Colorectal Cancer: Update 2008

1. Colorectal Cancer:Update 2008 Durado Brooks, MD, MPH Director, Prostate and Colorectal Cancer

2. Colorectal Cancer • The third most common cancer in U.S. • 148,810 new cases expected in 2008 • The second deadliest cancer • 49,960 deaths nationwide • More than 1 million Americans living with colorectal cancer

3. CENTERS FOR DISEASE CONTROL AND PREVENTION Colorectal Cancer Sporadic (average risk) (65%–85%) Family history(10%–30%) Rare syndromes (<0.1%) Hereditary nonpolyposis colorectal cancer (HNPCC) (5%) Familial adenomatous polyposis (FAP) (1%)

4. Risk Factor - Polyps Different types • Hyperplastic • minimal cancer potential • Adenomatous • approximately 90% of colon and rectal cancers arise from adenomas

5. Risk Factor - Polyps

6. Benefits of Screening • Cancer Prevention • Removal of pre-cancerous polyps prevent cancer (unique aspect of colon cancer screening) • Improved survival • Early detection markedly improves chances of long term survival

7. Benefits of Screening

8. Colorectal Screening Rates • Just 40% of colorectal cancers are detected at the earliest stage. • A little more than half* of Americans over age 50 report having had a recent colorectal cancer screening test • Slow but steady improvement in these numbers over the past decade (but all are not benefiting to the same degree) *varies based on data source

9. Trends in Recent* Endoscopy Prevalence (%), by Educational Attainment and Health Insurance Status, Adults 50 Years and Older, US, 1997-2004 *A flexible sigmoidoscopy or colonoscopy within the past five years. Note: Data from participating states and the District of Columbia were aggregated to represent the United States. Source: Behavioral Risk Factor Surveillance System CD-ROM (1996-1997, 1999) and Public Use Data Tape (2001, 2002, 2004), National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention and Prevention, 1999, 2000, 2002, 2003, 2005.

10. Trends in Recent* Fecal Occult Blood Test Prevalence (%), by Educational Attainment and Health Insurance Status, Adults 50 Years and Older, US, 1997-2004 *A fecal occult blood test within the past year. Note: Data from participating states and the District of Columbia were aggregated to represent the United States. Source: Behavioral Risk Factor Surveillance System CD-ROM (1996-1997, 1999) and Public Use Data Tape (2001, 2002, 2004), National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention and Prevention, 1999, 2000, 2002, 2003, 2005.

11. Colorectal Screening Rates Low:Reasons (according to Patients) • Low awareness of CRC as a personal health threat • Lack of knowledge of screening benefits • Fear, embarrassment, discomfort • Time • Cost • Access • “My doctor never talked to me about it!”

12. ACS 2003 CRC Prevention and Early Detection Recommendations • Fecal Occult Blood Testing (FOBT) *Guaiac *Immunochemical • Flexible Sigmoidoscopy (FSIG) • FSIG + FOBT • Colonoscopy • Double Contrast Barium Enema (DCBE)

13. Colorectal Cancer Screening 2008

14. The 2008 CRC Guidelines Update was a Joint Effort of 5 Organizations • American Cancer Society • U. S. Multi-Society Task Force on Colorectal Cancer • American Gastroenterological Association • American College of Gastroenterology • American Society of Gastrointestinal Endoscopists • American College of Radiology

15. CRC Screening Guidelines: What’s New? CRC screening tests are grouped into two categories: • Tests that detect cancer and precancerous polyps* • Tests that primarily detect cancer • It is the strong opinion of the ACS CRC Advisory Group that colon cancer prevention should be the primary goal of CRC screening. • Exams that are designed to detect both early cancer and precancerous polyps should be encouraged if resources are available and patients are willing to undergo an invasive test • If the full range of screening tests are not available, physicians should make every effort to offer at least one test from each category

16. CRC Screening Guidelines: What Else is New? • Two new tests recommended: • stool DNA (sDNA) and • computerized tomographic colonography (CTC) – sometimes referred to as virtual colonoscopy • The guidelines: • establish a sensitivity threshold for recommended tests • delineate important quality-related factors for each form of testing • continue to emphasize options for testing • An overriding goal of this update is to provide a practical guideline for physicians and the public The full article can be accessed at: http://caonline.amcancersoc.org/cgi/content/full/CA.2007.0018v1

17. 2008 CRC Screening Guidelines Average risk adults age 50 and older • Tests that detect adenomatous polyps and cancer • Flexible sigmoidoscopy (FSIG) every 5 years*, or • Colonoscopy every 10 years, or • Double contrast barium enema (DCBE) every 5 years*, or • CT colonography (CTC) every 5 years* • Tests that primarily detect cancer • Annual guaiac-based fecal occult blood test (gFOBT)* with high test sensitivity for cancer, or • Annual fecal immunochemical test (FIT)* with high test sensitivity for cancer, or • Stool DNA test (sDNA)*, with high sensitivity for cancer, interval uncertain *Note: All positive screening tests should be followed up with colonoscopy

