Annals of Internal Medicine BEYOND THE GUIDELINES

How Would You Screen This Patient for Colorectal Cancer?

Grand Rounds Discussion From Beth Israel Deaconess Medical Center
Risa B. Burns, MD, MPH; Carol M. Mangione, MD, MSPH; David S. Weinberg, MD, MSc; and Zahir Kanjee, MD, MPH

Colorectal cancer (CRC) is the third leading cause of cancer death for men and women
in the United States, with an estimated 52 580 people expected to die in 2022. Most
frequently, CRC is diagnosed among persons aged 65 to 74 years. However, among
persons younger than 50 years, incidence rates have been increasing since the mid-
1990s. In 2021, partially because of the rising incidence, the U.S. Preventive Services
Task Force (USPSTF) recommended CRC screening for adults aged 45 to 49 years
(Grade B recommendation). Options for CRC screening include stool-based and
direct visualization tests. The USPSTF did not recommend a specific screening test;
rather, its guidance was to select a test after a discussion with the patient. Here, a
primary care physician and a gastroenterologist discuss the recommendation to
begin CRC screening at age 45, review options for CRC screening, and discuss how
to choose among the available options.

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ABOUT BEYOND THE GUIDELINES

Beyond the Guidelines is a multimedia feature based on
selected clinical conferences at Beth Israel Deaconess
Medical Center (BIDMC). Each educational feature focuses
on the care of a patient who “falls between the cracks”
in available evidence and for whom the optimal clinical
management is unclear. Such situations include those
in which a guideline finds evidence insufficient to make
a recommendation, a patient does not fit criteria mapped
out in recommendations, or different organizations pro-
vide conflicting recommendations. Clinical experts provide
opinions and comment on how they would approach the
patient's care. Videos of the patient and conference,
the slide presentation, and a CME/MOC activity accom-
pany each article. For more information, visit Annals.
org/GrandRounds.
Series Editor, Annals: Deborah Cotton, MD, MPH
Series Editor, BIDMC: Risa B. Burns, MD, MPH
Series Assistant Editors: Zahir Kanjee, MD, MPH;
Howard Libman, MD; Eileen E. Reynolds, MD; Gerald
W. Smetana, MD
This article is based on the Medical Grand Rounds con-
ference held on 14 April 2022.
M s. N is a 44-year-old woman with a history of hyper-
tension, migraine headaches, and gastroesophageal
reflux. At a recent annual examination, her primary care
physician (PCP) recommended colorectal cancer (CRC)
screening. Ms. N is married and has 2 children at home.
She has no family history of CRC or colonic polyps. She
has undergone routine screening for breast and cervi-
cal cancer. She works full-time and is trying to walk for
exercise. She reports no tobacco or alcohol use. Ms. N
is unsure how to decide among available options for
CRC screening.
MS. N'S STORY (VIDEO AT ANNALS.ORG)
See the Patient Video (Video 1, available at Annals.
org) to view the patient telling her story.
At my most recent visit, my PCP brought up that the
age for colon cancer screening had been lowered from
50 to 45 and I was just about to turn 45. She asked me if I
would like to get screened and I didn't know really much
about anything. I had a few friends who are older than me
who had gotten screened, so I knew that there was a
pretty heavy preparation process for it, but I wasn't aware
that I had options. My PCP explained that I could have a
colonoscopy or that I could use a stool DNA test. I don't
think it's as effective a screening process, but it is another
option that would not be as invasive, I believe. At that
appointment, I told her that I would be comfortable get-
ting a colonoscopy because it was all I knew about. I

