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Chemoprevention of Colorectal Cancer 2011

Chemoprevention of Colorectal Cancer 2011. First Tirana Mediterranean Cancer Congress Tirana, April 29-30, 2011. Background. Colon Cancer: Second most common cancer in developed countries Lifetime risk of 5% 1 million new cases/year 600,000 deaths/year. Background. . Early detection

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Chemoprevention of Colorectal Cancer 2011

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  1. Chemoprevention of Colorectal Cancer 2011 First Tirana Mediterranean Cancer Congress Tirana, April 29-30, 2011

  2. Background Colon Cancer: • Second most common cancer in developed countries • Lifetime risk of 5% • 1 million new cases/year • 600,000 deaths/year

  3. Background . • Early detection • Chemo prevention ,using long term oral agents ,nutritional supplements ,or pharmacological elements that can prevent adenoma development and subsequent progress to cancer

  4. Candidates Fiber. Calcium / Vitamin D. Folate. Antioxidants. Aspirin / NSAIDs. Postmenopausal hormones.

  5. Fiber Mechanism - May bind fecal carcinogens. May alter bile acid metabolism. May ↓ colonic Ph. May ↑ production of short-chain fatty acids. May modulate insulin secretion. Data from case-control studies suggest ↓ risk. Meta-analysis of 13 studies, 47% ↓ risk. Data from cohort studies are only weakly supportive or null.

  6. Fiber and Adenoma Trails

  7. Calcium Mechanism: May bind carcinogenic bile acids. May directly inhabit colonic proliferation. Meta-analysis of observational studies suggests↓14% risk of cancer.

  8. Calcium and Adenoma Trials

  9. Plasma 25(OH)D and Colorectal CancerColorectal Cancer: Serum Studies

  10. Vitamin D + Calcium Trial – All Cancers RR for Ca + D = 0.23 (Cl:0.09, 0.60)lappe Am j clin nut2007

  11. Folate Several observational studies show lower risk of colorectal cancer associated with deity folate and folate supplements. Mechanism: Folic acid and metabolites vital for DNA repair.

  12. Folic Acid and Adenoma Trials Baseline plasma folate level

  13. Candidates Antioxidants no evidence Selenium alone or with vitamin E Beta carotene ,vitamin C, E . Diet rich in fruits and vegetables. Meta analyses of randomized trials failed to find effect in reducing incidence of G/I cancers.

  14. COX-2 and The Adenoma-Carcinoma Sequence Based on Eberhart et al , Gastroenterology 1994

  15. Background Journal of Clinical Oncology, 2005 ASCO Vol 23, No 16S (June 1 Supplement), 2005: 3530 Regular aspirin use for at least 5 to 10 years is associated with lower colorectal cancer (CRC) incidence, fewer polyps detected by colonoscopy, and fewer recurrent adenomas.

  16. Mechanisms of Action of Aspirin, Other Nonsteroidal Anti inflammatory Drugs, and Selective Cyclooxygenase-2 (COX-2) Inhibitors Janne P and Mayer R. N Engl J Med 2000;342:1960-1968

  17. Background • Numerous observational and randomized trials that ASA reduce risk of Colon cancer • Mechanism of action COX-2 • Tumor differentiation • Angiogenesis • Recurrence and metastasis • 80-85% over expressed in colon cancers

  18. Aspirin and Adenoma Trials

  19. ResultsEffect of aspirin (75-1200 mg) vs control on long term risk of colon cancer

  20. Colon Carcinogenesis and the Effects of Chemopreventive Agents Janne P and Mayer R. N Engl J Med 2000;342:1960-1968

  21. Adenoma Carcinoma sequence

  22. Duration of Aspirin Use and Risk of Colorectal Cancer P for trend = <0.0001

  23. Dose of Aspirin and Risk of Colorectal Cancer P trend= 0.0003

  24. Aspirin and Risk of Cancer By COX-2 Expression P heterogeity = 0.02

  25. Conclusion • Aspirin taken for several years (75mg) reduced • Long term incidence • Mortality due to colon cancer • Greatest benefit was seen in the proximal colon. • Latent period of 7-8 years • Dose of <30mg no benefit

  26. Celecoxib and Risk of Recurrent Adenoma

  27. Celecoxib and Risk of Cardiovascular Events

  28. 120 participants would need to be treated for at least 5 years to prevent 1 case of colorectal cancer. • 1/25 treat people with aspirin to cause any bleed. NNH • Risk of bleed per person 18% per five years.

  29. Hormone Replacement Mechanism: ↓Bile acid flow  ↓ concentration of carcinogenic bile acids. ↓Circulating IGF-1 levels. May inhabit DNA mismatch errors. Observational studies: HRT ↓ CRC Ever use: ~ 20% ↓ in risk. Current use: ~ 34% ↓ in risk.

  30. Women’s Health Initiative Overall relative risk of colorectal cancer in HRT users: 0.56 (0.38-0.81) Chlebowski, NEJM 2004

  31. Take home message Bleeding Aspirin

  32. Exposure : Celecoxib (COX2) • Outcome: tumor growth • Population: Mouse and cancer cell lines • Results: • blocks growth of colon cancer cells • Numerous mouse studies and cell line studies replicated that NEJM Arber N 2006.355;9 CANCER RESEARCH 60, 6045–6051, 2000

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