Optimizimg Colorectal Cancer Screening and Surveillance

1. Optimizimg Colorectal Cancer Screening and Surveillance Thomas B. Hargrave M.D March 23, 2013

2. CRC: Overview • In 2012, colorectal cancer (CRC) was estimated to be diagnosed in 143,460 persons and responsible for the death of 51,690 persons in the US • Colorectal cancer is the third most common cancer in California, and second deadliest cancer in men and women • The incidence of CRC has been declining over the last 2 decades • Screening for and removal of colonic adenomas appears to significantly reduce the incidence of and risk of dying from colorectal cancer

4. Colorectal Cancer Rates by Race and Ethnicity

5. Projected Annual Hospital Admissions for Colon Cancer in the US: 1990-2050 Number of admissions (thousands) Year Seifeldin and Hantsch, Clin Ther 1999; 21: 1370

6. Rationale for Screening

7. Rationale for Screening • Most CRC are slow growing with a doubling time of approximately 600 days • Estimated 75-80% of colon cancers develop from a polypoid adenoma (>10 years) “Polyp-Cancer Sequence” • Removal of advanced adenomas (over 10 mm, or associated with villous features) reduces the incidence of invasive CRC • Cancers discovered by screening tend to be less advanced and associated with greater probability of curative resection

8. Benefit of Screening: Earlier Stage = Improved Survival

10. Distribution of Cancer Stages at Time of Diagnosis: 1999-2006 American Cancer Society Facts and Figures 2012

11. Flexible Sigmoidoscopy in the Randomized Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial • Of 77 447 enrollees, 67 073 (86.6%) had at least one FSG and 39 443 (50.9%) had two FSGs. • Repeat FSG increased colorectal cancer or advanced adenoma detection in women by one-fourth and in men by one-third • Of 223 pts who received a diagnosis of colorectal carcinoma within 1 year of a positive FSG, 64.6% had stage I and 17.5% had stage II disease ( i.e. 82% localized disease) J Natl Cancer Inst. 2012;104(4):280-289

12. 2012 CRC Screening and Surveillance Guidelines

13. CRC Screening Options • Colonoscopy, • Flexible sigmoidoscopy, • CT colonography (CTC), • Stool tests • Guaiac-based tests • FIT • Fecal DNA

14. CRC Screening Options: Average Risk • In 2008 two important CRC screening guidelines were published: • American Cancer Society and the US Multi-Society Task Force with the American College of Radiology • US Preventative Services Task Force (USPSTF) • The USPSTF recently updated surveillance guidelines in August 2012

15. CRC Screening Options: Average RiskACS and Multi-Society Task Force • Annual screening with high-sensitivity FOBT • FIT vs guaiac-based tests • Sigmoidoscopy every 5 years with high sensitivity FOBT every 3 years • Colonoscopy every 10 years • Double contrast BE every 5 years • CT colonography (CTC) every 5 years

16. CRC Screening Options: Average RiskUSPSTF • Annual screening with high-sensitivity FOBT • FIT vsguaiac-based tests • Sigmoidoscopy every 5 years with high sensitivity FOBT every 3 years • Colonoscopy every 10 years • Insufficient evidence • CT colonography - ACBE • Fecal DNA

17. Family History of Colon Cancer • Single first-degree relative with CRC or advanced adenoma (adenoma 1 cm in size, or with high-grade dysplasia or villous elements) diagnosed over age 60 years. • Recommended screening: same as average risk (colonoscopy every 10 years beginning at age 50 years) • Single first-degree relative with CRC or advanced adenoma diagnosed at age <60 years or two first-degree relatives with CRC or advanced adenomas. • Recommended screening: colonoscopy every 5 years beginning at age 40, or 10 years younger than age at diagnosis of the youngest affected relative

18. Importance of Surveillance Colonoscopies

19. Cumulative Probabilities of CRC Based on Adenoma Histology and the Presence or Absence of Surveillance. Gut. 2012;61(8):1180-1186

20. 2012 Consensus Update by the USPSTF on Colorectal Cancer Surveillance

21. 2012 Consensus Update by the USPSTF on Colorectal Cancer Surveillance ** 1) at least 5 serrated polyps proximal to sigmoid, with 2 or more ≥10 mm; (2) any serrated polyps proximal to sigmoid with family history of serrated polyposis syndrome; and (3) >20 serrated polyps of any size throughout the colon.

