II & 844 st III
    • More MSI, and mucinous ADK, and less high grade tumours in stage II
    • only 5 genes / 375 differs
    Stage II & III are very similar ! M. J. O’Connell et al ., ASCO 2010, A 3503
  • 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)
  • 29. Colon Cancer Technical Feasibility Development Studies Surgery Alone NSABP C-01/C-02 (n=270) CCF (n = 765) Selection of Final Gene List & Algorithm Development Studies Surgery + 5FU/LV NSABP C-04 (n=308) NSABP C-06 (n=508) Clinical Validation Study – Stage II Colon Cancer QUASAR (n=1,436) Test Prognosis and Treatment Benefit Development and Validation of a Multi-Gene RT-PCR Colon Cancer Assay Validation of Analytical Methods
    • NSABP and CCF Collaborations - 761 genes studied in 1,851 patients to select genes which predict recurrence and/or differential 5FU/LV benefit
    • Clinical Validation of final assay in a large, prospectively-designed independent study
    D. Kerr et al., ASCO 2009, A 4000
  • 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
  • 33. Adjuvant CT: 2 questions
    • What to propose to elderly patients ?
    • Targeted therapies in adjt tt ?
  • 34. Adjt Tt for Colorectal Cancer in Elderly Pts using 5FU-based chemotherapy
      • Sargent NEJM 2001 – N=3351 (15%  70 yrs)
        • 7 trials of 5-FU + levamisole/leucovorin vs surgery
        • No significant interaction observed between age and efficacy of treatment
        • => 5FU-based CT is a valid option in stage III
    DFS <70 <70 >70 >70 OS < 70 yrs > 70 yrs
  • 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 ?
  • 43. 24 weeks 24 weeks BEVACIZUMAB ? ….NSABP C-08: study design / results
    • Primary endpoint: DFS at 3 years ( 25% ↓ ev rate HR = 0.75)
    • Inclusion: 09-2004 - 10-06
    • Accrual: 2710 patiens
    • Med F-U: 35.6 months
    • End Pt: DFS (592 /603 events)
    • 25% stage II
    mFOLFOX6 alone mFOLFOX6 + bevacizumab 5mg/kg every 2 weeks Bevacizumab 5mg/kg every 2 weeks Observation CC (stage II and III) (n=2,710) Duration of treatment phases N. Wolmark et al., JCO 2010
  • 44. AVANT: study design
    • Randomised, open-label study (inclusion closed in Mai 2007)
    • Primary endpoint: disease-free survival
    • Secondary endpoints: overall survival and safety
    • recruitment completed (Dec 2004 – June 2007)*
    Surgery for high risk stage II + stage III colon cancer (n=3,450) FOLFOX4 FOLF O X4 + Avastin (5mg/kg every 2 weeks) XELOX + Avastin (7.5mg/kg every 3 weeks) Avastin alone (7.5mg/kg every 3 weeks) Avastin alone (7.5mg/kg every 3 weeks) Observation Duration of treatment phases 24 weeks 24 weeks
  • 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
  • 47. Conclusions NSABP C08 & AVANT trials
    • - The addition of bevacizumab to mFF6 did not result in an overall statistically significant prolongation in DFS
    • There was a transient benefit in DFS during the one year that bevacizumab was utilized
    • there no evidence of improvement of overall survival with the use of bevacizumab combined to FOLFOX like regimen
    • Bevacizumab has no place in adjuvant in CC
  • 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
  • 49. S. R. Alberts et al ., ASCO 2010, LBA 3507 Etude NO147: FOLFOX6 +/- cetuximab Cetuximab in adjuvant tt ? Results in KRAS wt Tumors 0 % Survivants sans maladie 0 6 12 18 24 30 36 Temps (Mois) Disease Free Survival (n=1847) Folfox Folfox + Cmab 0 % Survivants 0 6 12 18 24 30 36 Temps (Mois) Overall Survival (n=1847) Folfox Folfox + Cmab NS NS Phase III Stage III KRAS WT N=1760
    • primary endpoint : DFS at 3 years
    • Interim Analysis when 50% of events observed
    10 20 30 40 50 60 70 80 90 100 10 20 30 40 50 60 70 80 90 100
  • 50.
    • Cetuximab does not improve DFS at 3 years and increases the risk of severe toxicity.
    • A low dose-intensity may explane part of these poor results ?
    • This may be explain by different sensitivity of tumor cells in adjuvant and in metastatic situation ?
    S. R. Alberts et al ., ASCO 2010, LBA 3507 Etude NO147: FOLFOX6 +/- cetuximab Cetuximab in adjuvant tt ? Results in KRAS wt Tumors Folfox + cetux Folfox DFS 3 years 72.3% 75.8% NS Toxicity gr 3/4 71% 51% < 0,001 12 cycles 65% 77% < 0,001
  • 51. Adjuvant CT & rectal cancer
  • 52. Adjuvant CT & rectal cancer (1)
    • No absolute proof of efficacy of adjuvant CT ,
    • - absence or low number of trials evaluating properly this question
    • - frequent combination with radiotherapy
    • .
  • 53. Adjuvant CT & rectal cancer (2)
    • « historical studies» reported before 1990,
    • + Meta-analysis
    • + QUASAR studies
    • Are in favor of adjuvant chemotherapy using fluoropyrimidines (iv or oral),
    • in absence of preopérative tt it may decrease the risk of recurrence after R0 resection of stage II or III rectal cancer.
    • This benefit seems similar at what is observed in colon cancer (HR: 0.70- 0.80) .
  • 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
  • 55.
    • Relative Reduction risk recurrence/death: 15% (p<.001)
    • Relative Reduction of death: 11% (p=0.03)
    • Similar benefit in rectal and colon cancer
    • Higher benefit for low stage tumors !
    • Absolut benefit similar in stage I & III:
      • 5% increase in DFS at 5 years
      • 3.5% increase overall survival at 5 year
    Japan Meta-analyses: Oral Fluoropyrimidines vs. control Japan Meta-analyses ( J Clin Oncol 2004, 22:484-92)
  • 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.
  • 58. Adjuvant CT & rectal cancer: Conclusions
    • ESMO : « similar to the situation in colon stage III (and « high risk » stage II), adjuvant chemotherapy can be provided, even if the scientific support for sufficient effect is less than in colon cancer. It is possible that the efficacy of adjuvant chemotherapy is less if the tumour has not responded to the (chemo)radiotherapy.» (Ann Oncol 2010 ; 21: v82-v86).
    • Adjuvant CT using fluoropyrimidines & oxaliplatin as in colon cancer (FOLFOX4, FOLFOX6 or XELOX) is an option (experts’opinion, French « tncd.org ») for high stages III.
    • Ongoing trial PETACC6 :
    • CapeOX-RT vs Capecitabine-RT + same regimen of chemotherapy after rectal resection …in T3-4, N0/+
    www.esmo.org/.../esmo-clinical-practice-guidelines.html -
  • 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)