Evidence Synthesis Number 135 Screening for Colorectal Cancer: An Updated Systematic Review for the U.S. Preventive Services Task Force Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 540 Gaither Road Rockville, MD 20850 www.ahrq.gov Contract No. HHSA-290-2012-00015-I-EPC4, Task Order No. 2 Prepared by: Kaiser Permanente Research Affiliates Evidence-based Practice Center Kaiser Permanente Center for Health Research Portland, OR Investigators: Jennifer S. Lin, MD, MCR Margaret A. Piper, PhD, MPH Leslie A. Perdue, MPH Carolyn Rutter, PhD Elizabeth M. Webber, MS Elizabeth O’Connor, PhD Ning Smith, PhD Evelyn P. Whitlock, MD, MPH AHRQ Publication No. 14-05203-EF-1 October 2015 This report is based on research conducted by the Kaiser Permanente Research Affiliates Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. HHSA-290-2012-00015-I-EPC4, Task Order No. 2). The findings and conclusions in this document are those of the authors, who are responsible for its contents, and do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services. The information in this report is intended to help health care decisionmakers—patients and clinicians, health system leaders, and policymakers, among others—make well-informed decisions and thereby improve the quality of health care services. This report is not intended to be a substitute for the application of clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information (i.e., in the context of available resources and circumstances presented by individual patients). The final report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied. None of the investigators has any affiliations or financial involvement that conflicts with the material presented in this report. Acknowledgments The authors acknowledge the following individuals for their contributions to this project: Smyth Lai, MLS, for creating and conducting the literature searches; Kevin Lutz, MFA, for his editorial assistance; Jennifer Croswell, MD, MPH, at AHRQ; current and former members of the U.S. Preventive Services Task Force who contributed to topic deliberations; and James Allison, MD, Jason Dominitz, MD, Samir Gupta, MD, MSCS, Linda Kinsinger, MD, Carrie Klabunde, PhD, Barnett Kramer, MD, MPH, Theodore R. Levin, MD, David Lieberman, MD, Marion Nadel, PhD, Perry Pickhardt, MD, MPH, Paul Pinsky, PhD, MPH, David Ransohoff, MD, and Jean Shapiro, PhD, for their expert feedback on this report. Screening for Colorectal Cancer ii Kaiser Permanente Research Affiliates EPC Structured Abstract Objective: We conducted this systematic review to support the U.S. Preventive Services Task Force in updating its recommendation on screening for colorectal cancer (CRC). Our review addresses three questions: 1) What is the effectiveness of screening programs in reducing incidence of and mortality from CRC? 2) What are the test performance characteristics of the different screening tests for detecting CRC, advanced adenomas, and/or adenomatous polyps based on size? and 3) What are the adverse effects of the different screening tests and do adverse effects vary by important subpopulations? Data Sources: We updated our prior systematic review and searched MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials to locate relevant studies for all key questions, from the end of our prior review through December 31, 2014. Study Selection: We reviewed 8492 abstracts and 696 articles against the specified inclusion criteria. We carried an additional 33 studies forward from our prior review. Eligible studies included English language studies conducted in asymptomatic screening populations, age 40 years and older, at average risk or unselected for risk factors. Data Analysis: We conducted dual independent critical appraisal of all included studies and extracted all important study details and outcomes from fair- or good-quality studies. We synthesized results by key question and type of screening test. We primarily used qualitative synthesis. We used random-effects meta-analyses when appropriate. We also summarized the overall strength of evidence for each key question. Results: Key Question 1. We included 26 unique, fair- to good-quality studies that assessed the effectiveness or comparative effectiveness of screening tests as a single application or in a screening program on CRC incidence and mortality. Flexible sigmoidoscopy (FS). Based on four RCTs (n=458,002), FS consistently