22. Sessile Serrated Polyps

23. Sessile Serrated Polyps • Serrated polyps are distinct from conventional adenomas and represent a heterogeneous group of polyps with varying histology and malignant potential • Certain serrated polyps may be precursors for colorectal cancers that develop via a "serrated polyp pathway“ • Molecular markers suggest a link between SSPs and colorectal cancers characterized as having a CpG island methylator phenotype (CIMP) • Precursors of CIMP-positive colorectal cancer, such as SSPs, have been proposed to have a particularly important role in proximal colon cancer development.

24. 75-80%

25. Serrated Adenomas Can be Difficuly to Identify Mucous cap

26. Sessile Serrated Adenoma with Focus of HGD

27. So Which Screening Test Is Best for Average Risk Patients? “The best test is the one that gets done.” John M. Inadomi, M.D. N Engl J Med 2012

28. Adults 50-75 with Up-to-date CRC Screening 2012 Fecal occult blood test (FOBT) during the previous year, a sigmoidoscopy within the previous five years and a FOBT within the previous three years, or a colonoscopy within the previous 10 years

29. CRC Screening Options • Colonoscopy, • Flexible sigmoidoscopy, • CT colonography (CTC) • Stool tests • Guaiac-based tests • FIT • Fecal DNA 59% reduction in CRC mortality >90% sensitivity for adenomas > 1 cm 86% sensitivity for adenomas >6 mm

30. Screening Colonoscopy : Statistics • The use of colonoscopy for screening has increased steadily over the last decade • Estimates 15 million colonoscopies performed each year in US • No randomized, controlled trials have tested whether colonoscopy reduces the incidence of colon cancer. • Support for the role of colonoscopy in CRC prevention derives entirely from indirect evidence and observational studies • Only 50% of eligible adults screened

31. Use of Colonoscopy and Flexible Sigmoidoscopy Among Medicare Fee-for-Service Beneficiaries Procedures per 100 000 beneficiaries from a piecewise linear regression model. JAMA. 2006;296:2815-2822.

32. Which CRC Screening Approach is Most Cost-Effective?

33. Markov Model: Estimated Reductions in CRC Deaths for Various Screening Protocols Gastroenterology 2005;129:1151-62

34. Estimated Cost Per Life-Year Gained Compared With Natural History This is the Kaiser rationale for the use of annual FIT over colonoscopy Gastroenterology 2005;129:1151-62

35. Colonoscopic Polypectomy is the Therapeutic “Tip of the Spear” of CRC Prevention Positive F.I.T Positive FS Colonoscopy Surveillance Positive FOBT Virtual CTC Family History DC Ba Enema

36. Colonoscopic Screening: How Well Does It Actually Work?

37. Screening Colonoscopy Efficacy • Although the National Polyp Study suggested that colonoscopic polypectomy reduced subsequent cancer risk by 70-90%, real-world studies indicate significantly less efficacy • Population studies from Germany and Canada have reported reductions of as low as only 30% to 50%. • The ability of colonoscopy to reduce proximal colon cancer appears significantly less than in distal cancers

38. Retrospective Analysis from the National Polyp Study (NPS): Removal of Adenomatous Polyps Associated with a 53% Reduction in CRC Mortality: Mean Follow-up of 15.8 years. 53% mortality reduction Zauber AG et al. N Engl J Med 2012;366:687-696