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BEYOND THE GUIDELINES
Table 1. Characteristics of Recommended Colorectal Cancer Screening Strategies
Screening Method*
Stool-based tests
High-sensitivity gFOBT
FIT
sDNA-FIT
Direct visualization tests
Colonoscopy
CT colonography
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How Would You Screen This Patient for Colorectal Cancer?
Frequency† Evidence of Efficacy
Every year • Evidence from RCTs that gFOBT
reduces colorectal cancer mortality
• High-sensitivity versions (eg,
Hemoccult SENSA) have superior test
performance characteristics than older
tests (eg, Hemoccult II), although there
is still uncertainty about the precision
of test sensitivity estimates. Given this
uncertainty, it is unclear whether high-
sensitivity gFOBT can detect as many
cases of advanced adenomas and
colorectal cancer as other stool-based
tests
Every year • Evidence from 1 large cohort study
that screening with FIT reduces colo-
rectal cancer mortality
• Certain types of FIT have improved ac-
curacy compared to gFOBT and
HSgFOBT (20 μg hemoglobin per
gram of feces threshold was used in
the CISNET modeling)
Every 1 to 3‡ y • Improved sensitivity compared with
FIT per 1-time application of screening
test
• Specificity is lower than that of FIT,
resulting in more false-positive results,
more follow-up colonoscopies, and
more associated adverse events per
sDNA-FIT screening test compared
with per FIT test
• Modeling suggests that screening ev-
ery 3 y does not provide a favorable
(ie, efficient) balance of benefits and
harms compared with other stool-
based screening options (ie, annual
FIT or sDNA-FIT every 1 or 2 y)
• Insufficient evidence about appropri-
ate longitudinal follow-up of abnormal
findings after a negative follow-up
colonoscopy
• No direct evidence evaluating the
effect of sDNA-FIT on colorectal can-
cer mortality
Every 10 y • Evidence from cohort studies that
colonoscopy reduces colorectal can-
cer mortality
• Harms from colonoscopy include
bleeding and perforation, which both
increase with age
Every 5 y • Evidence available that CT colonogra-
phy has reasonable accuracy to detect
colorectal cancer and adenomas
• No direct evidence evaluating effect
of CT colonography on colorectal can-
cer mortality
• Limited evidence about the potential
benefits or harms of possible evalua-
tion and treatment of incidental
extracolonic findings, which are com-
mon. Extracolonic findings detected in
1.3% to 11.4% of examinations; <3%
required medical or surgical treatment
Other Considerations
• Harms from screening with gFOBT
arise from colonoscopy to follow up
abnormal gFOBT results
• Requires dietary restrictions and 3
stool samples
• Requires good adherence over multi-
ple rounds of testing
• Does not require bowel preparation,
anesthesia or sedation, or transporta-
tion to and from the screening exami-
nation (test is performed at home)
• Harms from screening with FIT arise
from colonoscopy to follow up abnor-
mal FIT results
• Can be done with a single stool
sample
• Requires good adherence over multi-
ple rounds of testing
• Does not require bowel preparation,
anesthesia or sedation, or transporta-
tion to and from the screening exami-
nation (test is performed at home)
• Harms from screening with sDNA-FIT
arise from colonoscopy to follow up
abnormal sDNA-FIT results
• Can be done with a single stool sam-
ple but involves collecting an entire
bowel movement
• Requires good adherence over multi-
ple rounds of testing
• Does not require bowel preparation,
anesthesia or sedation, or transporta-
tion to and from the screening exami-
nation (test is performed at home)
• Screening and follow-up of positive
results can be performed during the
same examination
• Requires less frequent screening
• Requires bowel preparation, anesthe-
sia or sedation, and transportation to
and from the screening examination
• Additional harms from screening with
CT colonography arise from colono-
scopy to follow up abnormal CT colo-
nography results
• Requires bowel preparation
• Does not require anesthesia or seda-
tion or transportation to and from the
screening examination
Continued on following page
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How Would You Screen This Patient for Colorectal Cancer? BEYOND THE GUIDELINES

Table 1–Continued
Screening Method* Frequency† Evidence of Efficacy Other Considerations

Flexible sigmoidoscopy
Flexible sigmoidoscopy with FIT
Every 5 y • Evidence from RCTs that flexible sig-
moidoscopy reduces colorectal cancer
mortality
• Risk of bleeding and perforation but
less than risk with colonoscopy
• Modeling suggests that it provides
fewer life-years gained alone than
when combined with FIT or in compar-
ison to other strategies
Flexible sigmoido- • Evidence from RCTs that flexible
scopy every 10 y sigmoidoscopy þ FIT reduces colo-
plus FIT every rectal cancer mortality
year • Modeling suggests combination test-
ing provides benefits similar to those
of colonoscopy, with fewer
complications
• Risk of bleeding and perforation from
flexible sigmoidoscopy but less than
risk with colonoscopy
• Additional harms may arise from colo-
noscopy to follow up abnormal flexi-
ble sigmoidoscopy results
• Test availability has declined in the US
but may be available in some com-
munities where colonoscopy is less
available
• Additional potential harms from colo-
noscopy to follow up abnormal flexi-
ble sigmoidoscopy or FIT results
• Flexible sigmoidoscopy availability
has declined in the US but may be
available in some communities where
colonoscopy is less available
• Screening with FIT requires good ad-
herence over multiple rounds of
testing

CISNET = Cancer Intervention and Surveillance Modeling Network; CT = computed tomography; FIT = fecal immunochemical test; gFOBT = guaiac
fecal occult blood test; RCT = randomized clinical trial; sDNA-FIT = stool DNA test with fecal immunochemical test. Reproduced with permission
from Davidson KW, Barry MJ, Mangione CM, et al; US Preventive Services Task Force. Screening for colorectal cancer: US Preventive Services Task
Force recommendation statement. JAMA. 2021;325:1965-1977. [PMID: 34003218] doi:10.1001/jama.2021.6238. Copyright© 2021 American
Medical Association. All rights reserved.
* To achieve the benefits of screening, abnormal results from stool-based tests, CT colonography, and flexible sigmoidoscopy should be followed
up with colonoscopy.
† Applies to persons with negative findings (including hyperplastic polyps) and is not intended for persons in surveillance programs. Evidence of
efficacy is not informative of screening frequency, with the exception of gFOBT and flexible sigmoidoscopy alone.
‡ As stated by the manufacturer.

