1. N ational S urgical A djuvant B reast and B owel P roject

2. Oxaliplatin, Fluorouracil, and Leucovorin as Adjuvant Treatment for Colon Cancer Thierry André, M.D., Corrado Boni, M.D., Lamia Mounedji-Boudiaf, M.D.,Matilde Navarro, M.D., Josep Tabernero, M.D., Tamas Hickish, M.D.,Clare Topham, M.D., Marta Zaninelli, M.D., Philip Clingan, M.D., John Bridgewater, M.D., Isabelle Tabah-Fisch, M.D.,and Aimery de Gramont, M.D., for the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators

3. Mayo v. RPMI Bolus v. Infusion of 5FU Efficacy of levamisole High v. Low dose levamisole, LV Dukes’ B v C American v. European Advocacy neglect Consensus statement abstinence Paucity of trials 1993-2003: A Decade of Decadence

4. Two Steps Forward in the Treatment of Colorectal Cancer EDITORIAL New England Journal of Medicine

5. Curative Options for Colorectal Cancer: Folklore, fables, and mythes Curative Options for Colorectal Cancer: Folklore, fables, and mythes

6. Variations on a theme of B (minor)

7. On November 4, 2004, the FDA approved oxaliplatin in combination with infusional FULV for adjuvant stage III colon cancer.

8. The Global test for interaction between treatment and tumor stage (II+III) was not significant (p=0.71)

9. INT 0035 ’85-’87 Dukes B Dukes C Control FU+LEV LEV n=318 n=929

10. NSABP DeathRecurrenceDFS event Stage II 0.512.00.512.00.512.0 All patients Stage III Pooled analysis of NSABP C-01 through C-04

11. INT 0035 Dukes B RFS 159 Cont FuLev % P = 0.10 Yrs. 70 78 45 32 31% reduction in recurrence Source: Moertel CG et al. J Clin Oncol 1995;13(12):2936-43.

12. COMBINED ANALYSIS 11.77-12.90 C-01 C-02 C-03 C-04 OP MOF FU+LEV MOF PVI FU+LV Treatment 1Treatment 2 N = 1924N = 1896 Vs 0.05 0.02 <0.001 0.03 JCO 1999;17:1349

13. PATIENT POPULATION DUKES’ B 1567 DUKES’ C 2254 JCO 1999;17:1349

14. American Society of Clinical Oncology Recommendations on Adjuvant Chemotherapy for Stage II Colon Cancer Al B. Benson III, Deborah Schrag, Mark R. Somerfield, Alfred M. Cohen, Alvaro T. Figueredo, Patrick J. Flynn, Monika K. Krzyzanowska, Jean Maroun, Pamela McAllister, Eric Van Cutsem, Melissa Brouwers, Manya Charette, and Daniel G. Haller

15. 'Uncertain indication' for chemotherapy (3239 patients ’94 -’03 MTS 4.6 yrs) Observation (n=1617) FULV ± Lev (n=1622) Randomize Quick & Simple & Reliable Richard G. Gray MS 92% Dukes B

16. Quasar Survival n dths 5yS p Chemo 1622 281 80.3 0.02 None 1617 328 77.4 Source: With permission. Gray RG et al. Presentation. ASCO 2004. Abstract 3501.

17. Quasar Dukes B Survival dths p Chemo 224 0.04 None 262 Source: With permission. Gray RG et al. Presentation. ASCO 2004. Abstract 3501.

18. Stage II: Putative Prognostic Discriminates MSI Allelic instability (18q del) Venous invasion T differentiation Number N examined (ignored or absent) High Risk Stage II Mayo algorithm

19. Gene Identification: C-01/C-02 Univariate analysis 142 of 757 genes were associated with RFS (p<0.05)

20. Gene Identification: C-01/C-02 Multivariate analysis Individual Genes # Pos Nodes Tumor Grade Tumor Location 66 of the 142 genes retained independent significance (p<0.05)

21. % risk reduction Survey: N=150 pt with CRC Cum % rec treatment Love N. Asco GI 2006

22. Survey: N=150 pt with CRC Love N. Asco GI 2006 # 373 FFox 68% Cape 21% FU 10% None 1% Stage II FFox 87% 6% None 1% Stage III

23. % risk reduction Survey: N=100 Medical Oncologists % likely to treat Love N. Asco GI 2006 Breast CRC