1. Colorectal Cancer Screening Contributors: Molly Gabel, M.D. Michael Nissenblatt, M.D. Tamir Ben-Menachem, M.D. David August, M.D. Rebecca A. Moss, M.D. The American Cancer Society Project made possible by The Robert Wood Johnson Foundation

2. Colon Cancer Overview I.Pathogenesis II.Definition of Risk III.Screening Tests: Methods and Comparison IV.Overcoming Barriers to Screening V.2009 Screening Recommendations

3. Colorectal Cancer Screening: Technologic and Social Factors Education Patients Physicians Administrators Advocacy Government: Screen for Life Act! Social Molecular Testing Improved Genetic Testing Fecal DNA Polyp Detection CT Colonography Improved Preparation Improved Sedation Better Colonoscopes Improved Screening || More Lives Saved

4. Copyright ©2008 American Cancer Society United States 2008 Ten Leading Cancer Types Estimated New Cancer Cases and Deaths by Sex

5. Burden of Disease Too Many People Dying from CRC – 57,000 deaths per year in the U.S. – Second leading cause of cancer deaths – Rate not declining appreciably Far Too Few Being Screened for CRC – 30-40% of eligible patients have ever been screened – Many of those screened infrequently – Disease- and test-specific reasons for lack of screening Disease Curable if Caught Early

6. Pathogenesis

7. Definition of Risk Average Above Average High

8. Simplified Risk Classification Average RiskIncreased Risk > Age 50 No other risk factors Hereditary syndromes FAP HNPCC Personal history of polyps or CRC Family history of polyps or CRC Inflammatory bowel disease

9. Modifiable Risk Factors Low fiber diet Obesity Smoking Heavy alcohol consumption –All place patient at increased risk, but no data to support more aggressive surveillance

11. Risk by Medical/Genetic Risk Factor

12. Lifetime Risk by Familial Risk Classification

13. Incidence of CRC According to Risk

14. Familial Adenomatous Polyposis(FAP) Mutation in APC (Autosomal Dominance) >100 adenomas in colon 100% Cancer Risk if untreated (endoscopic surveillance +/- colectomy) –90% will develop colorectal cancer –After colectomy, 10% still develop extracolonic tumors: duodenal adenomas/Ca Ampullary tumors Desmoid tumors Thyroid cancer Hepatoblastoma (pediatric patients) Glioblastoma Adrenal tumors –Other manifestation: congenital hypertrophy of retinal pigmented epithelium

15. Lynch Syndrome (HNPCC): Hereditary Non-Polyposis Colon Cancer Also associated with thyroid, pancreatic, hepatobiliary and prostate Ca Muir-Torre: sebaceous gland tumors, keratoxanthomas CancerRisk CRC Most.in proximal colon 40-70% Endometrial40-60% Ovarian (mucinous) 9% Urinary tractRR 0-76 Small bowelRR 103-292 GastricRR 4.4-19.3

16. Carriers not at increased risk Endoscopic surveillance is of proven benefit to increase survival No evidence that increased surveillance of other cancers increases survival Lynch Syndrome (HNPCC):

17. What are the Amsterdam & Bethesda Criteria? 1. Amsterdam Criteria: Used to r/o HNPCC in patients with clinical family history  3 relatives with an HNPCC-associated cancer 1 is a 1st degree relative of the other 2  2 successive generations affected  1 diagnosed before age 50 FAP excluded in the colorectal cancer case(s) Tumors verified by pathological examination

18. 2. Modified Bethesda Criteria: Used to determine if benefit from genetic testing for HNPCC Meet Amsterdam criteria 2 HNPCC-related cancers Has CRC and a 1 st degree relative with CRC and/or HNPCC-related extracolonic cancer and/or a colorectal adenoma before age 40. Right-sided CRC having an undifferentiated pattern before age 45. Signet-ring cell type before age 45. Adenomas before age 40. The Audience Month Day, Year

19. Other Genetic Syndromes Familial CRC Type X –Meet Amsterdam criteria, but negative genetic testing –No risk for other cancers, except possibly endometrial Juvenile Polyposis Peutz-Jeghers Syndrome Common Familial Colon Cancer The Audience Month Day, Year