knew from mammograms, at least, that those are really
effective measures of catching cancer early on and that if
there was an opportunity to catch any kind of problem
early on, I wanted to take that route. So, she suggested
that I call and schedule an appointment. I think the main
thing that swayed my decision is I just knew nothing.
For screening purposes, I have had Pap smears and
mammograms. I think it's great to have awareness about
these opportunities to have screenings so that you can
see if you are higher risk.
The question I think would be helpful to learn about
with regards to a colonoscopy, especially, is, what are the
risks of the procedure and why would a patient and/or
doctor recommend using stool DNA test versus a colono-
scopy if colonoscopy is the gold standard?
CONTEXT, EVIDENCE, AND GUIDELINES
Colorectal cancer is the third leading cause of cancer
death for men and women in the United States, with an
estimated 52 580 people expected to die of CRC in 2022
(1). Most frequently, CRC is diagnosed among persons
aged 65 to 74 years. However, among persons younger
than 50 years, incidence rates have been increasing
since the mid-1990s (2). Specifically, for adults aged 40
to 49 years, CRC incidence increased by almost 15%
from 2000–2002 to 2014–2016 (3).
Male sex and Black race are also associated with an
increased incidence of CRC, which is concerning because
Black men and women also have a disproportionately
high rate of mortality from CRC. Although most CRC cases
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are sporadic, with 75% developing in people at average
risk and about 20% in those with a family history, modifi-
able risk factors have been linked to the risk for develop-
ing CRC, including obesity, diabetes, long-term smoking,
and alcohol use (4).
Options for CRC screening include stool-based and
direct visualization tests, which have all been found to
be cost-effective (DNA-based tests were not studied) (5).
However, the tests require different screening frequency,
location (home or office), method (stool-based or direct
visualization), bowel preparation, procedural sedation, and
follow-up colonoscopy for abnormal findings (Tables 1
and 2) (6). Stool-based tests include those that detect
blood in the stool (high-sensitivity guaiac fecal occult
blood test [HSgFOBT] and fecal immunochemical test [FIT])
and those that detect DNA biomarkers for cancer cells
in the stool (sDNA-FIT) (6).
Direct visualization tests include flexible sigmoido-
scopy, computed tomographic (CT) colonography, and
colonoscopy. Flexible sigmoidoscopy visualizes only the
rectum, sigmoid colon, and descending colon whereas
the other 2 visualize the entire colon. When abnormal
results are found on a stool-based test, flexible sigmoido-
scopy, or CT colonography, follow-up testing with colono-
scopy is needed for further evaluation (6).
The National Colorectal Cancer Roundtable was
established by the American Cancer Society and the
Centers for Disease Control and Prevention in 1997 and
set a goal that 80% of persons 50 years of age and older
be screened for CRC (7). However, the 2018 Behavioral
Risk Factor Surveillance System found that only 68.8% of
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BEYOND THE GUIDELINES How Would You Screen This Patient for Colorectal Cancer?

eligible adults were up to date with CRC screening.
Screening was lowest among those 50 to 54 years old
(50%) and highest among those 70 to 75 years old
(81.3%). Among those 50 to 64 years old, CRC screening
prevalence was lowest among those without a regular
health care provider (32.7%) and those without health in-
surance (32.6%) and highest among those with reported
annual income of $75 000 or higher (70.8%) (8).
In 2021, the U.S. Preventive Services Task Force
(USPSTF) concluded, as it had in 2016 (9), that there is sub-
stantial net benefit to CRC screening, as evidenced by a
reduction in CRC mortality in adults aged 50 to 75 years.
Based on this finding, the USPSTF continued to recom-
mend CRC screening for adults aged 50 to 75 years
(Grade A recommendation) (6). To receive a Grade A rec-
ommendation, the available evidence has to include con-
sistent results from well-designed, well-conducted studies
in representative primary care populations and assess the
effects of screening on health outcomes, such as death
(10). In 2021, the USPSTF continued to recommend
elective screening for adults 76 to 85 years old after
consideration of patients' preferences, overall health,
and prior screening history (Grade C recommendation).
New in 2021, the USPSTF recommended CRC screening
for adults 45 to 49 years old (Grade B recommendation)
(6). The USPSTF did not recommend a specific screening
test; rather, its guidance was consistent with an earlier
statement from the American College of Physicians that
suggested clinicians select a test after a discussion with
the patient (Tables 1 and 2) (11).
Despite the potential benefit of initiating screening at
age 45 for early detection of CRC, several questions have
been raised. First, the resources required to screen an
additional 21 million persons between 45 and 49 years of
age may detract from efforts to screen persons 50 years of
age and older to reach the target goal of 80% set by the
National Colorectal Cancer Roundtable (12, 13). Second, a
recent Markov model found that although lowering the
screening age to 45 years may be cost-effective, elevating
the screening rate in those aged 50 to 75 years to the tar-
get of 80% would prevent 3 times as many deaths attrib-
uted to CRC for approximately 66% less cost (14).
CLINICAL QUESTIONS
To structure a debate between our 2 discussants, we
mutually agreed on the following key questions to con-
sider when applying this guideline to clinical practice
and to Ms. N in particular:

