Objectives Review the various colorectal cancer screening tests - PDF document

Colorectal Cancer Screening and Surveillance Jeffrey Lee MD, MAS Assistant Clinical Professor of Medicine University of California, San Francisco jeff.lee@ucsf.edu Objectives  Review the various colorectal cancer screening tests recommended by our guidelines  Discuss potential factors associated with interval colorectal cancers after a clearing colonoscopy  Review the evidence of our current surveillance guideline recommendations for patients after colonoscopic polypectomy 1

Colorectal cancer remains a public health problem  Colorectal cancer (CRC) is the 2 nd leading cause of cancer- related death in the US  CRC is the 4 th most common cause of cancer worldwide  143,000 new cases are diagnosed annually in the US and 50,000 die from this disease  Lifetime risk of CRC ~ 5% Jemal et al. CA Cancer J Clin 2011 Siegel et al. CA Cancer J Clin 2013 Molecular Basis of Colorectal Cancer Pathway Frequency Genes MSI Precursor Speed CIN 65-70% No Adenoma Slow APC K-ras p53 Lynch 3% MLH1 Yes Adenoma Fast MLH2 MLH6 PMS2 CIMP 30-35% Sometimes Serrated Can be BRAF fast 2

Average annual age-specific CRC incidence Number / 100,000 population 600 Incidence in men 500 Incidence in women 400 Mortality in men 300 Mortality in women 200 100 0 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+ Age group (years) Age recommended to start screening Natl Cancer Inst, SEER Cancer Statistics Review Clinical Case  53 year old AA male who presents for a physical  Healthy, plays basketball weekly  History of smoking but no family history of CRC  Had a negative CT colonography 5 years ago  Wants to discuss CRC screening options 3

Which screening tests are recommended by the USPSTF guideline? A. FOBT/FIT B. Flexible sigmoidoscopy C. Colonoscopy D. CT colonography E. A, B, and C F. All of the above Guideline recommendations Screening USPSTF US Multi- ACG* EU Test society FIT/FOBT ✔ ✔ ✔ ✔ annually ✔ ✔ ✔ ✔ Flex sig q5 yrs Colonoscopy ✔ ✔ ✔ ✔ q10 years ✔ ✔ CT colonography q5 years ✔ ✔ Fecal DNA q? years * ACG favors colonoscopy as the primary screening test 4

Existing screening tests for CRC FOBT reduces CRC mortality Patients Years of Reduction Reduction Study (n) follow-up annual FOBT biennial FOBT Mandel 46,551 13 33% 21% (US) 61,933 10 18% Kronborg (Denmark) Hardcastle 150,251 8 15% (UK) 68,308 15.5 16% Kewenter (Sweden) Shaukat 46,551 30 32% 22% (US) Kewenter et al. Scan J Gastroenterol 1994, Mandel et al. N Engl J Med 1993, Kronborg et al. Lancet 1996, Hardcastle et al. Lancet 1996, Shaukat et al. N Engl J Med 2013 5

FOBT performance characteristics Sensitivity Specificity Sensitivity Specificity Study CRC CRC AA AA Rosman 36% 96% NR NR 2010 Park 30.8% 92.4% 13.7% 92.4% 2010 Brenner 24.2% 95.2% 8.6% 95.2% 2013 Rosman et al. J Gen Intern Med 2010 Park et al. Am J Gastroenterol 2010 Brenner et al. Am J Gastroenterol 2013 Fecal Immunochemical Test (FIT)  Labeled antibody that detects the globin protein of human hemoglobin  Several advantages with FIT compared with FOBT  Hemoglobin measurement can be quantified and automated - facilitates high throughput screening efforts  No dietary or medication restriction - improved adherence  More specific to colorectal origin because globin protein is degraded by pancreatic enzymes - lower false positivity rate  Cheap – costs around $20 6

FIT performance for CRC screening  Meta-analysis: 19 studies  8 different FIT brands  Sensitivity for CRC – 79% [0.69-0.86]; 71% for colonoscopy subgroup  Specificity for CRC – 94% [0.92-0.95]  1-sample FIT with a low cut-off <20 mcg/g – SN 89%, SP 91% Lee et al. Ann Intern Med 2014 FIT performance for advanced adenomas 7

FIT performance over multiple rounds FIT versus colonoscopy  Biennial FIT versus 1-time colonoscopy for 10 years  Higher participation rates with FIT compared with colonoscopy (34.2% vs. 24.6%, P<0.001)  Similar CRC detection with both FIT and colonoscopy (0.1%, P=0.99)  Higher advanced adenoma detection with colonoscopy than FIT (1.9% vs. 0.9%, P<0.001) Quintero et al. N Engl J Med 2012 8

Stool DNA testing  Strong biological rationale for measuring mutated DNA in stool  Colonocytes are continuously shed into the lumen  Neoplastic cells including its intact DNA exfoliate at a higher rate  Point mutations in oncogenes or tumor suppressor genes are specific for cancer and precancerous lesions Stool DNA Testing for CRC screening  COLOGUARD  Methylated BMP3 and NDRG4  Mutant KRAS  B-actin  FIT  9989 participants  FIT OC Auto (20 mcg/g) was the comparison Imperiale et al. N Engl J Med 2014 9

