COLORECTAL CANCER SCREENING in December of 2002

1. COLORECTAL CANCER SCREENING in December of 2002 Jeffrey W. Frank, MD

2. Colon Cancer ScreeningWhy Screen? • 2nd leading cause of cancer deaths in the USA • 1 in 20 over the age of 50 will develop colorectal cancer in lifetime • Pre-malignant lesion - the adenomatous polyp • Removal of adenomas prevents cancer • Established cancer generally progresses slowly and early stages are curable

3. COLORECTAL NEOPLASIAAdenoma/Carcinoma Sequence 1. Mismatch repair genes (HNPCC) Kras DCC 2. APC (both alleles) Normal Epithelium Hyperproliferative Epithelium ADENOMA p53 (17p) other factors CARCINOMA METASTASIS

4. 15% 15% 10% 50% 25% 35% 50% COLORECTAL NEOPLASIADistribution ADENOMAS CARCINOMAS

5. Colorectal Cancer ScreeningWho should be screened? Asymptomatic Symptomatic AGE most important High risk groups Distal adenomas Race Gender

6. Colorectal Cancer ScreeningAge - the most important factor • 90% of colon cancer in age >50 • Benign adenomas are more prevalent after age 50 and especially after age 60 • Chances of finding a polyp is about 25% • Proximal colon cancers increase with age

7. Age and Colorectal Cancer Winawer SJ. Gastro 1997 ColonCancer Adenomas

8. Colorectal Cancer ScreeningDo distal polyps predict proximal polyps? • Patients who have distal adenomas have a 3-6% chance of having a significant proximal adenoma • >2/3 of patients with proximal cancer will not have a distal polyp • Therefore, distal adenomas are insensitive markers for proximal lesions and proximal lesions are unassociated with distal lesions Schoen RE, Gastro 1998 Rex DK, Gastroentest Endosc 1999

9. COLORECTAL NEOPLASIAPathologic Subtypes Probability of Malignancy

10. 80% sporadic; 20% genetic Of genetic Cancers: 1% FAP 6% HNPCC 10-15% familial Lifetime risk: Average American- 6% One1st degree relative >50 - 12% One1st degree relative <50 - 22% Two1st degree relatives - 34% One2nd degree relative - 9% One3rd degree relative - 7% Average risk Ashkenazic Jew - 9% Ashkenazic Jew with FH and APC gene mutation - 28% Women with h/o Breast or Genital cancer - 10% COLORECTAL NEOPLASIAHeritability

11. HNPCC • Amsterdam Criteria-II • 3 or more relatives with a histologically verified HNPCC-associated cancer (colorectal, endometrial, small bowel, ureter or renal pelvis), one of whom is a first-degree relative of the other two; AND • Colorectal cancer involving at least two generations; AND • One or more colorectal cancer cases diagnosed before the age of 50

12. COLORECTAL NEOPLASIAAssociations • Risk Factors: • high serum cholesterol • high saturated fat diet • high “red” meat diet • increased bowel anerobic flora • increased colon pH • low fiber diet • obesity • smoking

13. COLORECTAL NEOPLASIAChemoprevention • ?Fiber • Low red meat (animal fat) • Folic acid • Calcium/vitamin D • Selenium • Omega-3 fatty acids • ?NSAIDs

14. Nonparticipation estimated 50% of population to be screened will not participate Screening insensitivity FOBT miss rate ~ 70% Incomplete colorectal evaluation estimated 33% with positive FOBT will not undergo complete evaluation Old Age ~20% of colorectal cancers are found in patients older than age 80 detecting asymptomatic cancers may not benefit them Advanced Stage estimated 25% of asymptomatic cancers are stage C or D Lead-Time Artifact estimated 50% of asymptomatic cancers remain stage A or B when symptoms develop Screen-Related Mortality false negatives with false reassurance, delayed diagnosis false positives subject to anxiety, lost work days, procedure morbidity and mortality Screening Populations for Colorectal CancerObstacles