Table 2. Benefits and Limits of Colorectal Screening Tests

Test Benefits Limits
Fecal immunochemical test (FIT) No direct risk to the colon Can miss many polyps and some cancers
No bowel prep Can have false-positive test results
No pretest diet or medication changes needed Needs to be done every year
Sampling done at home Colonoscopy will be needed if abnormal
Fairly inexpensive
Guaiac-based fecal occult blood test (gFOBT) No direct risk to the colon Can miss many polyps and some cancers
No bowel prep Can have false-positive test results
Sampling done at home Pretest diet changes (and possibly medication
Inexpensive changes) are needed
Needs to be done every year
Colonoscopy will be needed if abnormal
Stool DNA test No direct risk to the colon Can miss many polyps and some cancers
No bowel prep Can have false-positive test results
No pretest diet or medication changes needed Should be done every 3 years
Sampling done at home Colonoscopy will be needed if abnormal
Still fairly new—may have insurance coverage issues
Colonoscopy Can usually look at the entire colon Can miss small polyps
Can biopsy and remove polyps Full bowel prep needed
Done every 10 years Costs more on a one-time basis than other forms of
Can help find some other diseases testing
Sedation is usually needed, in which case you will
need someone to drive you home
You may miss a day of work
Small risk for bleeding, bowel tears, or infection
Computed tomographic (CT) colonography Fairly quick and safe Can miss small polyps
(virtual colonoscopy) Can usually see the entire colon Full bowel prep needed
Done every 5 years Some false-positive test results
No sedation needed Exposure to a small amount of radiation
Can’t remove polyps during testing
Colonoscopy will be needed if abnormal
Still fairly new—may have insurance coverage issues
Flexible sigmoidoscopy Fairly quick and safe Not widely used as a screening test
Usually doesn’t require full bowel prep Looks at only about a third of the colon
Sedation usually not used Can miss small polyps
Does not require a specialist Can’t remove all polyps
Done every 5 years May be some discomfort
Very small risk for bleeding, infection, or bowel tear
Colonoscopy will be needed if abnormal
From reference 40.

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How Would You Screen This Patient for Colorectal Cancer? BEYOND THE GUIDELINES

Figure 1. Benefit: Estimated number of CRC deaths averted per 1000 individuals screened.

Screening modality and frequency Mean CRC deaths Additional CRC

averted if start deaths averted if 50 y 45 y
screening, n start screening at
At age At age age 45 y, n
50 y 45 y
Stool tests
FIT every year 25 26 1
HSgFOBT every year 23 24 1
sDNA-FIT every year 27 28 1
sDNA-FIT every 3 y 24 25 1
Direct visualization tests
COL every 10 y 27 28 1
CT colonography every 5 y 26 26 0.9
Flexible SIG every 5 y 23 24 0.9
Flexible SIG every 10 y plus FIT every year 26 28 1

0 5 10 15 20 25 30
CRC deaths averted per 1000 screened,
by age to begin screening, n

COL = colonoscopy; CRC = colorectal cancer; CT = computed tomography; FIT = fecal immunochemical test; HSgFOBT = high-sensitivity guaiac fecal
occult blood test; SIG = sigmoidoscopy; sDNA-FIT= stool DNA fecal immunochemical test. Reproduced with permission from Davidson KW, Barry MJ,
Mangione CM, et al; US Preventive Services Task Force. Screening for colorectal cancer: US Preventive Services Task Force recommendation statement.
JAMA. 2021;325:1965-1977. [PMID: 34003218] doi:10.1001/jama.2021.6238. Copyright© 2021 American Medical Association. All rights reserved.

