1. 1 Stage III Colon Cancer What Works? Thierry André, MD Medical Oncology Departement, Hôpital Saint Antoine, APHP, Paris, France and University Pierre et Marie Curie (Paris VI) What Doesn't and Why? Bert H. O’Neil, MD University of North Carolina, Chapel Hill, NC And What's Next? Jeffrey A. Meyerhardt, MD, MPH Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA

2. 2 Key Points: What Works? Adjuvant therapy for colon cancer: the first step ! 5FU + Levamisole then Leucovorin Oral fluoropyrimidines, capecitabine and UFT are equivalent to 5-FU/LV Oxaliplatin plus fluoropyrimidines is better than fluoropyrimidines alone: the second step ! Can elderly patients benefit from adjuvant therapy ?

3. 3 The First Step (5FU) StudiesTreatment3-year DFS Moertel 1 Observation52% IMPACT 2 Observation44% Moertel 1 5FU/Lev64% IMPACT 2 5FU/LV62% MOSAIC 3 LV5FU265% X-Act 4 FUFOL61% XELOXA 5 FUFOL66% No treatment FU + LV or Lev 1 Moertel CG, N Engl J Med 1990 2 IMPACT investigators, Lancet 1995 3 André T, J Clin Oncol 2009 4 Twelves C, N Engl J Med 2005 5 Haller D, J Clin Oncol 2011 DFS at 3 Years (Stage III) 5FU was discovered by C Heidelberger in 1957

4. 4 DFS 1996: 5FU bolus + LV Francini 1994 IMPACT 1995 NCCTG 1997 NCCTG-NCIC 1998 INT 0089 1998 NSABP C04 1999 QUASAR 2000 Moertel Adjuvant Therapy Stage III 6 months = 12 months Leucovorin demonstrated synergy with 5FU in 1992 (D Machover) 1990: 5FU levamisole Machover D, J Natl Cancer Inst 1992

5. 5 5FU Increases OS and Cure Patients: Stage III CC Sargent D, J Clin Oncol 2009 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%) 012345678012345678 Follow-up time (years) OS estimate 1.0 0.8 0.6 0.4 0.2 0 10.3% Evidence in 13,793 Patients with Stage III

6. 6 5FU+lev DFS 5FU bolus + LV Adjuvant Therapy Stage III LV5FU2/5FU protracted infusion UK intergroup, Saini A et al. Br J Cancer 2003 GERCOR 96-1, André T et al. J Clin Oncol, 2003 PETTACC 2 Capecitabine NSABPC06, Lambersky BC, J Clin Oncol 2006 UFT+LV X-Act, Twelves C, N Engl J Med 2005 Better tolerance

7. 7 Oral FluoroP in Adjuvant Setting DFS capecitabine 64.2% FU-LV60.6% nDFS UFT-LV78274.5% LV-LV77174.5% 100 80 60 40 20 0 012 Year % DFS 3 p=0.0528 100 80 60 40 20 0 01234 Year DFS % OS 56 p = 0,88 DFS HR = 0.87 (95% CI: 0.75–1.00 ) Twelves,C et al. N. Engl. J. Med. 2005 Lembersky BC, J Clin Oncol 2006 X-ACT (n=1987, only stage 3) End Point: DFS at 3 years NSABP-C06 (n=1608, stage 2 & 3)

8. 8 DFS at 3-years is the New Endpoint for Adjuvant Colon Cancer Studies: 3-year DFS 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 May 2004: ODAC recommends 3-yr DFS as new regulatory endpoint for FULL approval in adjuvant colon cancer HR: 3-Year DFS vs 5-Year OS Sargent D, J Clin Oncol.2005 Data from Randomized Trials

9. 9 The Second Step (2004): 1 André T, N Engl J Med 2004 2 Yothers G, J Clin Oncol 2011 3 Haller D, J Clin Oncol 2011 Oxaliplatin + FluoroP (3 Studies) Primary end-point for these 3 steudies: Disease-free Survival

10. 10 DFS by Treatment Arm All Patients (ITT) Stage II and III (months) Probability Hazard ratio: 0.77 [0.65 – 0.91] p =0.002 23% risk reduction in the FOLFOX4 arm 3-year DFS André T, N Engl J Med 2004 5.3% MOSAIC 2004 FOLFOX4 (n=1123) LV5FU2 (n=1123) 78.2% 72.9%