20. The Genetic Testing Process: Key Points Consider multiple motivations for testing Counsel patients on the benefits, risks, and limitations of testing Facilitate informed decision making Begin testing with an affected person, if possible Use multidisciplinary approach Keep current with continuing research

21. Informed Consent: Potential Benefits of Genetic Testing Improved cancer risk management Relief from uncertainty and anxiety about cancer risk Information for individual and family members Lifestyle decision making

22. Informed Consent: Limitations of Genetic Testing Not all mutations are detectable Uncertain significance of some mutations Negative results is fully informative only if mutation has been identified in family Results indicate probability, not certainty, of developing cancer Unproven efficacy of most interventions

23. Cancer Genetics Professionals Can Assist With: Pedigree interpretation and cancer risk assessment Complex psychosocial issues In-depth counseling and education Ordering and interpreting genetic test Facilitating entry into clinical studies

24. Importance of Longitudinal Follow-Up Review management plan periodically Assess and promote adherence to plan Coordinate primary care and specialty services Provide psychological support Keep current on new information and tools for managing inherited cancer susceptibility Update family history

25. Points to Remember Genetic Susceptibility Testing Is not a screening test for the general population Can be one component of a comprehensive cancer risk- assessment plan

26. Increased Risk: –Surveillance is all colonoscopy-based –Refer for risk-specific management Average Risk: –Follow consensus guidelines General Screening Guidelines

28. Improved survival –Early detection markedly improves chances of long term survival Cancer Prevention –Removal of pre-cancerous polyps prevent cancer (unique for colon cancer screening) Screening Purpose

29. Test Categories Invasive Tests: Diagnostic and Therapeutic –Colonoscopy Endoscopic –Flexible Sigmoidoscopy Non-Invasive Tests: Diagnostic –Fecal Occult Blood Testing (FOBT) –Barium Enema –CT Colography Virtual Colonoscopy –Stool DNA Analysis

30. How Did We Screen for CRC circa 2003? Look for Blood in StoolLook for Polyps Occult blood test Barium enema Colonoscopy

31. New Tests Since 2003 Guidelines Stool DNA CT Colography

32. 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 American Cancer Society, 2008

33. Study with One-Time TestingSensitivity for Cancer Ahlquist, et al Gastro, 2000 91% Imperiale, et al NEJM, 2004 51.6% Syngal, et. al Cancer, 2006 63% Whitney, et al J Mol Diagn, 2004 70% Chen, et al JNCI, 2005 46% Itzkowitz, et al DDW-AB, 2006 88% sDNA: Evidence

34. 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

35. Stool DNA: Limitations Sensitivity for adenomas with current commercial version of test is low misses some cancers 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

36. CT Colography “Virtual Colonoscopy”

37. 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

38. CT Colography: Process Colon is prepped Gas is insufflated into the colon (air or CO 2 ). CT scan with patient in two positions. Computer processing. Radiologist reading and problem- solving.

39. Virtual Colonoscopy 2D Image Standard

40. Virtual Colonoscopy “Fly Through”

41. CT Colography Sensitivity: Polyp Size AuthorYear Patient s Polyps ≥10 mm 5-10 mm ≤5mm Rockey2005614 76 (>10mm) 53% Pickardt20041233 298 (>6 mm) 92.2%~90% Cotton2002>50044%42% Langhi20021655292%82%50% Yee200130052490.2%80.1%59% Fletcher200018026375.2%47.2%__ Fenlon199910011491%82%59% Dachman1998442283%33%15%

42. CT Colography vs. Optical (Endoscopic) Colonoscopy: Sensitivities for All Polyps Polyp Size >10mm>8mm>6mm CTC92.2%92.6%85.7% Colonoscopy88.2%89.5%90.0% Pickhardt et al, NEJM 2003

43. CT Colography: Potential Applications Screening? –Public appeal? High-risk Colonoscopy –Warfarin –Sedation risk –Previous complication Incomplete Colonoscopy: –superior to barium enema

44. CT Colonography: Limitations Requires full bowel prep (which most patients find to be the most unpleasant aspect of colonoscopy) Non-therapeutic: colonoscopy is required if abnormalities detected, requiring 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

45. Current Controversies over CTC No defined method of communicating findings to gastroenterologist Unclear threshold of detection: what size polyp should be “followed”? –Implications for repeat exam recommendations and cost Ethical concerns over implementation to a vulnerable public Particularly when test is not covered by insurance

46. CT Colography: Summary and Recommendations Although there is a desperate need for better screening tests and improved compliance, new tests should be rigorously studied prior to widespread adoption. –CT colography is making strides in its potential application in CRC screening, but remains experimental in most situations. –Patients at increased risk and especially those suspected or known to have cancer syndromes should not use this test as their primary tool.