Question 1: At what age do you recommend CRC
screening begin?
Question 2: What are the options for CRC screening,
and what are the pros and cons of each approach?
Question 3: How do you choose among the available
screening modalities, and what would you recommend
for our patient?
DISCUSSION
Viewpoint: Carol M. Mangione, MD, MSPH
Question 1: At what age do you recommend CRC
screening begin?
As of 2021, the USPSTF recommends beginning
CRC screening at 45 years because it determined that
screening adults aged 45 to 49 provides moderate ben-
efit for reducing CRC mortality and increasing life-years
gained (Grade B recommendation). Although no studies
report on the benefits of screening specifically in adults
younger than 50 years, the Task Force based its recom-
mendation on 3 types of evidence. First was epidemio-
logic data showing increasing incidence of CRC among
persons younger than 50 years. Second were studies
that included persons younger than 50 years and exam-
ined the benefits and accuracy of screening tests (6),
including 3 randomized clinical trials (n = 304 107) of per-
sons aged 45 to 74 that compared fecal occult blood
testing with no screening and found a reduction in the rate
of CRC-specific mortality ranging from 9% to 22% after 2 to
9 rounds of screening (15–17). Third were independently
developed microsimulation models commissioned from
the Cancer Intervention and Surveillance Modeling
Network by the USPSTF. All 3 models assessed screening
starting at age 45, 50, or 55 years and stopping at age 70,
75, 80, or 85 years, and all assumed that an abnormal
Annals.org
finding on a noncolonoscopy test would be followed
up with a colonoscopy with full adherence to all pro-
cedures. All models accounted for recently observed
population-based trends in CRC risk. These models
showed increases in CRC deaths averted (approximately
1 per 1000 persons screened), CRC cases averted (2 to 3
per 1000 persons screened), and life-years gained (22 to
27 per 1000 persons screened) (18). The models estimate
that more life-years are gained and fewer colorectal can-
cer deaths occur when screening begins at age 45 than at
50 years (Figure 1) (6). The models also estimate slightly
more lifetime complications per 1000 persons screened
(Figure 2) (6).
Question 2: What are the options for CRC screening,
and what are the pros and cons of each approach?
The USPSTF recommends use of either stool-based
or direct visualization tests for screening. Each test has
considerations about accuracy when compared with
colonoscopy, location of screening, and need for a
bowel preparation. Colonoscopy accuracy is reported
with a reference standard of either repeat colonoscopy
or CT colonography–enhanced colonoscopy.
For stool-based tests, the specificity of sDNA-FIT is
lower than that of FIT, resulting in more false-positive
results, more follow-up colonoscopies, and more associ-
ated adverse events per screening test performed. The
high-sensitivity versions of FOBT (for example, Hemoccult
SENSA) have superior test performance characteristics
than older gFOBT tests (for example, Hemoccult II),
although there is still uncertainty about the precision of
sensitivity estimates, making it unclear if the test can
detect as many advanced adenomas and CRCs as other
stool-based tests. Among the direct visualization tests,
there is evidence that CT colonography has reasonable
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BEYOND THE GUIDELINES How Would You Screen This Patient for Colorectal Cancer?

accuracy to detect CRC and adenomas. The USPSTF did
not identify studies that reported on the accuracy of flex-
ible sigmoidoscopy using colonoscopy as the reference
standard (4).
The USPSTF found limited evidence on differences
in accuracy of specific screening tests by age group.
Some literature suggests there may be decreased speci-
ficity with some stool tests with older age, and potentially
decreased sensitivity of CT colonography with older age,
but these findings are exploratory (6).
Harms from follow-up colonoscopies after a positive
stool-based test are estimated to be 17.5 serious hemor-
rhages (95% CI, 7.6 to 27.5) and 5.4 perforations (CI, 2.8
to 8.7) per 10 000 colonoscopies. Serious harms from CT
colonography are uncommon, and the reported radiation
dose for CT colonography ranges from 0.8 to 5.3 mSv
(compared to an average annual background radiation
dose of 3.0 mSv per person in the United States).
Extracolonic findings on CT colonography are common.
Based on 27 studies that included 48 235 participants,
1.3% to 11.4% of examinations identified extracolonic
findings that required work-up. Only a few studies reported
long-term follow-up of extracolonic findings, making it
difficult to know whether these findings represent a
benefit or harm of CT colonography. Limited evidence
suggests that rates of serious complications from colo-
noscopy, like perforation and bleeding, and the identifi-
cation of extracolonic findings on CT colonography,
increase with age. The USPSTF focused on clinical effec-
tiveness (that is, “what works”) and did not consider cost in
its determination of benefits and harms. The USPSTF did
this to avoid any misperception that its purpose is to limit
health care based on cost.
The USPSTF found direct evidence that CRC screen-
ing with FOBT, FIT, flexible sigmoidoscopy, and colono-
scopy all reduce CRC mortality and, given the similarities
in test accuracy, recommends considering all available
screening tests. Newer screening tests, such as sDNA-FIT,
were included in the most recent USPSTF recommenda-
tions based on similar test accuracy, as well as other attrib-
utes such as similarities in the population that screens
positive when compared with those who screen positive
on established tests.
Question 3: How do you choose among the available
screening modalities, and what would you recommend
for our patient?
When recommending screening for CRC, it is crit-
ically important to keep in mind that although the bene-
fits of screening are well established, almost a third of
eligible persons in the United States are not up to date
with screening. Giving informed patients a choice between
stool-based and direct visualization tests should contrib-
ute to improved screening rates. For patients to make an
informed choice, the PCP must explain that stool-based
tests do not require bowel preparation but do require
adherence to more frequent screening (yearly for high-
sensitivity gFOBT or FIT and every 1 to 3 years for sDNA-
Fit) and a willingness to get a follow-up colonoscopy if
the test result is positive. Direct visualization tests, such
as colonoscopy, require bowel preparation, anesthesia,
and transportation to and from the procedure but have
the advantage that follow-up for an abnormal test result
can be performed at the same time and screening is every
5 to 10 years, depending on the findings. Computed to-
mographic colonography requires bowel prepara-
tion and a willingness of the patient to get a follow-
up colonoscopy if the examination result is positive
(Tables 1 and 2) (6).
So, the best CRC screening test for our patient is the
one that she would prefer after being informed about
the benefits of screening and the logistics associated
with each test.