11. 11 DFS at 3 Years (ITT) Stage III Patients FOLFOX4 – 672 Stage III LV5FU2 – 675 Stage III HR [95% CI]: 0.76 [0.62 – 0.92] Stage III 1.0 0.9 0.8 0.7 0.6 0.5 0.3 0.4 0.2 0.1 Months DFS rate 0666121824303642485460 MOSAIC 2004 DFS Survival rate at 3 years 72.2% for FOLFOX4 65.3% for LV5FU2 André T, N Engl J Med 2004 6.9%

12. 12 Overall Survival: Stage II and Stage III Data cut-off: January 2007 Overall survival (months) Probability André T, J Clin Oncol 2009 MOSAIC 2004 FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III 1.0 0.8 0.6 0.4 0.2 0 0.9 0.7 0.5 0.3 0.1 06121824603036424854669672788490 HR [95% CI] Stage II 1.00 [0.70–1.41] Stage III 0.80 [0.65–0.97] p=0.996 p=0.029 Stade II Stade III 0.1% 4.2%

13. 13 Fluoropyrimidines ± Oxaliplatin Stage III HR for DFS P valueDFS Delta (%) HR for OSP valueOS Delta (%) MOSAIC (1) 0.78 CI, 0.65-0.93 At 5 year 0.005 7.5% 58.9% vs 66.4% At 5 year 0.80 CI, 0.65-0.97 At 6 year 0.023 4.2% 68.7% vs 72.9% At 6 year NSABP C-07 (2) 0.78 CI, 0.68-0.90 At 5 year 0.0007 6.6 % 57.8% vs 64.4% At 5 year 0.85 CI, 0.72-1.00 At 5 year 0.052 2.7% 73.8% vs 76.5% At 5 year XELOXA (3) 0.80 CI, 0.69-0.93 At 3 year 0.0045 4.4% 66.5% vs 70.9% At 3 year 0.87 CI, 0.72-1.05 At 5 year 0.1486 3.4% ND (57 months FU) 1 André T, J Clin Oncol. 2009 2 Yothers G, J Clin Oncol 2011 3 Haller D, J Clin Oncol 2011 Evidence Based Medicine

14. 14 Years No benefit of chemotherapy Cured by chemotherapy FluoroP + oxali Already cured by surgery Adjuvant Therapy for Colon Cancer Stage III 0 20 40 60 80 100 012345 exposed to toxicit y Surgery alone Surgery plus Chemotherapy 20% % Disease Free Survival 60% 20% Moertel CG, N Engl J Med 1990 IMPACT investigators, Lancet 1995 André T, J Clin Oncol. 2009 Yothers G, J Clin Oncol 2011 Haller D, J Clin Oncol 2011

15. 15 Grade 3/4FOLFOX4 1 N=1123 FLOX 2 N=1247 XELOX 3 N=944 mFOLFOX6 4 N=1321 Neutropenia40%NR9%33% Febrile neutrop.<2%>2%<1%<2% Platelets2%NR5%3% Diarrhea11%38%19%10% Nausea5%16%5%NR HFS2%NR5%NR Neuropathy12%8%11%14% 60 day Mortality3 (0.3%)15 (1.2%)9 (1.0%)12 (0.96%) Within 6 months Oxaliplatin/FluoroP Trials - Safety Median oxaliplatin 810 mg/m2 (9.5 cycles) in the MOSAIC trial and 667 mg/m2 (7.8 cycles) in NSABP C-07 1 André T, J Clin Oncol. 2009; 2 Yothers G, J Clin Oncol 2011, 3 Haller D, J Clin Oncol 2011; 4 Allegra CJ, J Clin Oncol 2011

16. 16 Could mFOLFOX6 Regimen Replace FOLFOX4? Cycles every 14 days Dose mg/m 2 - LV m 2 (l-LV 1/2 dose) H0 H2 H24 H48 Oxali 85 FOLFOX4 5-FU 600 LV 400 5-FU 600 LV 400 5FUb 400 LV 400 5-FU 2400 Oxali 85 mFOLFOX6 5FUb 400 MOSAIC FOLFOX4: DFS at 3 years for stage 3: 72.2 % NSABP C08 mFOLFOX6: DFS at 3 years for stage 3: 75.5 % André T, N Engl J Med 2004 Allegra CJ, J Clin Oncol 2011

17. 17 Can Elderly Patients Benefit From Adjuvant Therapy?