47. Colorectal Cancer Screening: Choosing the Method SensitivityCostRiskCommunity Access Evidence FOBTLow Unlimited++ FOBT & Flexible Sigmoidoscopy High Limited++ Fecal DNAHighModLowUnlimited+ B.E.Mod (later stage) Mod Limited (evaluation) +/- Virtual ColonoscopyHigh (> 1cm)HighModLimited (evaluation) + ColonoscopyHigh Limited++ Ideal ScreenHighLow Unlimited++

48. Corporate Physicians Encouraging Systematic Screening Managing health; not health care costs Getting people screened whom otherwise would not get screened Detecting cancers / pre-cancerous lesions that might have been fatal if not detected early Save company and medical system cost associated with treating late stage disease

49. Barriers to Colorectal Cancer Screening Patient Barriers: –cost, discomfort, fear, misunderstand diet or prep, embarrassing System Barriers: –lack of insurance, access to health care Physician Barriers: –knowledge, time, inadequate training –biases:gender, asymptomatic patients

50. Subjects Reporting FOBT (Age>50) Flex Sig or colonoscopy (Age>50) Mammogram (Age>40) Ever Completed 40%44%82% Up to date 21% (in last year) 34% (in last 5 years) 71% (in last 2 years) General Cancer Screening Compliance

51. Cancer Screening Compliance in New Jersey ScreeningU.S. Average Screening Rate N.J. Average Screening Rate U.S. No Usual Source of Medical Care Screening Rate N.J. No Usual Source of Medical Care Screening Rate U.S. No Health Insurance Screening Rate N.J. No Health Insurance Screening Rate Colorectal60%59%33%34%32% Breast67%63%32%43%35%44% Cervix80%84%73% Behavioral Risk Factor Surveillance System, 2006

52. Trends in Recent* Fecal Occult Blood Test Prevalence (%), by Educational Attainment and Health Insurance Status, Adults 50 Years and Older, US, 1997-2004 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.

53. Trends in Recent* Endoscopy Prevalence (%), by Educational Attainment and Health Insurance Status, Adults 50 Years and Older, US, 1997-2004 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.

54. Colorectal Screening Rate 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!”

55. Patient FactorsPhysician Factors Clinician recommendationPersonal beliefs Understanding alternatives Familiarity with data Personal beliefs Access to services Family effects Insurance coverage Access to services Fear / embarrassment Insurance coverage Factors At Play During Counseling About CRC Screening

56. Evaluating the Evidence: Cost

57. Counseling Patients Above Average Risk: refer to –Colorectal surgeon –Gastroenterologist Average Risk –Follow Consensus Guidelines

58. History: 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)

59. CRC Screening Guidelines: Need for New Consensus Statement Two new tests developed with evidence: stool DNA (sDNA) and computerized tomographic colonography 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 the updated consensus statement was to provide a practical guideline for physicians and the public

60. 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

61. 2008 CRC Screening Guidelines 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

62. A Joint Guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology CA Cancer J Clin 2008; 58:130-160 The Audience Month Day, Year

63. Joint Guidelines, continued

64. 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

65. 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

66. Colorectal Cancer Screening: Choosing the Method SensitivityCostRiskCommunity Access Evidence FOBTLow Unlimited++ FOBT & Flexible Sigmoidoscopy High Limited++ Fecal DNAHighModLowUnlimited+ B.E.Mod (later stage) Mod Limited (evaluation) +/- Virtual ColonoscopyHigh (> 1cm)HighModLimited (evaluation) + ColonoscopyHigh Limited++ Ideal ScreenHighLow Unlimited++

67. 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!”