Figure 2. Harms: Estimated lifetime number of complications (gastrointestinal and cardiovascular) of CRC screening and follow-up
procedures per 1000 individuals screened.

Screening modality and frequency Mean estimate of complications Additional 50 y 45 y

if start screening, n complications if start
At age 50 y At age 45 y screening at age 45 y, n
Stool tests
FIT every year 10 11 0.2
HSgFOBT every year 9 10 0.3
sDNA-FIT every year 12 13 0.2
sDNA-FIT every 3 y 10 10 0.3
Direct visualization tests
COL every 10 y 14 16 2
CT colonography every 5 y 11 11 0.2
Flexible SIG every 5 y 11 11 0.1
Flexible SIG every 10 y plus FIT every year 12 13 0.6

0 2 4 6 8 10 12 14 16
Lifetime complications per 1000 screened,
by age to begin screening, n

COL = colonoscopy; CRC = colorectal cancer; CT = computed tomography; FIT = fecal immunochemical test; HSgFOBT = high-sensitivity guaiac fecal
occult blood test; sDNA-FIT = stool DNA fecal immunochemical test; SIG = sigmoidoscopy. Reproduced with permission from Davidson KW, Barry MJ,
Mangione CM, et al; US Preventive Services Task Force. Screening for colorectal cancer: US Preventive Services Task Force recommendation statement.
JAMA. 2021;325:1965-1977. [PMID: 34003218] doi:10.1001/jama.2021.6238. Copyright© 2021 American Medical Association. All rights reserved.