18. 2008 CRC Screening Guidelines New Tests

19. Stool DNA Test (sDNA) Rationale • Fecal occult blood tests detect blood in the stool – which is intermittent and non-specific • Colon cells are shed continuously • Polyps and cancer cells contain abnormal DNA • Stool DNA tests detect abnormal DNA from cells that are passed in the stool* *All positive tests should be followed with colonoscopy

20. Early Cancer Late Cancer Adenoma Late Adenoma Normal Epithelium Optimum phase for early detection Genetic Model of Colorectal Cancer Bat-26 (Sporadic) p53 APC Mutation Bat-26 (HNPCC) K-ras Dwell Time: Many decades2-5 years 2-5 years Courtesy of Barry M. Berger. MD, FCAP EXACT Sciences

21. sDNA - Sample Collection

22. sDNA - Sample Collection Patient seals container and ships back to designated lab (all packing materials and labels supplied) Collection bucket inserted into bracket and installed under toilet seat Patient supplies whole stool sample; no diet or medication restrictions Patient seals sample in outer container and freezer pack

23. sDNA: Evidence Three versions of the Exact Sciences test have been evaluated • Version 1 (K-ras, APC, p53,BAT-26, DIA) was evaluated in the Imperiale trial • Version 1.1 (K-ras, APC, P53), PreGen-Plus is the currently marketed test • Version 2 (Vimentin only, or Vimentin + DIA) is currently under evaluation • Earlier and more recent versions were evaluated in smaller, mixed populations

24. Stool DNA: Potential Advantages • No dietary restrictions needed • Specificity for cancer may be significantly higher than other forms of stool testing • No stool sampling required (entire bowel movement collected) • Company-sponsored studies report high levels of patient acceptance

25. Stool DNA: Limitations • Misses some cancers • Sensitivity for adenomas with current commercial version of test is low • Technology (and test versions) are in transition • Appropriate re-screening interval is not known • Costs much more than other forms of stool testing (approximately $300 - $400 per test) • Not covered by most insurers • Not clear how to manage positive stool DNA test if colonoscopy is negative • FDA approval concerns

26. CT Colonography (CTC) CTC Image Optical Colonoscopy Courtesy of Beth McFarland, MD

27. CT Colonography 2-D view 3-D view Polyp Courtesy of Beth McFarland, MD

28. CT Colonography: Rationale • Allows detailed evaluation of the entire colon • Minimally invasive (rectal tube for air insufflation) • No sedation required • A number of studies have demonstrated a high level of sensitivity for cancer and large polyps

29. CTC vs. Optical Colonoscopy: Sensitivities for All Polyps Polyp Size >10mm >8mm >6mm CTC 92.2% 92.6% 85.7% Colonoscopy 88.2% 89.5% 90.0% Pickhardt et al, NEJM 2003

30. CTC: Additional Findings • CTC identified 55 polyps not seen on initial colonoscopy • 21 adenomas • One 11 mm malignant polyp • Extra-colonic findings • 5 asymptomatic cancers • Aortic aneurysms • Renal and gall bladder calculi Pickhardt et al, NEJM 2003

31. CTC: Follow-up colonoscopy • Indication for diagnostic/therapeutic colonoscopy varies markedly based on selected polyp size threshold • Important implications for cost-effectiveness of CTC Pickhardt et al, NEJM 2003

32. CT Colonography: Additional Evidence • A number of other studies have demonstrated a high level of sensitivity for cancer and large polyps • Findings from the recently completed multi-center ACRIN trial reportedly are similar to those of Pickhardt et al • Some results from this trial have been reported at medical meetings, but have not yet been published • Manuscript has been prepared and is currently under review

33. CT Colonography: Limitations • Requires full bowel prep (which most patients find to be the most unpleasant aspect of colonoscopy) • Colonoscopy is required if abnormalities detected, sometimes necessitating a second bowel prep • Extra-colonic findings can lead to additional testing (may have both positive and negative implications) • Controversy regarding management of small polyps, sensitivity for “flat polyps” • Radiation exposure • Steep learning curve for radiologists • Limited availability to high quality exams in many parts of the country • Most insurers do not currently cover CTC as a screening modality

34. 2008 CRC Guidelines continue to emphasize options because: • Evidence does not yet support any single test as “best” • Uncertainty exists about performance of different screening methods with regard to benefits, harms, and costs (especially on programmatic basis) • Uptake of screening remains disappointingly low • Individuals differ in their preferences for one test or another • Primary care physicians differ in their ability to offer, explain, or refer patients to all options equally • Access is uneven geographically, and in terms of test charges and insurance coverage

35. If tests that can prevent CRC are preferred, why not recommend them alone? • Greater patient requirements for successful completion • Endoscopic and radiologic exams require a bowel prep and an office or facility visit • Higher potential for patient injury than fecal testing • Risk levels vary between tests, facilities, practitioners • Patient preference • Many individuals don’t want an invasive test or a test that requires a bowel prep • Some prefer to have screening in the privacy of their home • Some may not have access to the invasive tests due to lack of coverage or local resources