Objectives Review the various colorectal cancer screening tests - - PDF document

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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

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Colorectal cancer remains a public health problem

 Colorectal cancer (CRC) is the 2nd leading cause of cancer- related death in the US  CRC is the 4th 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% APC K-ras p53 No Adenoma Slow Lynch 3% MLH1 MLH2 MLH6 PMS2 Yes Adenoma Fast CIMP 30-35% BRAF Sometimes Serrated Can be fast

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Natl Cancer Inst, SEER Cancer Statistics Review

30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+ 600 500 400 300 200 100 Incidence in men Incidence in women Mortality in men Mortality in women Age group (years) Number / 100,000 population

Age recommended to start screening

Average annual age-specific CRC incidence 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

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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

Screening Test USPSTF US Multi- society ACG* EU 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

Guideline recommendations

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Existing screening tests for CRC FOBT reduces CRC mortality

Study Patients (n) Years of follow-up Reduction annual FOBT Reduction biennial FOBT Mandel (US)

46,551 13

33%

21%

Kronborg (Denmark)

61,933 10 18%

Hardcastle (UK)

150,251 8 15%

Kewenter (Sweden)

68,308 15.5 16%

Shaukat (US)

46,551 30

32%

22%

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

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FOBT performance characteristics

Study Sensitivity CRC Specificity CRC Sensitivity AA Specificity AA Rosman 2010 36% 96% NR NR Park 2010 30.8% 92.4% 13.7% 92.4% Brenner 2013 24.2% 95.2% 8.6% 95.2%

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

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 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 CRC screening FIT performance for advanced adenomas

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FIT performance over multiple rounds

 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

FIT versus colonoscopy

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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

• r tumor suppressor genes

are specific for cancer and precancerous lesions  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

Stool DNA Testing for CRC screening

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Stool DNA performance characteristics

Test Sensitivity CRC Specificity CRC Sensitivity AA Specificity 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)

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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%

Johnson et al. N Engl J Med 2008

* Multicenter, 2600 average-risk adults, proven radiologists (top 75% of performers), 64 and 16-slice

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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

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Sigmoidoscopy reduces CRC incidence and mortality

Study Patients (n) Years of follow-up CRC incidence reduction CRC mortality reduction Atkin* (UK)

170,432 11.2

23% [0.70-0.84]

31% [0.59-0.82]

Segnan* (Italy)

34,292 11.4

18% [0.69-0.96]

22% [0.56-1.08]

Schoen (US)

154,900 11.9

21% [0.72-0.85]

26% [0.63-0.87]

Atkin et al. Lancet 2010 Segnan et al. J Natl Cancer I 2011 Schoen et al. N Engl J Med 2012

* Once-only lifetime FS with polypectomy of small polyps, full colo for pts with high-risk findings

Sigmoidoscopy mainly protects the distal colon

Study Distal CRC incidence reduction Proximal CRC incidence reduction Distal CRC mortality reduction Proximal CRC mortality reduction Atkin (UK) 36% [0.57- 0.72] 2% [0.85-1.12] NR

NR

Segnan (Italy) 24% [0.61-0.96] 11% [0.69-1.14] 27% [0.47-1.12] 15% [0.52-1.39] Schoen* (US) 29% [0.64-0.80] 14% [0.76-0.97] 50% [0.38-0.64] 3% [0.77-1.22]

Atkin et al. Lancet 2010 Segnan et al. J Natl Cancer I 2011 Schoen et al. N Engl J Med 2012

* 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

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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

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Zauber et al. N Engl J Med 2012

Colonoscopy reduces CRC mortality 53%

Author Study design Overall incidence OR Left-sided OR Right-sided Brenner (Germany) Case-control 0.23 (0.19-0.27) 0.16 (0.12-0.20) 0.44 (0.35-0.55) Doubeni (US) Case-control 0.29 (0.15-0.58) 0.26 (0.06-1.11) 0.36 (0.16-0.80) Nishihara (US) Cohort 0.44 (0.38-0.52) 0.24 (0.18-0.32) 0.73 (0.57-0.92)

Brenner et al. Ann Intern Med 2011 Doubeni et al. Ann Intern Med 2013 Nishihara et al. NEJM 2013