18. 18 Can Elderly Patients Benefit from Adjuvant Therapy?: Yes for FluoroP! Adjuvant setting (meta-analysis; N=3351 (15% ≥ 70 yrs) DFS OS < 70 yrs > 70 yrs Sargent D, NEJM 2001 7 trials of 5-FU + levamisole/leucovorin vs surgery No significant interaction observed between age and efficacy of treatment

19. 19 Toxicity in Elderly with Adjuvant CT (≥ 70 Years) If Fluoropyrimidines alone, except for leucopenia, the incidence of toxic effects of chemotherapy is not higher in elderly patients For capecitabine, be careful in elderly patients (need good renal function and good follow-up) FOLFOX was well tolerated in elderly patients with only a significant increase in Grade 3-4 hematologic toxicity: neutropenia [43% vs 49%; p=0.04] and thrombocytopenia [2% vs 5%; p=0.04] Sargent D, NEJM 2001 Goldberg R, J Clin Oncol 2006

20. 20 N>70% DFS HR And CI RFS HROS HR reference C-0738816.91.17 0.94 -1.46 -1.32 1.03-1.70 Kuebler JP, J Clin Oncol 2007 MOSAIC31514.00.93 0.64-1.35 0.72 0.47–1.11 1.10 0.73-1.65 In press Tournigand C, J Clin Oncol 2012 ACCENT C-07 and MOSAIC 70315.01.04 0.80-1.35 0.92 0.69 - 1.23 1.18 0.90 – 1.57 Mc Cleary NJ, ASCO 2009, abstr 4010 XELOXA NO16968 40921.70.87 0.63-1.18 -0.94 0.66-1.34 Haller D, ASCO GI 2010, abst 284 Treatment test interaction with age for DFS is not significant in C07 (p<0.05) and in MOSAIC (p=0.418) but is significant in the ACCENT meta-analysis of the 2 studies (p=0.016) suggesting that the effect of oxaliplatin in patients younger than 70 is different from the effect in patients aged 70 or older Can Elderly Patients Benefit from Adj Therapy with Oxaliplatin?: No, but… !.

21. 21 Adjuvant CT for Stage III in Elderly Patients (> 70 years) 6 months of FU and Leucovorin (Simplified LV5FU2 or capecitabine) are the standard of care no statistically significant benefit (OS and DFS) for adding oxaliplatin to FU and Leucovorin The patient population for whom adding oxaliplatin to FluoroP is justified needs to be identified in the elderly

22. 22 Neuroprotection To prevent grade III sensory neuropathy: discontinuing oxaliplatin in case of grade 2 or 3 Level of evidence (evidence-based medicine) regarding the utility of Ca/Mg infusion for preventing oxaliplatin-induced neuropathy is low and needs additional data 1-2 In case of acute sensory neuropathy, venlafaxine? Further prospective studies are needed 3. Reduction in duration of chemotherapy is a way to reduce neurosensory neuropathy (IDEA: International Duration Evaluation of Adjuvant Chemotherapy) 1 Gamelin E, Clin Cancer Reseach 2004 2 Grothey A, J Clin Oncol 2011 3 Durand JP, Ann Oncol 2011

23. 23 Conclusion: Adjuvant Treatment for Stage III Colon Cancer in 2012: Standard patients (< 70 years old) 12 cycles of FOLFOX4 1 or mFOLFOX6 2 with oxaliplatin discontinuation in case of neuropathy grade 2 – 3 (continuing with sLV5FU2) or 8 cycles of XELOX 2 (oxaliplatin 130 mg/m 2 day 1 and capecitabine bid 1000 mg/m² x 2; day 1-14/21) Standard elderly (≥ 70 years old) 5FU/LV (12 cycles of LV5FU2 simplified) or 8 cycles of capecitabine alone (capecitabine 1000 to 1250 mg/m² x 2 for 14 days) 1 André T, N Engl J Med 2004 2 Allegra CA, J Clin Oncol 2010 3 Haller D, J Clin Oncol 2011 4 Twelves, C et al. N. Engl. J. 2005 What is the Standard?

24. 24 Thank you for your attention