Stool DNA performance characteristics Sensitivity Specificity Sensitivity Specificity Test CRC CRC AA AA Fecal DNA 92.3% 86.6% 42.4% 86.6% FIT 73.8% 94.9% 23.8% 94.9% Imperiale et al. N Engl J Med 2014 Concerns with Stool DNA testing  Cost - $500!  Screening interval of 3 years – is this cost-effective?  Patient acceptance – 6.3% dropped out of the study  Is it truly better than FIT in terms of performance (what if we used FIT with a lower cut-off) 10

CT colonography CT Colonography – ACRIN Trial >5mm >6mm >7mm >8mm >9mm >10mm Sensitivity 65% 78% 84% 87% 90% 90% Specificity 89% 88% 87% 87% 86% 86% PPV 45% 40% 35% 31% 25% 23% NPV 95% 98% 99% 99% 99% 99% * Multicenter, 2600 average-risk adults, proven radiologists (top 75% of performers), 64 and 16-slice Johnson et al. N Engl J Med 2008 11

CT colonography issues  Radiation risk from repeated studies (5 mSv/scan)  Unknown potential to increase adherence  Rational approach to extra-colonic findings  Difficulty getting same day colonoscopy if a polyp is found Flexible sigmoidoscopy 12

Sigmoidoscopy reduces CRC incidence and mortality CRC CRC Patients Years of incidence mortality Study (n) follow-up reduction reduction Atkin* 170,432 11.2 23% 31% [0.59-0.82] (UK) [0.70-0.84] 34,292 11.4 22% Segnan* 18% [0.56-1.08] (Italy) [0.69-0.96] Schoen 154,900 11.9 21% 26% [0.63-0.87] (US) [0.72-0.85] * Once-only lifetime FS with polypectomy of small polyps, full colo for pts with high-risk findings Atkin et al. Lancet 2010 Segnan et al. J Natl Cancer I 2011 Schoen et al. N Engl J Med 2012 Sigmoidoscopy mainly protects the distal colon Distal CRC Proximal CRC Distal CRC Proximal incidence incidence mortality CRC Study reduction reduction reduction mortality reduction Atkin 36% [0.57- 2% NR NR (UK) 0.72] [0.85-1.12] Segnan 24% 11% 27% 15% (Italy) [0.61-0.96] [0.69-1.14] [0.47-1.12] [0.52-1.39] Schoen* 29% 14% 50% 3% (US) [0.64-0.80] [0.76-0.97] [0.38-0.64] [0.77-1.22] * Although the PLCO trial showed a mild reduction in proximal CRC incidence, there has not been a significant reduction of mortality from proximal CRC seen in any RCT Atkin et al. Lancet 2010 Segnan et al. J Natl Cancer I 2011 Schoen et al. N Engl J Med 2012 13

Going the distance – in defense of colonoscopy Evidence for colonoscopy - National Polyp Study  1418 patients referred for colonoscopy  Included only patients who underwent removal of adenoma  CRC incidence reduced by 76- 90% Reference SIR Mayo 0.10 St. Marks 0.12 SEER 0.24 Winawer et al. NEJM 1993 14

Colonoscopy reduces CRC mortality 53% Zauber et al. N Engl J Med 2012 Colonoscopy and site-specific CRC risk Overall OR OR Author Study design incidence Left-sided Right-sided Brenner Case-control 0.23 0.16 0.44 (Germany) (0.19-0.27) (0.12-0.20) (0.35-0.55) Doubeni Case-control 0.29 0.26 0.36 (US) (0.15-0.58) (0.06-1.11) (0.16-0.80) Nishihara Cohort 0.44 0.24 0.73 (US) (0.38-0.52) (0.18-0.32) (0.57-0.92) Brenner et al. Ann Intern Med 2011 Doubeni et al. Ann Intern Med 2013 Nishihara et al. NEJM 2013 15

Colonoscopy and CRC mortality by site Overall OR OR Author Study design mortality Left-sided Right-sided Baxter Case-control 0.69 0.33 0.99 (Canada) (0.63-0.74) (0.28-0.39) (0.86-1.14) Singh Cohort 0.71 0.53 0.94 (Canada) (0.61-0.82) (0.42-0.67) (0.77-1.17) Main issues with the Canadian studies were: low cecal intubation rates (e.g., 81%) and the large proportion of non-gastroenterologists performing colonoscopies (e.g., surgeons 40%) Baxter et al. Ann Intern Med 2009 Singh et al. Gastroenterology 2010 Colonoscopy and CRC mortality by site Overall OR OR Author Study design mortality Left-sided Right-sided Baxter Case-control 0.69 0.33 0.99 (Canada) (0.63-0.74) (0.28-0.39) (0.86-1.14) Singh Cohort 0.71 0.53 0.94 (Canada) (0.61-0.82) (0.42-0.67) (0.77-1.17) Baxter Case-control 0.40 0.24 0.58 (US) (0.37-0.43) (0.21-0.27) (0.53-0.64) Nishihara Cohort 0.32 0.18 0.47 (US) (0.24-0.45) (0.10-0.31) (0.29-0.76) Baxter et al. Ann Intern Med 2009 Singh et al. Gastroenterology 2010 Baxter et al. J Clin Oncol 2012 Nishihara et al. NEJM 2013 16