Colonoscopy and site-specific CRC risk

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Author Study design Overall mortality OR Left-sided OR Right-sided Baxter (Canada) Case-control 0.69 (0.63-0.74) 0.33 (0.28-0.39) 0.99 (0.86-1.14) Singh (Canada) Cohort 0.71 (0.61-0.82) 0.53 (0.42-0.67) 0.94 (0.77-1.17)

Baxter et al. Ann Intern Med 2009 Singh et al. Gastroenterology 2010

Colonoscopy and CRC mortality by site

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%)

Author Study design Overall mortality OR Left-sided OR Right-sided Baxter (Canada) Case-control 0.69 (0.63-0.74) 0.33 (0.28-0.39) 0.99 (0.86-1.14) Singh (Canada) Cohort 0.71 (0.61-0.82) 0.53 (0.42-0.67) 0.94 (0.77-1.17) Baxter (US) Case-control 0.40 (0.37-0.43) 0.24 (0.21-0.27) 0.58 (0.53-0.64) Nishihara (US) Cohort 0.32 (0.24-0.45) 0.18 (0.10-0.31) 0.47 (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

Colonoscopy and CRC mortality by site

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Clinical Case

 60 year old healthy active female with no significant PMH underwent a screening colonoscopy in 2011, which was normal  Instructed to undergo a repeat colonoscopy in 10 years  3 years later, she developed severe iron deficiency anemia  Colonoscopy showed a large friable mass in the transverse colon  CT negative for metastasis; underwent a laparoscopic hemi- colectomy (Stage IIIb CRC)  True or False, this case is an interval colorectal cancer

Is this a case of an interval colorectal cancer?

• A. True
• B. False

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Interval CRC occurs despite colonoscopy

 Interval cancer – CRC diagnosed after a screening or surveillance exam in which no cancer is detected, and before the date of the next recommended exam  Prevalence of interval CRC: 3.7% (1 in 27 CRCs)  Possibly due to bad biology (CIMP, MSI, etc)  Possibly due to technical failures  Poor prep  Incomplete exam  Poor polyp detection by the endoscopist  Incomplete polypectomy

Singh et al. Am J Gastroenterol 2014 Soetikno et al. JAMA 2008

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Where’s the lesion? Where’s the lesion?

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Adenoma Detection Rate

 Adenoma detection rate (ADR) – the proportion of screening colonoscopy exams by a physician that detect one or more adenomas  Validated quality indicator for colonoscopy  Proposed by CMS as a reportable quality measure  Recommended ADR target: 25%

Rex et al. Am J Gastroenterol 2015

 Evaluated the association between ADR and risk of CRC after clearing colonoscopy  42 interval CRCs, cecal intubation rate 94%, 100% adequate bowel prep, mean ADR 12.2%

Kaminski et al. N Engl J Med 2010

ADR and risk of interval CRC

ADR Hazard Ratio (95% CI) ≥20.0 1.00 15.0-19.9 10.94 (1.37-87.01) 11.0-14.9 10.75 (1.36-85.06) <11.0 12.50 (1.51-103.43)

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 Kaiser study: 314,872 subjects, 136 gastroenterologists, 712 interval cancers  Each 1% increase in ADR was associated with 3% decrease in CRC risk and 4% decrease in CRC death

Corley et al. N Engl J Med 2014

ADR and risk of CRC and death

ADR Hazard Ratio (95% CI) <19 1.00 19.1-23.9 0.93 (0.70-1.23) 24.0-28.4 0.85 (0.68-1.06) 28.5-33.5 0.70 (0.54-0.91) >33.5 0.52 (0.39-0.69)

Variation in ADR among gastroenterologists

Study Number of GI doctors Lowest ADR Highest ADR Barclay, 2006 12 9.4% 32.7% Chen, 2007 9 15.5% 41.1% Imperiale, 2009 25 7% 44% Shaukat, 2009 51 10% 39% Corley, 2014 136 7.4% 52.5%

Barclay et al. N Engl J Med 2006 Chen et al. Am J Gastroenterol 2007 Imperiale et al. GIE 2009 Shaukat et al. CGH 2009 Corley et al. N Engl J Med 2014

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Surveillance for colorectal cancer Why do we need surveillance?

