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Discussion abstracts 4006-4009

Discussion abstracts 4006-4009. Alberto Sobrero MD Ospedale San Martino Genoa , Italy. Abstracts 4006-4009. Meyers 4006 l.node ratio Rectal De Gramont 4007 Mosaic Colon Sargent 4008 early DFS Colon O’ Connell 4009 Px factors Colon . very predictable results

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Discussion abstracts 4006-4009

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  1. Discussion abstracts4006-4009 Alberto Sobrero MD Ospedale San Martino Genoa , Italy

  2. Abstracts 4006-4009 Meyers 4006 l.node ratio Rectal De Gramont 4007 Mosaic Colon Sargent 4008 early DFS Colon O’ Connell 4009 Px factors Colon very predictable results highly plausible

  3. 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” THE LYMPH NODE WORLD OF THE SURGEON & PATHOLOGIST

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

  5. RATIO OF METASTATIC /EXAMINED LYMPH NODES Colon CancerBerger , J Clin Oncol,2005Gastric CancerInoue , Ann Surg Oncol, 2002PancreaticCancer Slidell, SEER database

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

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

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

  9. 1.0 FOLFOX4 LV5FU2 0.9 0.8 0.7 0.6 Probability 0.5 0.4 0.3 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 Months Disease-free Survival: ITT HR [95% CI]: 0.80 [0.68–0.93] p=0.003 Data cut-off: June 2006

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

  11. 1.0 FOLFOX4 LV5FU2 0.9 0.8 0.7 0.6 Probability 0.5 0.4 0.3 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Months Overall Survival: ITT HR [95% CI]: 0.85 [0.72–1.01] p=0.057 Data cut-off: January 2007

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

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

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

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

  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. 4009, O’ Connell • Impact of “hystorical” clinical px factors on outcome HR, survival • RFS > 3 yrs 0.6 • Initial stage II 0.6 • No adjuvant 0.8 • Impact of therapy on outcome • Beva + IFL 0.6 • Beva + folfox 0.8 (PFS) • Cetuximab+ Irinot. 0.7 (PFS) • Clinically relevant treatment effects may be about the same magnitude as potential biases !

  19. 1.0 FOLFOX4 LV5FU2 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 Time from Relapse to Death: ITT Probability Patients alive with relapse (%) FOLFOX4 69 (6.1) LV5FU2 88 (7.8) Months Data cut-off: January 2007

  20. 4009, O’ Connell : implications • 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 • 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 • Relevant ΔDFS • Consistent with NSABP C-07 • OS benefit BUT • 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 .005 7.5% II high risk .74 ns 7.2% II and III .80 .003 5.9% II .84 ns 3.8%

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

  25. UK QUASAR2: adjuvant Cape± Bevacizumab Cape 8 cycles (24 weeks) Stage II/III colon cancer n=3510 Cape 8 cycles (24 weeks) Bevacizumab 16 cycles (48 weeks)

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

  27. Peripheral Sensory Neuropathy Grade 1 60 Grade 2 Grade 3 48.1 50 % of treated patients 40 27.6 17.4 14.2 11.4 31.4 30.9 30 22.2 20 14 12.5 12 8.8 10 7.2 4.2 2.9 2.1 1.7 1.4 1.2 0.5 0.5 0.5 0 During Tx 6 months 1 year 2 years 3 years 4 years

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