decreased CRC-specific mortality compared to no screening at 11 to 12 years of followup, IRR 0.73 (95% CI, 0.66 to 0.82). Guaiac fecal occult blood test (gFOBT). Based on five RCTs (n=442,088), biennial screening with Hemoccult II compared to no screening resulted in reduction of CRC-specific mortality, ranging from 9 to 22 percentage points after two to nine rounds of screening with 11 to 30 years of followup. Colonoscopy. One prospective cohort (n=88,902) found CRC-specific mortality rate was lower at 24 years, in persons with self-reported screening colonoscopies, adjusted HR 0.32 (95% CI, 0.24 to 0.45), compared with those who had never had screening endoscopy. Key Question 2. We included 33 unique studies evaluating the one-time diagnostic accuracy of various screening tests compared to an adequate reference standard. Screening for Colorectal Cancer iii Kaiser Permanente Research Affiliates EPC Colonoscopy. Only four fair- to good-quality studies (n=4821) reported the diagnostic accuracy of colonoscopy generalizable to community practice. Based on three studies comparing colonoscopy to CTC or CTC-enhanced colonoscopy (n=2290), the per-person sensitivity for adenomas ≥10 mm ranged from 89.1 (95% CI, 77.8 to 95.7) to 94.7 (95% CI, 74.0 to 99.9) percent, and the per-person sensitivity for adenomas ≥6 mm ranged from 74.6 (95% CI, 62.9 to 84.2) to 92.8 (95% CI, 88.1 to 96.0) percent. Computed tomographic colonography (CTC). Based on studies of CTC with bowel preparation (prep) (k=7), the per-person sensitivity and specificity to detect adenomas ≥10 mm ranged from 66.7 percent (95% CI, 45.4 to 83.7) to 93.5 percent (95% CI, 83.6 to 98.1) and 86.0 percent (95% CI, 84.6 to 87.3) to 97.9 percent (95% CI, 95.7 to 99.1), respectively. The per- person sensitivity and specificity to detect adenomas ≥6 mm ranged from 72.7 percent (95% CI, 58.4 to 84.1) to 98.0 percent (95% CI, 90.9 to 99.8) and 79.6 percent (95% CI, 77.1 to 82.0) to 93.1 percent (95% CI, 89.5 to 95.7), respectively. Fecal immunochemical test (FIT)-based stool tests. The sensitivity varied considerably across different qualitative and quantitative FIT assays in the included diagnostic accuracy studies. Based on studies using colonoscopy as the reference standard (k=14), we focused on selected FDA-cleared qualitative and quantitative tests (i.e., OC-Light and OC FIT-CHEK respectively) evaluated in more than one study. Lowest sensitivity with accompanying specificity for CRC in studies using one stool specimen was 73.3 percent (95% CI, 48.3 to 90.2) and 95.5 percent (95% CI, 94.6 to 96.3), respectively. Similarly, the highest sensitivity and paired specificity was 87.5 percent (95% CI, 54.6 to 98.6) and 90.0 percent (95% CI, 89.2 to 92.4), respectively. In the largest studies, sensitivity ranged from 73.8 percent (95% CI, 62.3 to 83.3) for quantitative (n=9989) to 78.6 percent (95% CI, 61.0 to 90.5) for qualitative (n=18,296) test categories. In one small study (n=770) that tested three stool specimens, sensitivity was 92.3 percent (95% CI, 69.3 to 99.2) and specificity was reduced to 87 percent (95% CI, 85 to 89). Results from studies using differential followup generally fell within these ranges. One fair- quality study (n=9989) evaluated an mtsDNA assay (FIT plus stool DNA) in comparison to an OC FIT-CHEK test and found that the sensitivity to detect CRC was higher than FIT (92.3 percent [95% CI, 84.0 to 97.0]) but with a tradeoff of a lower specificity to detect CRC (84.4 percent [95% CI, 83.6 to 85.1]). Blood test. Thus far, only one blood test, which detects circulating methylated SEPT9 DNA, has been prospectively evaluated in a screening population. This test had a sensitivity of only 48.2 percent (95% CI, 32.4 to 63.6) to detect CRC. Key Question 3. We included 97 fair- to good-quality studies for the harms of CRC screening. Endoscopy (colonoscopy and FS). Serious adverse events from screening colonoscopy or colonoscopy in asymptomatic persons is relatively uncommon, with a pooled estimate of four perforations (k=26) per 10,000 procedures (95% CI, 2 to 5 per 10,000) and eight major bleeds (k=22) per 10,000 procedures (95% CI, 5 to 14 per 10,000). Serious adverse events from screening FS are even less common, with a pooled estimate of one perforation (k=16) per 10,000 procedures (95% CI, 0.4 to 1.4 per 10,000), and two major bleeds (k=10) per 10,000 procedures (95% CI, 1 to 4 per 10,000).