Final Research Plan

Colorectal Cancer: Screening

May 16, 2019

Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

The final Research Plan will be used to guide a systematic review of the evidence by researchers at an Evidence-based Practice Center. The resulting Evidence Report will form the basis of the USPSTF Recommendation Statement on this topic.

The draft Research Plan was available for comment from January 3 until January 30, 2019 at 5:00 p.m., ET.

Figure 1 is the analytic framework that depicts the three Key Questions to be addressed in the systematic review. The figure illustrates how screening for colorectal cancer in adults age 40 years or older may result in a decrease in colorectal cancer incidence, colorectal cancer mortality, or all-cause mortality (Key Question 1). There is also a question related to the accuracy of screening tests used to detect colorectal cancer or adenomatous polyps (Key Question 2) and potential harms of screening (Key Question 3).

* Screening technologies with conditional approval from the U.S. Food and Drug Administration for screening for colorectal cancer.

Abbreviations: CTC=computed tomography colonography; FIT=fecal immunochemical test; FS=flexible sigmoidoscopy; gFOBT=guaiac-based fecal occult blood test; mSEPT9=methylated septin 9 gene DNA; sDNA test (+/- FIT)= stool DNA test with or without FIT; SSP=sessile serrated polyp.

  1. What is the effectiveness or comparative effectiveness of screening programs in reducing colorectal cancer, mortality, or both?
    1. Does the effectiveness of screening programs vary by subgroups (e.g., age, sex, or race/ethnicity)?
  2. What is the accuracy of direct visualization, stool-based, or serum-based screening tests for detecting colorectal cancer, advanced adenomas, or adenomatous polyps based on size?
    1. Does the accuracy of the screening tests vary by subgroups (e.g., age, sex, or race/ethnicity)?
  3. What are the serious harms of the different screening tests?
    1. Do the serious harms of screening tests vary by subgroups (e.g., age, sex, or race/ethnicity)?

Contextual questions will not be systematically reviewed and are not shown in the Analytic Framework.

  1. What is the adherence (or uptake) to testing for each of the currently available screening tests?
  2. What is the adherence to followup diagnostic colonoscopy for abnormal screening test results (i.e., stool-based testing, flexible sigmoidoscopy, or computed tomography colonography)?
  3. Does the natural history of adenomas vary by age, sex, or race/ethnicity?
  4. Does the prevalence or location of colorectal lesions (colorectal cancer, advanced adenomas, or small adenomatous polyps) vary by age, sex, or race/ethnicity?
  5. What models or tools are available for assessing the risk of developing colorectal cancer in average-risk screening populations?
  6. How are newer screening tests (e.g., stool DNA test with or without fecal immunochemical test, or computed tomography colonography) being implemented in clinical care, and what are the implementation considerations around these tests?
  7. Are there colorectal cancer screening decision models, other than those conducted by CISNET (Cancer Intervention and Surveillance Modeling Network), that address the age to start screening, age to stop screening, and comparative effectiveness of various screening strategies? What are their findings?
  8. What is the effectiveness of screening for colorectal cancer in adults younger than age 50 years who are at higher risk for colorectal cancer based on family history (excluding known genetic syndromes or a first-degree relative with colorectal cancer before age 60 years)?

The Research Approach identifies the study characteristics and criteria that the Evidence-based Practice Center will use to search for publications and to determine whether identified studies should be included or excluded from the Evidence Report. Criteria are overarching as well as specific to each of the key questions (KQs).

  Include Exclude
Populations Adults age ≥40 years in average-risk or unselected populations; screening populations (i.e., no symptoms) Populations selected for personal or family history of colorectal cancer (e.g., one or more first-degree relatives with colorectal cancer diagnosed before age 60 years or two or more first-degree relatives diagnosed at any age), known genetic susceptibility syndromes (e.g., Lynch Syndrome, familial adenomatous polyposis), or personal history of inflammatory bowel disease; nonscreening populations (e.g., persons who have symptoms, test positive on screening, have iron deficiency anemia, or are under surveillance for a previous colorectal lesion)
Settings Settings representative of community practice for flexible sigmoidoscopy and colonoscopy studies; studies conducted in developed countries (categorized as “very high” on the 2017 Human Development Index, as defined by the United Nations Development Programme) Primarily research-based settings for endoscopy studies (e.g., small studies aimed at evaluating new endoscopy technologies, studies with operator or resource characteristics that are not applicable to community practice); developing countries
Screening tests KQ 1: Any program of colorectal cancer screening, including endoscopy, imaging, urine, stool, or serum testing