39. 65% CRC Reduction May Be Best We Can Practically Achieve • 715 patients with screening and surveillance colonoscopies 1989-2003 (Univ. Indiana) • 10,492 patient-years of follow-up • Doctors, dentists, nurses and spouses • 95% White • 12 cases of colon cancer/ 3 cancer deaths at average of 8 years of follow-up • 8/12 (66%) cancers in proximal colon. • 67% reduction in cancer incidence • 65% reduction in cancer death Clin Gastro Hep 2009;7;770-775

40. Colonoscopy: Marginally Effective Against Proximal Cancers

41. CRC Mortality Reduction with Colonoscopy: Proximal vs. Distal 4) Ann Intern Med. 2011:154;22-30 5)Gastroenterology . 2010;139:1128–1137 6) Eur J Gastroenterol Hepatol . 2010;22:437–443 ) 7) J Clin Oncol . 2012;30:2664–2669 1)Annals Int Medicine 2009;150:1-82 2) J. of the National Cancer Institute 2010; 102: 89 – 95 3) Gastroenterology 2004;127:452–456.

42. Why Does Colonoscopy Fail to Reduce Proximal CRC?

43. Possible Reasons for Why Colonoscopy Protection is Imperfect • Operator- dependent factors • Missed lesions during the initial colonoscopy, • Incomplete adenoma removal, • Failed detection of cancer despite biopsy. • Poor bowel preparation • Tumor biology (sessile serrated adenomas, micro- satellite instability)

44. Possible Reasons for Why Colonoscopy Protection is Imperfect • Physician: Procedural/motor skill deficits • Perceptual factors (e.g., variation in color and depth perception) • Personality characteristics (e.g., conscientiousness, obsessiveness, impulsivity) • Knowledge and attitude deficits (e.g., awareness and appearance of flat lesions) • Incomplete colonoscopy • Withdrawal technique

45. Colonoscopy May Not Reduce the Incidence of Sessile Serrated Polyps • Group Health-based study population included 213 advanced adenoma cases, 172 SSP cases, and 1,704 controls aged 50–79 years, who received an index colonoscopy from 1998–2007 • Previous colonoscopy was inversely associated with advanced adenomas in both the rectum/distal colon (OR=0.38; 95% CI: 0.26–0.56) and proximal colon (OR=0.31; 95% CI: 0.19–0.52), but • There was no statistically significant association between previous colonoscopy and the incidence of SSPs Am J Gastroenterol. 2012;107(8):1213-1219

46. Logistic Regression Analyses of the Assoc. Between Previous Colonoscopy, Advanced Adenomas (AA), and Sessile Serrated Polyps (SSP) Am J Gastroenterol. 2012;107(8):1213-1219

47. Adenoma Detection Rate Predicts Future Cancer Reduction

48. Adenoma Detection Rate and Subsequent Cancer Risk • Multivariate Cox proportional-hazards regression model to evaluate the influence of quality indicators for colonoscopy on the risk of interval cancer. • Data were collected from 186 endoscopists who were involved in a colonoscopy-based colorectal-cancer screening program involving 45,026 subjects • A total of 42 interval colorectal cancers were identified during a period of 188,788 person-years. • The endoscopist's rate of detection of adenomas was significantly associated with the risk of interval colorectal cancer (P=0.008) Kaminski MF et al. N Engl J Med 2010;362:1795-1803.

49. Cumulative Hazard Rates for Interval Colorectal Cancer, According to the Endoscopist's Adenoma Detection Rate (ADR)‏ Kaminski M et al. N Engl J Med 2010;362:1795-1803

50. Wide Variation in Adenoma Detection Rates Between Gastroenterologists • Consecutive colonoscopy reports performed by nine attending gastroenterologists at Indiana University Hospital between January 1999 and January 2004 • Among patients 50 yr of age, the range of detection of at least one adenoma per colonoscopy by nine colonoscopists was 15.5–41.1%, • At least two adenomas was 4.9–20.0%, • At least three adenomas was 0.8–10.8%, and • At least one adenoma 1.0 cm was 1.7–6.2%, and • The range of average adenomas detected per colonoscopy was 0.21–0.86. (p<0.001) American Journal of Gastroenterology (2007) 102, 856–861