Cottet et al. Gut 2012

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Role of surveillance

 Goal of surveillance is to prevent the development of metachronous adenomas and cancers after a clearing colonoscopy  The frequency of surveillance should be determined by an accurate assessment of the individual patient’s risk of developing subsequent colonic neoplasm  Risk stratification is crucial to reduce the cost and risk of unnecessary examinations  Current guidelines identify 2 major risk groups based on the likelihood of developing advanced neoplasia during surveillance

Lieberman et al. Gastroenterology 2012

Two major risk groups

 Low risk adenomas  1-2 tubular adenomas < 10 mm  High risk adenomas  Adenoma with villous or tubulovillous histology  High-grade dysplasia  Tubular adenoma >10 mm  3 or more tubular adenomas < 10 mm

Lieberman et al. Gastroenterology 2012

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Follow-up of patients with adenomas at baseline colonoscopy

Study Type of study Risk of AN on surveillance

Saini, 2006 Meta-analysis >3 TA vs. 1-2 TA, RR 2.52 Villous vs. TA, RR 1.26 Adenoma >10 mm vs. <10 mm, RR 1.39 Lieberman, 2007 VA Cohort, 5 years N=895 1-2 TA < 10 mm, RR 1.92 (0.83-4.42) 3 or more, RR 5.01 (2.10-11.96) TA > 10 mm, RR 6.40 (2.74-14.94) Laiyemo, 2008 PPT LRA, 1.00 (ref) HRA, 1.68 (1.2-2.4) Martinez, 2009 Pooling of 8 studies Size >10 mm, RR 1.56 >3 adenomas, RR 1.32 Chung, 2011 Cohort, 5 year LRA (n=671), 2.4% HRA (n=539), 12.2% Cottet, 2011 Cohort LRA (n=3236), 0.8%; SIR 0.68 HRA (n=1899), 2.8%; SIR, 2.23 Lieberman et al. Gastroenterology 2012

Follow-up of patients with SSPs at baseline colonoscopy

Patients with only proximal serrated polyp were more likely to have non-advanced adenomas during surveillance; this rate of neoplasia (43.6%) is similar to the rate found in patients with TAs < 10 mm (41.8). This suggest that patients with proximal serrated polyps may be similar to patients small TAs

Schreiner et al. Gastroenterology 2010

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New surveillance guidelines include SSPs

 Low risk adenomas: 5-10 years

 1-2 tubular adenomas < 10 mm

 High risk adenomas: 3 years

 Adenoma with villous or tubulovillous histology  High-grade dysplasia  Tubular adenoma >10 mm  3 or more tubular adenomas < 10 mm

 Serrated polyps: 3-5 years

 Sessile serrated polyp(s) without cytological dysplasia < 10 mm  Sessile serrated polyp(s) >10 mm or with cytological dysplasia  Traditional serrated adenoma

Lieberman et al. Gastroenterology 2012

What do we do after adenoma removal?

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Clinical Case

 55 year old healthy male presents for surveillance colonoscopy  5 years ago, he had 1 tubular adenoma < 10 mm  On today’s colonoscopy, his bowel prep was excellent, the exam was complete, and no evidence of any polyps  When should he come back for his next surveillance colonoscopy?

 A. 3 years  B. 5 years  C. 10 years

When should he come back for his next surveillance colonoscopy?

• A. 3 years
• B. 5 years
• C. 10 years

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What do we do after first surveillance exam?

Baseline colonoscopy First surveillance Interval for second surveillance (y) LRA HRA LRA Normal 3 5 10 HRA HRA LRA Normal 3 5 5*

Lieberman et al. Gastroenterology 2012

HRA: high-risk adenoma (i.e., any adenoma with high-grade dysplastic or villous features, or any adenoma ≥ 10 mm, or 3 or more adenomas < 10 mm in size) LRA: low-risk adenoma (adenoma < 10 mm in size)

Multiple rounds of surveillance colonoscopy

Lieberman et al. Gastroenterology 2012

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Summary

 Screening is effective in reducing CRC incidence and mortality  FIT is the preferred fecal test based on its performance characteristics, cost, ease of use, and success with programmatic screening  ADR is the best quality indicator for colonoscopy and is associated with subsequent CRC risk and mortality  Surveillance is essential for patients with a prior history of adenomas and SSPs

Thank You