1. J. Macdonald, CRC Symposium, 1.23.2001 Oncology Spectrums, NYC Overview of Colorectal Cancer, Recent Studies, and Trial Design John S. Macdonald, MD Saint Vincent’s Comprehensive Cancer Center

2. J. Macdonald, CRC Symposium, 1.23.2001 Oncology Spectrums, NYC Cancer Incidence/Death IncidenceDeath Total (all cancers)1,220,100552,200 GI cancers 1.Large bowel 133,600 56,200 2.Pancreas 28,300 28,200 3.Stomach 21,500 13,000 4.Liver 15,300 13,800 5.Esophagus 12,300 12,100 6.Biliary 6,900 3,400 Greenlee RT, et al. Cancer Statistics 2000. CA: A Journal for Clinicians. 2000;50:7-33.

3. J. Macdonald, CRC Symposium, 1.23.2001 Oncology Spectrums, NYC Colorectal Cancer Etiology Population risk:Lifestyle Dietary Personal risk:Genetic Prevention:Long-term dietary modification Medical model: NSAIDs/ASA/others APCFNPCC

4. J. Macdonald, CRC Symposium, 1.23.2001 Oncology Spectrums, NYC Genetic Alterations Most Commonly Associated With Colorectal Cancer Dominant oncogenes c-srcc-src K-rasK-ras C-mycC-myc Tumor suppressor genes MCC (mutated in colorectal cancer)MCC (mutated in colorectal cancer) DCC (deleted in colorectal cancer)DCC (deleted in colorectal cancer) APC (adenomatosis polyposis coli)APC (adenomatosis polyposis coli) p53p53 DNA repair genes MSH2MSH2Prognosis MSIMSI

5. J. Macdonald, CRC Symposium, 1.23.2001 Oncology Spectrums, NYC Phase III Study Colon Cancer 683Advanced Cases RANDOM CPT-115-FU Leucovorin (222 cases) 5-FU Leucovorin (221 cases) CPT-11 (223 cases) Saltz, et al. NEJM 2000;343:905.

6. J. Macdonald, CRC Symposium, 1.23.2001 Oncology Spectrums, NYC Phase III Colon Cancer Toxicity  Gr 3 Regimen Cases RR PFS Diarrhea Mucositis ANCSurvival (N) (%) (%) (%) (%) (months) (N) (%) (%) (%) (%) (months)CPT-11/ 5-FU/LV 231 39* 7.0** 22 2.2 5414.8 *** 5-FU/LV 226 21 4.3 13 16.9 66 12.6 CPT-11 22618 4.2 312.2 31 12.0 * P<0.001 * P<0.001 ** P =0.004 ** P =0.004 *** P =0.04 *** P =0.04 Saltz, et al. NEJM 2000;343:905.

7. J. Macdonald, CRC Symposium, 1.23.2001 Oncology Spectrums, NYC Colorectal Cancer Current Adjuvant Study 5-FU 500 mg/m 2 Leucovorin 500 mg/m 2 weekly x6 followed by 2 weeks rest (4 cycles=32 weeks) 5-FU 500 mg/m 2 Leucovorin 20 mg/m 2 CPT-11 125 mg/m 2 weekly x4 followed by 2 weeks rest (5 cycles=30 weeks) RANDOM

8. J. Macdonald, CRC Symposium, 1.23.2001 Oncology Spectrums, NYC Structure Water-soluble platinum derivative with an oxalato ligand and a 1,2-diaminocyclohexane (DACH) carrier The DACH carrier ligand can exist in 3 stereochemical conformations: oxaliplatin (I-OHP) Pt(oxalato)(trans-I-dach) Pt(oxalato)(1R,2R-dach) MW 397.3

9. J. Macdonald, CRC Symposium, 1.23.2001 Oncology Spectrums, NYC Colorectal Cancer De Gramont survival and responseDe Gramont survival and response Survival PFS Response Survival PFS Response (Months)(Months) (%) (Months)(Months) (%) 5-FU/Leucovorin 14.7 6.0 28.6 5-FU/Leucovorin 14.7 6.0 28.6 5-FU/Leucovorin/ 5-FU/Leucovorin/ Oxaliplatin 16.2 8.2 49.5 Oxaliplatin 16.2 8.2 49.5 P=NS P=NS P=0.0001 P=0.0001 De Gramont, et al.: JCO 2000;18:2968. P=0.0003 P=0.0003

10. J. Macdonald, CRC Symposium, 1.23.2001 Oncology Spectrums, NYC NSABP C07 ARM 1 LeucovorinLeucovorin –500 mg/m 2 /2 hours 5FU5FU –500 mg/m 2 bolus –1 hour into leucovorin (GITSG schedule)(GITSG schedule) Weekly, 6 weeks/8Weekly, 6 weeks/8 Total of 3 cyclesTotal of 3 cycles ARM 2 5FU/leucovorin5FU/leucovorin –Same as Arm 1 –Weeks 1 though 6 of 8 OxaliplatinOxaliplatin –85 mg/m 2 –Weeks 1, 3, and 5 Total of 3 cyclesTotal of 3 cycles

11. J. Macdonald, CRC Symposium, 1.23.2001 Oncology Spectrums, NYC Oral Fluorinated Pyrimidines Advantages Oral Route Pharmacokinetics Radiation Sensitization

12. J. Macdonald, CRC Symposium, 1.23.2001 Oncology Spectrums, NYC Oral Fluorinated Pyrimidines UFT5-FU/776S-1Capecitabine 5'-deoxy-5- fluorouridine DPDinhibitionProdrugs

13. J. Macdonald, CRC Symposium, 1.23.2001 Oncology Spectrums, NYC Updated Survival HR*: 0.96 (95.6%; CI=0.83-1.13) * Ratio 5-FU/LV:UFT/LV

14. J. Macdonald, CRC Symposium, 1.23.2001 Oncology Spectrums, NYC Phase III Study Capecitabine Response RegimenCases PR Duration PFS SAE (N) % monthsmonths % (N) % monthsmonths %Capecitabine 2500 mg/m 2 /d 26.6 x14 days 301 (2.3% CR) 7.3 5.312.5 5-FU/LV Mayo 17.9 Regimen 301 (2.3% CR) 9.6 4.817.7 Twelves, et al. Proc ASCO. 1999;18:263.

15. J. Macdonald, CRC Symposium, 1.23.2001 Oncology Spectrums, NYC Cusp of the future CyanidesArsenicals Heavy metals XRTAlkylatorsAntimetabolites Tumor suppressor gene products EGFRAnti-angiogenesisAnti-RASAnti-sense Gene Rx Penicillin ID - 1900 Oncology - 2000