There is No One Best CRC Screening Test: The Proof and the Benefits of Getting FIT

There is No One Best CRC Screening Test: The Proof and the Benefits of Getting FIT James E. Allison, MD, FACP, AGAF Clinical Professor of Medicine Emeritus University of California San Francisco Emeritus Adjunct Investigator Kaiser Division of Research

Lecture Outline The CRC problem and screening as one solution The elephant in the screening test room and how it got there The current CRC Screening Guidelines (2008) ACS/Multisociety Taskforce, USPSTF, ACG What are precancerous polyps and how often are they fatal? Is there evidence that colonoscopy is the best/preferred CRC screening test? The U.S. isn t a FIT friendly environment The FOBT rap sheet and the evidence in support of FIT The PCP how you can help solve the problem? Summary Conclusion

Colorectal Cancer Sporadic (average risk) (65% 85%) Family history (10% 30%) Rare syndromes (<0.1%) Familial adenomatous polyposis (1%) Hereditary nonpolyposis colorectal cancer (Lynch Syndrome) (5%) CENTERS FOR DISEASE CONTROL AND PREVENTION

The Problem: Colorectal Cancer

The Problem: Colorectal Cancer High prevalence in patients 50 years In 2014 it is estimated that there will be 137,000 new cases and 50,000 deaths in U.S. Represents Cancer statistics, 2012. 9% CA Cancer of J Clin. all 2012;1:10-29 cancer deaths in the U.S Third most common cancer in women and men Third leading cause of cancer death in U.S. 67,000 cases and 28,600 (40%) deaths in women in the U.S. yearly Cancer statistics, 2012. CA Cancer J Clin. 2012;1:10-29. 2014, American Cancer Society, Inc., Surveillance Research

Colorectal Cancer: The Risk The lifetime risk of CR cancer in the U.S. approaches 6% for both men and women Almost 50% of those affected will die of the disease A person at age 50 has a 5% lifetime risk of being diagnosed with CR cancer and a 2.5% chance of dying from it Burt RW. Gastroenterology. 2000;119:837-853. USPSTF. Ann Intern Med. 2002;137:129-131.

Colorectal Cancer Screening Arguments for screening: In most cases colorectal cancer develops slowly from an adenomatous polyp, a process which can take up to 10 years The polyps most likely to become cancers can be identified and removed thus preventing cancer Detection of early stage cancers allows for CRC mortality reduction

Colorectal Cancer Screening We have a problem in U.S. Compelling argument for screening Multiple effective screening tests are available Cost-effectiveness established but.. 28% of Americans of screening age have never been screened and a disproportionate number of advanced cancers are found in the uninsured and underserved population

Colorectal Cancer Screening NCI Cancer Bulletin August 21, 2007 The Imperative of Improving Colorectal Cancer Screening Rates It s a troubling fact that colorectal cancer screening rates continue to lag well behind those for other cancers The reasons behind this shortfall are complex There is widespread agreement that if significant improvements in colorectal cancer screening are to be realized, the primary care setting will be the most crucial contributor

CDC MMWR January 2012 & November 2013 In the U.S. only 65% of adults are currently up-to-date with CRC screening recommendations CDC s Colorectal Cancer Control Program has set a goal of increasing the CRC screening rate to 80% by 2014 No CRC screening strategy has been shown to be superior but, colonoscopy is the predominant method for CRC screening in the U.S. Primary-care providers are the most common source for a CRC screening recommendation. Many providers believe that colonoscopy is the best test option and do not offer other screening tests to their patients The potential to increase screening rates exists if health-care providers identify the test that their patient is most likely to complete and consistently offer all recommended screening tests

2000-2009 American College of Gastroenterology CRC Screening Guidelines Colonoscopy every 10 years, beginning at age 50, remains the preferred CRC screening strategy It is impractical for a PCP to discuss 6 different options for CRC screening with each patient. Recommending one preferred strategy simplifies the discussion. Colonoscopy is the preferred strategy because it is the best test Rex D, Johnson DA, Anderson JC et al Am J Gastroenterol. 2009;104:739-750 Rex D Medscape Medical News March 10,2009

Flexible Sigmoidoscopy The Opinion Leaders Speak There is suspicion among physicians that in recommending flexible sigmoidoscopy to screen persons for colorectal cancer, we are promoting a suboptimal approach. Relying on flexible sigmoidoscopy is as clinically logical as performing mammography of one breast to screen women for breast cancer. The failure of insurance companies to cover the costs of colonoscopic screening is no longer tenable. Podolsky DK Editorial NEJM 2000:343:207-208

The Media Speaks The Katie Couric Effect It's considered the most effective test for detecting colon cancer, and as Katie Couric says in her special report, "It really didn't hurt." Katie s first colonoscopy Cram P, Fendrick MA, Inadomi J, et al. Arch Intern Med 2003;1601-1605.

