Colorectal Cancer Prevention & Screening

1. Colorectal Cancer Prevention & Screening Rajeev Jain, M.D.

2. 2007 Estimated US Cancer Cases* Men766,860 Women678,060 26% Breast 15% Lung & bronchus 11% Colon & rectum 6% Uterine corpus 4% Non-Hodgkin lymphoma 4% Melanoma of skin 4% Thyroid 3% Ovary 3% Kidney 3% Leukemia 21% All Other Sites Prostate 29% Lung & bronchus 15% Colon & rectum 10% Urinary bladder 7% Non-Hodgkin 4% lymphoma Melanoma of skin 4% Kidney 4% Leukemia 3% Oral cavity 3% Pancreas 2% All Other Sites 19% *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2007.

3. 2007 Estimated US Cancer Deaths* Men289,550 Women270,100 Lung & bronchus 31% Prostate 9% Colon & rectum 9% Pancreas 6% Leukemia 4% Liver & intrahepatic 4%bile duct Esophagus 4% Urinary bladder 3% Non-Hodgkin 3% lymphoma Kidney 3% All other sites 24% 26% Lung & bronchus 15% Breast 10% Colon & rectum 6% Pancreas 6% Ovary 4% Leukemia 3% Non-Hodgkin lymphoma 3% Uterine corpus 2% Brain/ONS 2% Liver & intrahepatic bile duct 23% All other sites ONS=Other nervous system. Source: American Cancer Society, 2007.

4. Colorectal Tumorogenesis p53 18q LOH K-ras APC/ß-Catenin Normal Early Adenoma Late Adenoma Carcinoma Fearon & Vogelstein. Cell 1990.

5. Age > 50 years Inflammatory Bowel Disease Familial Adenomatous Polyposis (FAP) Syndromes Hereditary Non-polyposis Colon Cancer (HNPCC) Family History Polyps Cancer Past History Polyps Colon Cancer Ovarian Cancer Uterine Cancer Breast Cancer Colorectal CancerRisk Factors Winawer, et al. Gastro 1997.

6. Colorectal CancerRisk Factors Winawer et al. J Natl Cancer Inst 1991.

7. Familial Adenomatous Polyposis(FAP) • Autosomal dominant • Mutant APC gene • > 100 polyps • Avg age of adenoma appearance: 16 yrs • Avg age of CRC diagnosis: 39 yrs • Risk of CRC ~ 100% Winawer, et al. Gastro 2003.

8. Hereditary Nonpolyposis Colorectal Cancer(HNPCC or Lynch Syndrome) • Autosomal dominant • Mutations in DNA mismatch repair genes • In comparison to sporadic CRC: • Earlier age of onset (mean, 44 yrs) • Right-sided • Synchronous or metachronous lesions • Poorly differentiated histology

9. CRC & Ulcerative Colitis Eaden, et al. Gut 2001.

10. Colorectal CancerUlcerative colitis & Crohn’s colitis • Risk of developing CRC increases with: • Duration of disease • Young age at diagnosis • Extent of disease • Primary sclerosing cholangitis (PSC) • Familial association Munkholm P. Aliment Pharmacol Ther 2003.

11. Colorectal CancerAge-Specific Incidence SEER 1973-1992.

12. Colorectal CancerIncidence with Positive Family History Mecklin et al. Gastro 1986.

13. Colon CancerFamilial Risk Burt. Gastro 2000.

14. Colon CancerRisk After Gynecologic Cancer Weinberg et al. Ann Intern Med 1999.

15. Distribution of Polyps & Cancer Adenomatous Polyps Adenocarcinoma 11% 11% 13% 9% 18% 6% 7% 13% 52% 55% Winawer, et al. Gastro 1997.

16. Colorectal CancerSummary of Risk Factors • Highest Risk • Genetic syndromes (FAP & HNPCC) • Inflammatory bowel disease • High Risk • Family history of polyps and/or CRC • Average Risk

17. Colorectal Cancer PREVENTION Dietary Habits Medical Therapy

18. Colorectal Cancer • Western countries have 10x risk for colon cancer in comparison to Asian & other developing countries. • Rapid increases in rates of colon cancer are found in: • migrants from low-risk to high-risk areas. • Japan since World War II.

19. Colorectal CancerDietary Hypotheses Conversion to secondary bile acids deoxycholic & lithocolic acid Excretion of bile acids Colorectal carcinogenesis Fiber RISK Animal Fat

20. Colon Cancer & Animal Fat Intake Willet et al. NEJM 1990.

21. Colon Cancer & Dietary FiberPossible Mechanisms of Action • Increased bulk of stool • Dilution of potential carcinogens • Decrease in transit time • Binding with potential carcinogens • Lowers fecal pH • Alters colonic flora • Fermentation by fecal flora to SCFA’s Kim. Gastro 2000.

22. Colon Cancer & Dietary Fiber • Current evidence (epidemiological, animal, and interventional studies) is supportive of an inverse association between dietary fiber intake and CRC risk. • Protective effects seen at 30-35 gm/d (US mean 11.1 gm/d) • Intervention should begin 10-20 yrs before the peak age for CRC incidence. Kim. Gastro 2000.