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How Would You Screen This Patient for Colorectal Cancer?
It is important to recognize that there are patient-
specific barriers to CRC screening that if not addressed
will continue to be associated with higher rates of pre-
sentation with advanced disease and higher mortality
rates. More research is needed to identify the most im-
portant barriers to screening and whether these are
operating at the health system, practice, clinician, or patient
level. Additional research is also needed to implement and
evaluate interventions to improve CRC screening for all per-
sons between the ages of 45 and 74 years.
Black adults have the highest incidence of and rate
of mortality from CRC compared with other groups
across all ages. Systemic racism influences access to in-
formation about disease risks and trust in health care,
which may directly influence a willingness to undergo
screening and the necessary follow-up after a positive
test result. Research is needed to identify the factors at all
levels of health care delivery that contribute to increased
CRC incidence and mortality rate in Black adults. This in-
formation will inform the design and implementation of
interventions to mitigate these differences. Although the
USPSTF guideline recommends expanding access to CRC
screening to persons between the ages of 45 and 49, it is
important to ensure that we simultaneously increase
efforts to screen a greater proportion of persons who
have the highest incidence and mortality rate from CRC
based on either their age or their race (19).
Viewpoint: David S. Weinberg, MD, MSc
Question 1: At what age do you recommend CRC screening
begin?
Lowering the CRC screening age to 45 years prompted
many questions about risks and benefits for individuals and
consequences for the health care system (20). Decisions
about screening should be based on absolute disease risk
and the absolute reduction of that risk by screening.
Earlier screening was recommended in part based on the
observed increase in CRC incidence from 19.7 to 22.6
cases per 100 000 person-years for people 40 to 49 years
of age between 2000 and 2016 (3). The reason for this
increase is the topic of intense research (21).
Starting screening at 45 years added about 20 million
eligible people in the United States. Although periodic
screening may generate the same benefits for younger
persons, there is no direct evidence to support this con-
tention. Instead, the new recommendations were derived
predominantly from modeling studies (22).
It is important to remember that CRC risk in younger
persons remains very low: about one third of the risk
in persons 50 to 59 years of age and one tenth of that in
persons 60 years old and older (23). Further, the benefits of
screening occur in the future, whereas harms can occur im-
mediately (24). For example, the 30-day postcolonoscopy,
all-cause mortality rate ranges from 2 to 9 per 100 000 per-
sons (25). Assuming the lower bound represents younger
patients and that screening reduces CRC incidence by 50%,
the harm of 2 immediate deaths per 100 000 colonoscopies
needs to be weighed against averting 11 future CRC cases
per 100 000 person-years (half of the 22.6 per 100 000
person-years incidence).
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BEYOND THE GUIDELINES
This comparison of deaths and cases averted is
based on several assumptions. For example, the impact
of screening (all methods combined) on CRC mortality
was estimated at 50%. Another effect size could be
assigned; however, the models driving earlier screening
also rely on assumptions open to debate. Some relevant
examples of these assumptions include the following:
Screening tests are equally effective in younger patients;
adherence will be 100% over time; and the risks and
benefits of screening are adequately captured by colo-
noscopies required and life-years gained. Varying the
model inputs has a large impact. For example, if adher-
ence stops after 1 colonoscopy at 45 years, lifetime risk
reduction decreases by 40% (22). In addition, a policy of
earlier screening might divert resources from those at
greater risk (such as older or underserved populations), in
whom screening provides greater value.
Regarding screening starting at age 45, the USPSTF
stated, “The USPSTF concludes with moderate certainty
that screening for colorectal cancer in adults aged 45 to 49
years has moderate net benefit.” In 2018, the American
Cancer Society, using the same modeling data, proffered a
“conditional” recommendation for earlier screening, mean-
ing that “clear evidence of benefit” exists, but so does
uncertainty “if the benefits really outweigh the harms” (26).
Acknowledging these considerations, CRC screening has
already increased more than 50% in persons aged 45 to 49
years in the United States (27).
Question 2: What are the options for CRC screening,
and what are the pros and cons of each approach?
Several countries have enacted centralized pro-
grams with strong evidence that CRC screening in
patients 50 years and older reduces disease incidence
and mortality rate (23). In the United States, screening is
largely opportunistic. With more widespread screening
(about 65% of the U.S. population is up to date), CRC
incidence and mortality rate have dropped steadily (2).
Since peaking in the mid-1980s, incidence has been
reduced by half. It is estimated that 50% of these reduc-
tions are attributable to screening (28).
Several stool-based or direct visualization screening
tools are now available. Evidence supporting different
methods varies widely (29). Only FOBT and sigmoido-
scopy are the subject of randomized controlled trials
demonstrating disease-specific mortality reduction, the
foremost goal of any screening test. For younger per-
sons, there are few age-specific empirical data regarding
screening effectiveness (22).
An important aspect of screening is the balance of
cost and benefit for individuals and society. For those 50
years and older, annual FIT and colonoscopy are similarly
cost-effective. The USPSTF explicitly did not consider cost.
Opponents of cost-effectiveness consideration are con-
cerned about perceived health care rationing or the
assignment of an arbitrary value to averting disease (30). In
younger populations, the false-positive rates, especially for
stool-based testing, are likely higher and cost-effectiveness
relatively lower. To not consider cost-effectiveness ignores
real concerns about cost variation among screening tests,
access to care, and insurance status.
Annals of Internal Medicine 7
BEYOND THE GUIDELINES
Question 3: How do you choose among the available
screening modalities, and what would you recommend
for our patient?
The best CRC screening test is one the patient will
complete. Although overall screening rates have improved,
only 40% of underserved populations are up to date (31).
Fecal immunochemical test and colonoscopy are the most
commonly pursued methods in the United States.
