Colorectal Cancer Screening and Surveillance

Transcription

1 1 Colorectal Cancer Screening and Surveillance Jeffrey Lee MD, MAS Assistant Clinical Professor of Medicine University of California, San Francisco 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

2 2 Colorectal cancer remains a public health problem Colorectal cancer (CRC) is the 2 nd leading cause of cancerrelated 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% APC K-ras p53 Lynch 3% MLH1 MLH2 MLH6 PMS2 No Adenoma Slow Yes Adenoma Fast CIMP 30-35% BRAF Sometimes Serrated Can be fast

3 3 Average annual age-specific CRC incidence Number / 100,000 population Incidence in men Incidence in women Mortality in men Mortality in women 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

4 4 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 Test FIT/FOBT annually Flex sig q5 yrs Colonoscopy q10 years CT colonography q5 years Fecal DNA q? years USPSTF US Multisociety ACG* EU * ACG favors colonoscopy as the primary screening test

5 5 Existing screening tests for CRC FOBT reduces CRC mortality Study Mandel (US) Kronborg (Denmark) Hardcastle (UK) Kewenter (Sweden) Shaukat (US) Patients (n) Years of follow-up Reduction annual FOBT Reduction biennial FOBT 46, % 21% 61, % 150, % 68, % 46, % 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

6 6 FOBT performance characteristics Study Rosman 2010 Park 2010 Brenner 2013 Sensitivity CRC Specificity CRC Sensitivity AA Specificity AA 36% 96% NR NR 30.8% 92.4% 13.7% 92.4% 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

7 7 FIT performance for CRC screening Meta-analysis: 19 studies 8 different FIT brands Sensitivity for CRC 79% [ ]; 71% for colonoscopy subgroup Specificity for CRC 94% [ ] 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

8 8 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

9 9 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

10 10 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)

11 11 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

12 12 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

13 13 Sigmoidoscopy reduces CRC incidence and mortality Study Atkin* (UK) Segnan* (Italy) Schoen (US) Patients (n) Years of follow-up CRC incidence reduction 170, % [ ] 34, % [ ] 154, % [ ] CRC mortality reduction 31% [ ] 22% [ ] 26% [ ] * 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 Study Atkin (UK) Segnan (Italy) Schoen* (US) Distal CRC incidence reduction 36% [ ] 24% [ ] 29% [ ] Proximal CRC incidence reduction 2% [ ] 11% [ ] 14% [ ] Distal CRC mortality reduction NR 27% [ ] 50% [ ] Proximal CRC mortality reduction NR 15% [ ] 3% [ ] * 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

14 14 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

15 15 Colonoscopy reduces CRC mortality 53% Zauber et al. N Engl J Med 2012 Colonoscopy and site-specific CRC risk Author Brenner (Germany) Doubeni (US) Nishihara (US) Study design Overall incidence Case-control 0.23 ( ) Case-control 0.29 ( ) Cohort 0.44 ( ) OR Left-sided 0.16 ( ) 0.26 ( ) 0.24 ( ) OR Right-sided 0.44 ( ) 0.36 ( ) 0.73 ( ) Brenner et al. Ann Intern Med 2011 Doubeni et al. Ann Intern Med 2013 Nishihara et al. NEJM 2013

16 16 Colonoscopy and CRC mortality by site Author Baxter (Canada) Singh (Canada) Study design Overall mortality Case-control 0.69 ( ) Cohort 0.71 ( ) OR Left-sided 0.33 ( ) 0.53 ( ) OR Right-sided 0.99 ( ) 0.94 ( ) 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 Author Baxter (Canada) Singh (Canada) Baxter (US) Nishihara (US) Study design Overall mortality Case-control 0.69 ( ) Cohort 0.71 ( ) Case-control 0.40 ( ) Cohort 0.32 ( ) OR Left-sided 0.33 ( ) 0.53 ( ) 0.24 ( ) 0.18 ( ) OR Right-sided 0.99 ( ) 0.94 ( ) 0.58 ( ) 0.47 ( ) Baxter et al. Ann Intern Med 2009 Singh et al. Gastroenterology 2010 Baxter et al. J Clin Oncol 2012 Nishihara et al. NEJM 2013

17 17 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 hemicolectomy (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

18 18 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

19 19 Where s the lesion? Where s the lesion?

20 20 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 ADR and risk of interval CRC 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% ADR Hazard Ratio (95% CI) ( ) ( ) < ( ) Kaminski et al. N Engl J Med 2010

21 21 ADR and risk of CRC and death Kaiser study: 314,872 subjects, 136 gastroenterologists, 712 interval cancers ADR < Hazard Ratio (95% CI) ( ) ( ) ( ) > ( ) 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 Variation in ADR among gastroenterologists Study Number of GI doctors Lowest ADR Highest ADR Barclay, % 32.7% Chen, % 41.1% Imperiale, % 44% Shaukat, % 39% Corley, % 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

22 22 Surveillance for colorectal cancer Why do we need surveillance? Cottet et al. Gut 2012

23 23 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

24 24 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= TA < 10 mm, RR 1.92 ( ) 3 or more, RR 5.01 ( ) TA > 10 mm, RR 6.40 ( ) Laiyemo, 2008 PPT LRA, 1.00 (ref) HRA, 1.68 ( ) 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

25 25 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?

26 26 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 7

27 27 What do we do after first surveillance exam? Baseline colonoscopy LRA HRA First surveillance HRA LRA Normal HRA LRA Normal Interval for second surveillance (y) * 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) Lieberman et al. Gastroenterology 2012 Multiple rounds of surveillance colonoscopy Lieberman et al. Gastroenterology 2012

28 28 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