15. FOBT in a Simulated Population at Moderate Risk for Colorectal CancerAdapted from Ahlquist DA, Cancer (Supplement), 1992 Assumed target population of 20,000 persons 50 yrs or older. At expected prevalence of 0.5%, an estimated 100 colorectal cancers would be present at the time of screening

16. Colorectal Cancer ScreeningMethods of Screening • Tests of Fecal Occult Blood • Digital rectal exam • Flexible Sigmoidoscopy • Barium Enema (SCBE vs DCBE) • Colonoscopy • “Virtual Colonoscopy”

17. Tests of Fecal Occult Blood • False Positives Occur - Specificity 90-98% (2-10% false positive) • many lesions bleed • dietary factors • False Negatives Occur - Sensitivity 38-92% (high false negative rate) • not all cancers bleed • reducing substances false neg (Vitamin C)

18. Tests of Fecal Occult Blood • Annual FOBT reduces mortality from CRC by 15-33% in randomized, controlled trials • Tends to detect earlier stage cancers • FOBT is insensitive for polyps • Poor patient compliance • Diagnostic follow-up is required and compliance with this is poor

19. Widely available Simple preparation/no sedation Minimal risk Relatively inexpensive Sensitive for polyp detection in visualized colon Biopsy possible Poor compliance Prep often inadequate At best, 1/3 of colon visualized so 1/2 of colon cancers missed “Like a mammogram of one breast” Full colonoscopy required if polyps found Colorectal Cancer ScreeningFlexible Sigmoidoscopy Pros Cons

20. Colorectal Cancer ScreeningFlexible Sigmoidoscopy • Few prospective studies • Flex sig and FOBT fails to detect 24% of advanced neoplasia Leiberman et al NEJM 2001 • Case control studies (predominantly of rigid sigmoidoscopy) show a 60% reduction in mortality from CRC in part of colon examined • Addition of FOBT to sigmoidoscopy may reduce mortality by an additional 50%

21. Colorectal Cancer ScreeningBarium Enema • No prospective or cohort trial for CRC screening • Double contrast better than single • DCBE is 50-80% sensitive for polyps <1 cm; 70-90% for polyps >1 cm; 55-85% for stage I and II cancer • Insensitive in rectosigmoid area (missed 25% of cancers in pts with positive FOBT) • Anecdotally less comfortable than colonoscopy • Abnormalities detected require colonoscopy Kewenter J. Endoscopy 1995

22. Colorectal Cancer ScreeningColonoscopy • No prospective trials for CRC screening and mortality • Sigmoidoscopy and polypectomy reduce CRC mortality • Nat’l polyp study cleared the colon of adenomas in high risk pts and there was a 76-90% reduction in CRC and no deaths • Colonoscopy screening studies show a prevalence of polyps twice that of flexible sigmoidoscopy

23. Evaluates entire colon Allows diagnosis and treatment of lesions found More sensitive than FOBT or sigmoidoscopy Theoretically prevents colon cancer Operator dependent Expensive Difficult preparation Poor compliance Uncomfortable, embarrassing Potentially risky Incomplete exam in 5-20% Polyps can be missed Colorectal Cancer ScreeningColonoscopy Pros Cons

24. Colorectal Cancer Screening“Virtual Colonoscopy” • Uses spiral CT technology • Bowel preparation required • Sensitivity for polyps >1 cm • 75% - 93% (<1cm 19-82%) • Specificity • 90% - 100% • Time will tell if improves patient compliance for screening • Colonoscopy still needed to remove polyps • ? Cost-effective at this time

25. Colorectal Cancer ScreeningRecommendations Average Risk Persons over age 50 • Annual FOBT and Flexible Sigmoidoscopy every 5 years • DCBE every 5 to 10 years • Colonoscopy every 10 years

26. Colorectal Cancer ScreeningThe Future • A test that detects “significant adenomas” • Non-invasive test of stool or preferably blood or saliva • Better tolerated colon preparation