Flex Sigmo FOBT CT/MRI Colonography Optical Colonoscopy

Colorectal Cancer Awareness Month Baltimore, MD March, 2012 The Message: Get a Colonoscopy not Be screened for Colorectal Cancer

Stool Tests 2008 ACS/MSTF and ACR CRC Screening Guidelines Average Risk Individuals Menu of recommended screening tests Fecal occult blood testing (sensitive GT or FIT) Stool DNA test (sdna) Structural Exams Double-contrast barium enema Flexible sigmoidoscopy CT Colonography (CTC) Colonoscopy ACS/MSTF and ACR Guidelines Levin B, Lieberman D, McFarland B, Smith RA et al. CA Cancer J Clin 2008

2008 ACS/USMSTF CRC Guidelines Precautions Re Menu of Options If fecal tests are used the opportunity for prevention is both limited and incidental and not the primary goal of CRC screening with these tests It is the strong opinion of this expert panel that colon cancer prevention should be the primary goal of CRC screening and that providers and patients should understand that noninvasive tests are less likely to prevent cancer compared with the invasive tests

Pathway to Colorectal Cancer 10+ years Normal Adenoma Carcinoma 25% of U.S. population by age 50 have polyps. Up to 50 percent of individuals will develop a colorectal adenoma (polyp) in their lifetime.

What are colonic polyps, adenomas, advanced neoplasms? Polyp Benign tumor that protrudes into the lumen of the colon Adenoma Benign polyp derived from the lining of the colon Advanced adenoma Refers to polyps 1 cm or greater or with villous features or high grade dysplasia Not cancers and natural history is unknown Colonic neoplasm Described in the gastroenterology literature as advanced; predominately advanced adenomas and very few Stage 4 cancers

How likely are they to kill you? Most polyps, even the advanced ones, do not directly lead to death from colon cancer Only 6% of these lesions will later develop into CRC Only about 2.5/1000 polyps per year progress to cancer Large polyps (>1cm) become colorectal cancers at a rate of roughly 1% per year A large polyp, left in situ, has a cumulative risk of malignancy at 20 years of only 24% The development of invasive cancer from a small (<10mm) adenoma is extremely unlikely in less than five years Ransohoff DF Editorial. The Lancet 2002; 359:1266-7. Stryker S, Wolff B, Culp C, et al. Gastroenterology 1987; 93:1009-13. Eide T. Int J Cancer 1986; 38:173-6. Ahlquist DA.. Gastroenterology 2010(6):2127-39.

Overdiagnosis - Definition Overdiagnosis labeling innocuous tumors cancer and treating them as though they could be lethal when in fact they are not dangerous Overdiagnosis is pure, unadulterated harm.. Barnett Kramer MD, MD Associate Director for disease prevention NIH The NY Times October 21, 2009

Flexible Sigmoidoscopy the facts Medicare data reveals that the use of sigmoidoscopy fell 54% from 1993 to 2003 Most of the fall occurred after 2001 when Congress approved Medicare reimbursement for screening colonoscopy Over the same period there has been a 6 fold increase in screening colonoscopies

Average Risk Individuals Menu of recommended screening tests: Fecal occult blood testing (FOBT) Double-contrast barium enema Colonoscopy CT Colonography (CTC) Stool DNA test (sdna) ACS/USMSTF and ACR Guidelines Levin B, Lieberman D, McFarland B, Smith RA et al. CA Cancer J Clin 2008

Double contrast BE - the facts Very little screening for colon cancer by DCBE occurs in the U.S. The utilization of this screening test has declined greatly in the Medicare population, the Department of Veterans Affairs, and in current clinical practice

Average Risk Individuals Menu of recommended screening tests: Fecal occult blood testing (FOBT) Colonoscopy CT Colonography (CTC) Stool DNA test (sdna) ACS/MSTF and ACR Guidelines Levin B, Lieberman D, McFarland B, Smith RA et al. CA Cancer J Clin 2008