KQs 2–3:

Direct visualization tests:

  • Colonoscopy
  • Flexible sigmoidoscopy
  • Computed tomography colonography
  • Capsule endoscopy*

Stool-based tests:

  • High-sensitivity guaiac fecal occult blood test
  • Fecal immunochemical test (quantitative and qualitative testing)
  • Multitarget stool DNA test (with or without fecal immunochemical testing)

Serum-based test:

  • Circulating methylated septin 9 gene DNA test (mSEPT9)*

Urine-based test

KQs 2, 3: New technologic enhancements to colonoscopy or computed tomography colonography; Hemoccult II (review of test performance and harms limited to include only high-sensitivity guaiac fecal occult blood test); stool testing using in-office digital rectal examination; double-contrast barium enema; magnetic resonance colonography
Comparisons KQ 1: No screening or alternate screening strategy

KQ 2: Diagnostic accuracy studies that use colonoscopy as a reference standard

KQ 3: No comparator necessary


Outcomes KQ 1: Colorectal cancer incidence (by stage and location) or interval colorectal cancer; colorectal cancer–specific or all-cause mortality

KQ 2: Test accuracy, including: sensitivity and specificity (per person for all tests and per lesion for direct visualization tests), positive and negative predictive value (per person for all tests and per lesion for direct visualization tests), and false-positive and false-negative rates for identifying colorectal cancer, advanced adenoma (high-grade dysplasia, villous histology, or size ≥10 mm), or adenomatous or sessile serrated polyps by size (i.e., ≤5 mm, 6 to 9 mm, ≥10 mm) or by location (e.g., proximal or distal colon, rectum)

KQ 3: Serious harms requiring unexpected or unwanted medical attention (e.g., requiring hospitalization) and/or resulting in death, including but not limited to perforation, major bleeding, severe abdominal symptoms, cardiovascular events; extracolonic findings, and subsequent diagnostic workup, and adverse events from diagnostic testing for incidental findings on computed tomography colonography; radiation exposure per each computed tomography colonography examination

KQ 1: Incidence of adenomas or advanced neoplasia (composite outcome of advanced adenomas and colorectal cancer)

KQ 3: Minor harms, defined as those not necessarily needing or resulting in medical attention (e.g., patient dissatisfaction, anxiety or worry, minor gastrointestinal complaints)

Study design All KQs: Fair- to good-quality studies

KQ 1: Randomized, controlled trials; controlled clinical trials; prospective cohort studies

KQ 2: Randomized, controlled trials; controlled clinical trials; cohort studies; nested case-control diagnostic accuracy studies; and screening registry studies

KQ 3: Randomized, controlled trials; controlled clinical trials; large screening registry or database observational studies; cohort studies; and systematically selected case series

All KQs: Poor-quality studies

KQ 1: Decision analyses

KQ 2: Diagnostic accuracy studies without a reference standard or without representation of a full spectrum of disease (e.g., case-control studies, studies that excluded indeterminate results)

KQ 3: Case studies

* Screening technologies with conditional approval by the U.S. Food and Drug Administration for screening for colorectal cancer.
This review will be accompanied by commissioned collaborative microsimulation decision analyses by CISNET.

In addition to this updated systematic review, the USPSTF has commissioned a set of decision analyses from CISNET to support the recommendation process, as it did for the previous updates in 2008 and 2016. The commissioned decision analyses will help inform how the benefits and harms of colorectal cancer screening strategies may vary by the type of screening test, different starting and stopping ages, and the time interval between repeated screenings.

The draft Research Plan was posted on the USPSTF Web site for public comment from January 3 to January 30, 2019. In response to public comment, the USPSTF modified the analytic framework to be more consistent with USPSTF methodology and to indicate which screening tests have conditional approval from the U.S. Food and Drug Administration. The USPSTF also added urine-based tests as a screening method. Additionally, in the inclusion and exclusion criteria, the USPSTF revised the language to distinguish between the cancer location (proximal or distal colon or rectum) and added sessile serrated polyps as an outcome of interest for test accuracy studies. The USPSTF made no other substantive changes that altered the scope of the review.