1. Discussion abstracts 4006-4009 Alberto Sobrero MD Ospedale San Martino Genoa, Italy

2. Abstracts 4006-4009 Meyers4006l.node ratioRectal De Gramont4007Mosaic Colon Sargent4008early DFSColon O’ Connell4009Px factorsColon

3. THE LYMPH NODE WORLD OF THE SURGEON & PATHOLOGIST Surgeon “ What do you mean there were only 4 l.-nodes in the rectal cancer specimen?” Pathologist “ That is all I could find “ Surgeon “Perhaps you ought to look harder “ Pathologist “Perhaps you ought to work harder at surgery”

4. Ratio of Metastatic/ Examined Lymph Nodes: Predictor of Overall Survival in Rectal Cancer LN ratio was the strongest predictor of overall survival. Predicts survival whether N1, N2, small or large number of LN’s examined

5. RATIO OF METASTATIC /EXAMINED LYMPH NODES Colon Cancer Berger, J Clin Oncol,2005 Gastric Cancer Inoue, Ann Surg Oncol, 2002 Pancreatic Cancer Slidell, SEER database

6. 4006, Meyers : implications Trials- Stratification factor Practice- empyrical evidence of what has been common practice

7. 4008, Sargent 1.Adjuvant FU CT prevents most relapses within 2 years 2.Benefit DFS  benefit OS  adjuvant FU CT:curative 3.Chances of recurring after 5 yrs < 5% 4.Standard approaches to trial design : OK

8. 4008, Sargent 1.Adjuvant FU CT prevents most relapses within 2 years 2.Benefit DFS  benefit OS  adjuvant FU CT:curative 3.Chances of recurring after 5 yrs < 5% 4.Standard approaches to trial design : OK

9. Disease-free Survival: ITT Data cut-off: June 2006 HR [95% CI]: 0.80 [0.68–0.93] p=0.003 Months FOLFOX4 LV5FU2 Probability 1.0 0.8 0.6 0.4 0.2 0 0.9 0.7 0.5 0.3 0.1 06121824603036424854

10. NSABP C-07 : DFS FLOX FU LV YEARS

11. Overall Survival: ITT HR [95% CI]: 0.85 [0.72–1.01] p=0.057 Data cut-off: January 2007 Months FOLFOX4 LV5FU2 Probability 1.0 0.8 0.6 0.4 0.2 0 0.9 0.7 0.5 0.3 0.1 06121824603036424854669672788490

12. 4008, Sargent 1.Adjuvant FU CT prevents most relapses within 2 years 2.Benefit DFS  benefit OS  adjuvant FU CT:curative 3.Chances of recurring after 5 yrs < 5% 4.Standard approaches to trial design : OK

13. Biologics in the adjuvant setting : the Trastuzumab experience early DFS early OS long term OS YesYes ? CAUTION: BIOLOGICS MAY IMPACT DFS DIFFERENTLY

14. 4008, Sargent 1.Benefit DFS within 2 years, not later 2.Benefit DFS  benefit OS  adjuvant CT:curative 3.Chances of recurring after 5 yrs < 5% 4.Standard exponential model is OK

15. CM923700-15 Time to recurrence curve flattens after 5 years(Moertel et al,NEJM 1990) FU levamisole control % pts free from recurrence Years from registration 1 2 3 4 5 6 7 8 9

16. CM923700-16 DFS curve continues to decline (Haller et al,JCO 2005) INT 0089 FU based adjuvant regimens

17. 4008, Sargent: implications Trials –early DFS as endpoint in CT trials : OK –early DFS as endpoint in trials on bio: careful –RFS vs DFS (Punt et al. JNCI 2007) Practice –No relapse within 5 yrs  “celebrate!” (1/20) –Long term F/U  Yes, but different –If late relapses rare  be sure of diagnosis !

18. Impact of “hystorical” clinical px factors on outcome HR, survival –RFS > 3 yrs0.6 –Initial stage II0.6 –No adjuvant0.8 Impact of therapy on outcome –Beva + IFL0.6 –Beva + folfox0.8(PFS) –Cetuximab+ Irinot.0.7(PFS) Clinically relevant treatment effects may be about the same magnitude as potential biases ! 4009, O’ Connell

19. Time from Relapse to Death: ITT Patients alive with relapse (%) FOLFOX4 69 (6.1) LV5FU2 88 (7.8) Months Probability 1.0 0.8 0.6 0.4 0.2 0 0.9 0.7 0.5 0.3 0.1 FOLFOX4 LV5FU2 0612182460303642485466847278 Data cut-off: January 2007

20. 4009, O’ Connell : implications 1.Trials Inadequacy of stage IV definition Room for improvement of px assessment on clinical ground –Combining historical and classical If px groups can be better identified: –Single arm phase II in poor px patients ….? –Window of op. trials with bio single agent in good px pts 2.Practice general paradigm for non surgical stage IV –lines of treatment vs continuum of care FOCUS, LIFE, CAIRO, GISCAD, OPTIMOX 2

21. 4007, De Gramont : Mosaic 1.Relevant Δ DFS 2.Consistent with NSABP C-07 3.OS benefit BUT 4.Substantial neuro toxicity (11.4% at 4 yrs)

22. How much absolute reduction in recurrence makes adjuvant CT worth for patients ( N= 150)? 1/3 = 1% 2/3 = 5% N. Love, ASCO 2007

23. Mosaic: 5-YR DFS Stage HR Δ III.78.0057.5% II high risk.74 ns7.2% II and III.80.0035.9% II.84 ns3.8%

24. Future of adjuvant folfox 1.Combination with biologics Bevacizumab ( Avant, NSABP C-08) Cetuximab ( Petacc-8, NO146) 2.Reduce neurotoxicity Reduce duration ( Italian 3 vs 6; SCOT) Use of neuroprotectors ( Xaliproden) 3.Limit oxali to high risk patients 4.No oxali Quasar 2

25. UK QUASAR2: adjuvant Cape ± Bevacizumab Cape 8 cycles (24 weeks) Cape 8 cycles (24 weeks) Bevacizumab 16 cycles (48 weeks) Stage II / III colon cancer n=3 510

26. Relevance: conclusion TRIALS PRACTICE L. Node ratio + - Folfox -+ early DFS ?+ Clin. Px factors ++ ++

27. Peripheral Sensory Neuropathy % of treated patients 48.1 30.9 22.2 14 12 8.8 31.4 7.2 4.2 2.9 1.7 2.1 12.5 1.4 1.2 0.5 0 10 20 30 40 50 60 During Tx6 months1 year2 years3 years4 years Grade 1 Grade 2 Grade 3 27.6 17.4 14.2 11.4