Virtual Colonoscopy - the facts The CMS ruled against covering this test for Medicare patients stating that the evidence was inadequate to conclude that CT colonography is an appropriate colorectal cancer screening test under 1861(pp) of the Social Security Act In 2008, The USPSTF did not include CTC on its list of recommended screening tests There is limited reimbursement for CTC in most states and that will continue until such time as CTC gets USPSTF and CMS endorsement

Average Risk Individuals Menu of recommended screening tests: Fecal occult blood testing (FOBT) Colonoscopy Stool DNA test (sdna) ACS/MSTF and ACR Guidelines Levin B, Lieberman D, McFarland B, Smith RA et al. CA Cancer J Clin 2008

Average Risk Individuals Menu of recommended screening tests: Colonoscopy Stool DNA test (sdna) ACS/MSTF and ACR Guidelines Levin B, Lieberman D, McFarland B, Smith RA et al. CA Cancer J Clin 2008

Average Risk Individuals Menu of recommended screening tests: Colonoscopy ACS/MSTF and ACR Guidelines Levin B, Lieberman D, McFarland B, Smith RA et al. CA Cancer J Clin 2008

2008 U.S. Preventive Services Task Force CRC Screening Guidelines Average Risk Individuals Age 50-75 Stool Tests Menu of recommended screening tests Fecal occult blood testing Fecal Immunochemical Test (FIT) or Sensitive Guaiac Test (Hemoccult Sensa) Structural Exams Flexible sigmoidoscopy + sensitive GT or FIT Colonoscopy Screening for colorectal cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med 2008;149:627-37

The Media and Opinion Leaders Speak: The Aftermath Congress bypassed CMS evaluation and added colonoscopy to the covered colon cancer screening tests for Medicare patients by mandate Since Medicare s decision to reimburse for screening colonoscopy, some gastroenterologists are spending up to 50% of their practice time simply performing colonoscopy Some commercial insurance plans are spending more every year on colonoscopies than on cardiac bypass, hip and knee surgeries, combined * *Health Care Incentives Improvement Institute, Inc.

Cecal Stampede: The Headlong Rush for Screening Colonoscopy Lawson MJ, Tobi M Dig Dis Sci 2008;53(4):871-4

CRC Screening Test Trends 2000-2008

Rodney Dangerfield and FOBT They just don t get no respect.

Trends in Endoscopy: US 1997-2004 Increasing for Everyone but the Uninsured 50 1997 1999 2001 2002 2004 Prevalence (%) 40 30 20 10 31 34 39 41 45 16 15 17 18 19 0 Total No Health Insurance A flexible sigmoidoscopy or colonoscopy within the past five years. 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.

Is Colonoscopy the Best Screening Test? Although two randomized controlled trials are in progress, there is no evidence yet proving the assertion that there is one best screening test. In 2008 a decision analysis using 2 microsimulation models supported the idea that CRC screening with annual sensitive FOBT (FIT) was as effective as colonoscopy screening every 10 years Data suggests that the protection against cancer afforded by having a negative colonoscopy is quite different in the proximal (right) colon (29-56%) than in the left colon (80%). Lakoff J, Paszat LF, Saskin R, et al Clinical Gastro and Hepatology. 2008;6:1117-1121. Baxter NN, Goldwasser MA, Paszat LF, et al Ann Intern Med. 2009 Jan 6;150(1):1-8. Brenner H, Hoffmeister M, Arndt V, et al. J Natl Cancer Inst 2010;102:89 95. Baxter NN, Rabeneck L, J Natl Cancer Inst. 2010 Jan 20;102(2):70-130. Brenner H, Chang-Claude J, Seiler CM, et al Ann Intern Med. 2011;154:22-30. Zauber AG, Lansdorp-Vogelaar I, et al Ann Intern Med. 2008 Nov 4;149(9):659-69.

Explanations Colonoscopy: reduction in benefit for proximal CRC Many proximal lesions are sessile, pale, and difficult to identify and remove completely Quality of bowel preparation is often less optimal in the proximal colon CRC surveillance recommendations are predicated upon a slow transition from adenoma to carcinoma but some proximal CRCs develop rapidly through microsatellite instability and CpG island Methylator phenotype pathways The precursor for this rapidly developing CRC is likely the serrated adenoma, a lesion difficult to visualize with colonoscopy and more likely found in the proximal colon Shaukat A Detection of serrated lesions: We are still in the teething stage CG&H 2014 in press

Is Colonoscopy the Best Screening Test? The risk (2.8 in 1000) of serious complications (perforations, hemorrhage, diverticulitis, CV events, severe abdominal pain and death) detracts from any benefit colonoscopy may have over other less invasive screening options Evidence suggests the manpower necessary to provide a skilled colonoscopic examination for all eligible U.S. citizens is inadequate. Seef LC, Manninen DL, et al. Gastroenterology 2004; 127:1661-1669. Levin TR, Editorial Gastroenterology 2004; 127:1841-1849. Lieberman, DA, et al. N Engl J Med 2000; 343:162-8.