23. Colon Cancer & DietWhat should we tell our patients ? • Nutritional education • Low animal fat • High fiber • Fiber supplementation (goal of 25 – 35 gm fiber/day) • Other lifestyle modifications • Weight loss • Physical activity • Avoid tobacco

24. Colorectal CancerProtectiveMicronutrients ? • Calcium and Vitamin D • Folic acid • Vitamins A, C, and E • Selenium • Curcumin

25. Colorectal CancerChemopreventive Agents • ASA & NSAIDs • Folate • Calcium • Estrogens

26. Chemoprevention with ASAU.S. Preventive Services Task Force • Colonic adenomas • RR 0.82 [95%CI, 0.70 – 0.95] RCTs • RR 0.87 [95%CI, 0.77 – 0.98] Case-control • RR 0.72 [95%CI, 0.61 – 0.85] Cohort • Colon cancer • 22% RR in cohort studies • 2 RCTs no protective benefit at low doses • Benefits seen with higher doses and for periods longer than 10 years • The USPSTF recommends against the routine use of ASA/NSAIDs to prevent CRC in average risk patients. Dube C et al. Ann Int Med 146:365-75, 2007.

27. ChemopreventionFolate • Mechanism unknown • Colorectal adenomas • Prospective cohort study (25,474 pts) • Folate 400 ug QD • 29% risk reduction • Colorectal cancer • Prospective cohort study (88,756 pts) • Folate in a multivitamin preparation • 75% risk reduction after 15 yrs

28. ChemopreventionCalcium • Mechanism • binding of bile and fatty acids • inhibit colorectal epithelium proliferation • Case-control and cohort studies show inverse relationship between calcium intake and CRC • imprecise assessment of calcium intake • confounding factors • RCT • 930 pts with h/o adenomas • 3 gm Ca carbonate (1200 mg elemental Ca) • Serial colonoscopy 1 and 4 yrs after randomization • 15% reduction in adenoma formation Baron et al. NEJM 1999.

29. ChemopreventionEstrogens • 1.Cancer Prevention Study II • 422,373 patients • End point – Death • 2.Nurses’ Health Study • 59,002 patients • End point - Cancer Calle et al. J Natl Cancer Inst 1995. Grodstein et al. Ann Intern Med 1998.

30. Colorectal Cancer Prevention • Dietary habits • Increase fiber intake • Decrease animal fat intake • Chemoprevention • Not enough data to firmly recommend

31. Definitions Screening: search for neoplasia in asymptomatic population with no prior neoplasia Surveillance: evaluation of patients with prior colorectal adenomas or cancer, or with IBD Diagnosis: evaluation of symptomatic patients and patients with positive screening tests

32. CRC Screening • Only 26% of eligible population has had FOBT within 3 yrs; 33% have never had FOBT • Most common reason given: test was never recommended • Of those offered screening, only 4% decline • Cancer Prevention Study (CPS) II Nutrition Cohort, cross-sectional data from 1997 • Men 86,404; women 97,786 • 42% men & 31% women underwent screening FS or colonoscopy • In pts > 50 yrs, 33% had undergone FS/C in 1999. By 2004, 52% had undergone screening FS/C. Vernon, J Natl Cancer Inst 1997. Leard et al, J Fam Prac 1997. Chao, Am J Public Health 2004. Smith,CA Cancer J Clin 2006.

33. CRC Screening • Women who underwent screening mammography and Pap smear • 52% underwent CRC screening • Men who underwent prostate cancer screening with PSA • 65% underwent CRC screening Carlos, Acad Radiol 2005. Carlos, J Am Coll Surg 2005.

34. Medicolegal Issues • Delay in diagnosis of CRC accounts for >50% of all litigation against PCPs for GI disease • Attributing rectal bleeding to hemorrhoids • Inadequate evaluation of positive FOBT • Failure to screen Gerstenberger & Plumeri. Gastrointest Endosc 1993.

35. Risk Stratification • Has the patient had colorectal cancer or an adenomatous polyp? • Does the patient have an illness that predisposes him or her to colorectal cancer? • Has a family member had colorectal cancer or an adenomatous polyp? Winawer et al. Gastroenterology 2003.

36. Screening Tests for Colorectal Cancer • Fecal occult blood test • Flexible sigmoidoscopy • Double-contrast barium enema • Colonoscopy

37. Fecal Occult Blood Tests • Rationale: colorectal cancers bleed • Guaiac-based • pseudoperoxidase activity of hemoglobin • Immunochemical • antibodies to human globin epitopes • Heme-porphyrin • hemoglobin derived porphyrin

38. Fecal Occult-Blood Tests Rockey. NEJM 1999.

39. Fecal Occult-Blood Tests Rockey. NEJM 1999.

40. Fecal Occult-Blood Tests Rockey. NEJM 1999.

41. Fecal Occult-Blood Tests Rockey. NEJM 1999.

42. Guaiac-based FOBT • 2 slides from 3 consecutive bowel movements • Dietary & medication restrictions • Slides should NOT be rehydrated • Slides should be stored at room temperature & developed within 7 days

43. Fecal Occult-Blood TestsComparison of RCTs Towler et al. BMJ 1998.

44. Screening SigmoidoscopyCase-Control Studies Selby et al. NEJM 1993. Newcomb et al. NEJM 1993. Muller & Sonnenberg. Arch Int Med 1995.

45. Observed and Expected CRC Incidence after Polypectomy Winawer et al. NEJM 1993.

46. ColonoscopyCase-Control Study Muller & Sonnenberg. Ann Intern Med 1995.

47. Screening Colonoscopy Lieberman et al. NEJM 2000. Imperiale et al. NEJM 2000.

48. Major Complication Rates of Screening Tests Winawer, et al. Gastro 1997.

49. Colorectal CancerInnovative Screening Techniques • Targeting exfoliated markers • Fecal • colonocytes • DNA • Immunochemical assays • p53 • CEA

50. Colorectal CancerInnovative Screening Techniques • Virtual colonoscopy (computed tomographic colonography). • Thin-section helical CT & air insufflation generating 2-D images converted to 3-D images. • Results of recent study (100 pts) • Cancer: 100% • Polyps > 10 mm: 91% • Polyps 6 – 9 mm: 82% • Polyps < 5: 55% Fenlon, et al. NEJM 1999.