FOBTs: The Options $4.75 $23.00

The Rap Sheet on FOBT If used the opportunity for CRC prevention is limited and incidental. Screening for occult blood has been proven to be an inherently insensitive and nonspecific marker for screen relevant neoplasia. Repeated testing required and unlikely to be done. It is not the most effective screening strategy.

The take home message is The yield for adenomas in the FIT group was low, which indicates that FIT is not a good test for detecting adenomas. N Engl J Med 2012;366:697-706.

FIT Education 101 Use the term FIT to describe fecal tests that measure hemoglobin in feces by immunochemical methodology Advantages of FIT over standard gfobt screening tests include: Fecal immunochemical tests (FITs) are more sensitive at detecting both CRC and adenoma Dietary restriction is not necessary and specimen collection allows for less stool handling Specific for colorectal bleeding Can be developed and interpreted by automation Inexpensive, less harm to patients, more participation by under screened groups and a lower overall cost for CRC screening Rabeneck L, Rumble RB, Thompson F, Can J Gastroenterol. 2012;26:131-47 Allison JE, Fraser CF, Halloran SP et al Gastroenterology 2012;142:422 431.

FIT Performance Characteristics Test Magstream 1000 HP Carcinoma Advanced Adenoma OC-Sensa Micro Carcinoma Advanced Adenoma Sensitivity Percent (95% CI) 66 (55-76) 20 (17-23) 92 (64-100) 34 (22-47) Specificity Percent (95% CI) 95 (94-95) 90 (88-93) 91 (89-91) Morikawa T, Katao J, Yamafi Y et al Gastroenterology 2005;125:422-428 Park D, Ryu S, Kim YH et al Am J Gastro 2010;105:20170-2025

Quantitative FIT Fecal Hgb level of Lesions Found at Colonoscopy Characteristics Patients (n) (%) Lesion size (SD) {95%CI}, mm Mean FIT result (SD) {95%CI}, ng/ml Normal 739 (73.9) 35 (143) {25-45} Advanced Adenoma 74 (7.4) 12.6 (6.4) {11.2-14.1} 485 (744) {315-654} Colon Site Proximal 31 (12.7) 12.4 (6.8) {10.1-14.7} 499 (774) {227-772} Distal 32 (17.2) 12.9 (6.2) {11.0-14.7} 501 (737) {229-724} Cancer Stages Dukes A & B 15 (88.2) 30.7 (9.3) {26.0-35.4} 1045 (777) {652-1439} Dukes C or D 2 (11.8) 50.0 (7.10) {40.2-59.8} 1399 (1452) {614-3411} Colon site Proximal 10 (58.8) 33.8 (10.30) {27.4-40.2} 701 (672) {285-1118} Distal 7 (41.2) 31.7 (12.5) {22.4-41.0} 1637 (720) {1104-2171} Levi Z, Rozen P, Hazazi R, et al. Ann Intern Med 2007;146:244-255.

Patient Adherence to FOBT Evidence Answers the Challenge Steele RJ et al. Gut. 2009 Apr;58(4):530-5

Kaiser FIT Screening Program

Kaiser FIT Screening Program Adherence rates for KP s annual FIT screenings are high Over a 5-year period more than 85 % of KP members were adequately screened FIT found 73 percent of the CRC cases diagnosed in 2007 and 80 percent of the cases found in 2008

Mirror Mirror on the wall Which is the Best FIT - Test of them all? Ann Intern Med. 2014;160:171-181.

2012 NCCRT /ACS FOBT Clinician s Reference Resource FOBT has been shown to decrease both incidence of and mortality from CRC Modeling studies suggest years of life saved through a high-quality FOBT screening program are the same as with a high-quality colonoscopy screening program These elements make FOBT a reasonable choice for patients http://nccrt.org/about/provider-education/fobt-clinicians-reference-resources/

Shared decision making is important when selecting a screening test because the currently available colorectal cancer screening tests are believed to be similarly efficacious. Screening for Colorectal Cancer: A Guidance Statement from the American College of Physicians Ann Intern Med. 2012;156:378-386.

GIE 2013 Screening and Surveillance for CRC: state of the art Colonoscopy remains the dominant CRC screening strategy in the U.S. but is less effective at preventing right sided CRC than previously thought FIT has emerged as an effective low cost alternative to colonoscopy and is considered by some an equivalent or superior approach to screening as compared to colonoscopy Kahi CJ, Anderson JC, Rex DK GIE 2013 77:335-350

JAMA PATIENT PAGE Options for CRC Screening Evidence does not yet support any one screening test over another, so in deciding which screening option is best for you, consider your personal health situation and talk with your doctor JAMA August 14, 2013 Volume 310, Number 6

Summary FIT/FOBT is a CRC screening test with proven effectiveness for both early detection and prevention FOBT/FIT is a cheap, effective and currently available way to estimate absolute risk for individual persons so that screening colonoscopy may be more efficiently targeted to those with advanced neoplasia Effective repeated screenings can be achieved in large average risk populations As of 2014, fecal blood remains the best stool marker for advanced neoplasms and cancer

The other screening tests Fecal DNA test

Fecal DNA 2014 What is it? Renamed Molecular Stool Test An automated multi-target stool DNA test (MT-sDNA) comprising two methylated DNA markers, mutant KRAS and fecal hemoglobin and a preservative buffer with stool collection to prevent DNA degradation Unpublished results in large multicenter study (N=10000) showed sensitivity of 92% for cancer and 42% for advanced adenomas but specificity only 88% Lidgard GP, Domanico MJ, Bruinsma JJ, et al Clin Gastroenterol Hepatol 2013; 11:1313-8

Role of the Primary Care Physician in Colon Cancer Screening Educate and Facilitate: Recommend colorectal cancer screening Provide information on the screening options Group classes lead by NP,PA or yourself Refer to website: practice, HMO, AHRQ, CDC Automated phone Be sure all positive tests are evaluated with colonoscopy

Conclusions It is unrealistic to believe that any one screening test will detect all advanced neoplasms Decisions on how to population screen for colon cancer should take into consideration upfront costs, patient preferences, and the potential risks of screening tests for otherwise healthy people As screening has been demonstrated to save lives, any evidence based, guideline recommended screening test should be acceptable at this time

Can we, with good conscience, recommend screening tests other than colonoscopy to our average risk patients?

QUESTIONS?

2008 USPSTF Guidelines Average risk adults ages 75-85 The United States Preventive Services Task Force (USPSTF) recommends colorectal cancer screening on a case-by-case basis for healthy adults without significant life-limiting co-morbidities between the ages of 75 and 85

The other screening tests Flexible Sigmoidoscopy

Flexible Sigmoidoscopy Data supporting use: 4 case-control studies have shown mortality reduction primarily in the area examined but also some more proximally 2010-2011 RCTs showing decrease in incidence (31-33%) and mortality (38-43%) per protocol with once only Flex Sig between ages of 55 and 64 2012 PLCO RCT showing decrease in incidence (21% - 26%) and mortality (50%) Atkin WS, Edwards R, Kralj-Hans I*Lancet. 2010 May 8;375(9726):1624-33. Segnan, N, Armaroli P, Bonelli L et al J Ntl Cancer Inst 2011;103:1-13 Schoen RE, Pinsky PF, Weissfeld JL, et N Engl J Med 2012

The other screening tests Virtual Colonoscopy (CTC)

Virtual Colonoscopy What is it? Imaging procedure uses computer programming to combine multiple helical CT scans in order to create two- or threedimensional images of the interior of a patient's colon

Case Examples

Virtual Colonoscopy Issues surrounding it: 10% of cases have a false positive result due to stool, diverticula, prominent fold. Unknown ability to detect flat adenomas Any lesions seen require colonoscopy to remove Radiation exposure* 10mSV per exam. The harms at this dose unknown but the linear-no-threshold model predicts 1 additional individual per 1000 would develop cancer in their lifetime at this level of radiation Detects extracolonic findings (up to 16% in patients having their first CTC) that often trigger a diagnostic search that only sometimes identifies important disease * *N Engl J Med 2007:357:2277-84. *USMSTF 7 October 2008 http://www.annals.org/