Fecal immunochemical test requires annual adherence
but potentially minimizes the need for colonoscopy.
Though invasive, colonoscopy can be performed as
infrequently as every 10 years in persons without colo-
nic neoplasia. There is ample evidence that offering
choice increases screening participation (32).
Given publicity regarding the younger screening age,
it would be difficult to row against the tide and argue this
patient should wait until 50. However, age alone seems a
blunt decision tool. Epidemiologic data argue there is risk
difference between a 45-year-old woman with no risk fac-
tors and a 45-year-old man with obesity who is a smoker
and has type 2 diabetes. The CRC incidence rates are 30%
higher in men than in women, who have a lower prevalence
of advanced adenomas and adenomas (33, 34). Long-term
follow-up of screening trials with FOBT and flexible sig-
moidoscopy report that younger women demonstrate
little reduction in CRC mortality, perhaps due to lower
disease risk and more proximally located neoplasia (35).
Access to screening and follow-up, rather than bio-
logical variation, seems to be the primary explanation for
racial disparities in CRC incidence (31, 36). Until 1985, CRC
incidence, overall and age specific, was similar across all
populations. Since then, overall incidence has dropped,
but more in White persons than in other groups. The basis
for the decline is increased screening and arguably
changes in modifiable risk factors (37). Despite reduced
overall incidence, for persons younger than 50, the mor-
tality rate has increased in White persons (1.4% annu-
ally) but decreased in Black persons (0.4% to 1.1%
annually) (38). However, the 5-year disease-specific sur-
vival rate for Black persons remains significantly less
(54.9% vs. 68.1%) (39).
Other risk factors have been identified in patients
with early-onset CRC, including male sex, family history
of CRC, and personal history of inflammatory bowel dis-
ease. A birth cohort effect implicates various early life
exposures, including obesity, reduced exercise, type 2
diabetes, antibiotic exposure, and diet change (21).
Their individual contributions cannot be easily teased
apart. Future research might describe more sophisti-
cated risk models that influence personalized screening
recommendations.
At the population level, new recommendations have
a magnified effect. It is not necessarily a zero-sum game:
More screening for people younger than 50 years does
not guarantee less screening for others, but that is a fear,
especially when health care resource allocations do not
create maximum value. For example, a recent study sug-
gests that for a cohort of 1000 people, it will cost nearly
$500 000 in incremental costs to start screening at 45
years, while saving more than $150 000 to devote the
same resources to unscreened 55-year-olds. Savings
8 Annals of Internal Medicine
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How Would You Screen This Patient for Colorectal Cancer?
increased to $450 000 per 1000 persons for unscreened
65-year-olds (14).
Although CRC at any age is terrible and CRC risk in
younger people is rising, it may be premature to advocate
earlier screening in the absence of rigorous evidence.
Recommendations to reduce the impact of CRC rarely
mention risk reduction strategies or improved provision
of treatment (24). Obesity and diabetes are increasing
worldwide. Reducing these risk factors early in life could
help reduce the incidence of CRC and other diseases.
There is no empirical evidence that screening younger
persons will reduce the rate of mortality from CRC. While
we continue to study this issue, plenty of need remains to
screen people 50 and older.
SUMMARY
Our patient's PCP recommended that she begin CRC
screening because she was turning 45, and yet Ms. N was
unsure how to choose among the available options. Dr.
Mangione reviewed that the USPSTF now recommends
beginning CRC screening at 45 years rather than 50 years
because the Task Force determined that screening adults
aged 45 to 49 provides moderate benefit for reducing the
CRC mortality rate and increasing life-years gained (Grade
B recommendation). The recommendation is based on
epidemiologic data, clinical trials, and observational stud-
ies as well as modeling data. Dr. Weinberg is concerned
that there is no direct evidence to support that persons 45
to 49 years of age will derive the same benefit from CRC
screening.
With regard to selecting a CRC screening test, Dr.
Mangione reviewed that the USPSTF recommends both
stool-based and direct visualization tests and found lim-
ited evidence on differences in the accuracy of specific
screening tests by age group. As all of the available tests
were found to have adequate accuracy and similar bene-
fit, she recommends discussing the test characteristics,
as shown in Tables 1 and 2, and selecting the test that the
patient is most likely to have performed. Dr. Weinberg
agrees with this approach but notes that there are no age-
specific empirical data regarding screening effectiveness
and that in younger populations the false-positive rates,
especially for stool-based testing, are likely higher and
cost-effectiveness relatively lower.
Finally, both of our discussants reviewed that the
CRC screening rate for persons 50 to 74 years of age is
below the goal of 80% and that it remains critically im-
portant as we start thinking about screening those 45 to
49 years of age that we simultaneously identify and
address barriers to screening the broader population.
GRAND ROUNDS CONFERENCE (VIDEO AT
ANNALS.ORG)
A transcript of the audience question-and-answer
period is available in the Appendix (available at Annals.
org). To view the conference video (Video 2), including
the question-and-answer session, go to Annals.org.
Annals.org
How Would You Screen This Patient for Colorectal Cancer?
AUTHOR BIOGRAPHIES
Dr. Burns is a member of the Division of General
Medicine at Beth Israel Deaconess Medical Center and
an Assistant Professor of Medicine at Harvard Medical
School, Boston, Massachusetts.
Dr. Mangione is Chair of the U.S. Preventive Services
Task Force, as well as Chief of the Division of General
Internal Medicine & Health Services Research and a
Professor of Medicine at David Geffen Medical School
at UCLA, Los Angeles, California.
Dr. Weinberg is Chair of the Department of Medicine at Fox
Chase Cancer Center and a Professor of Medicine at Temple
University Medical School, Philadelphia, Pennsylvania.
Dr. Kanjee is a member of the Division of General
Medicine at Beth Israel Deaconess Medical Center and
an Assistant Professor of Medicine at Harvard Medical
School, Boston, Massachusetts.
From Division of General Medicine, Beth Israel Deaconess
Medical Center, Harvard Medical School, Boston, Massachusetts
(R.B.B., Z.K.); Division of General Internal Medicine and Health
Services Research, University of California Los Angeles, Los
Angeles, California (C.M.M.); and Fox Chase Cancer Center,
Philadelphia, Pennsylvania (D.S.W.).
Acknowledgment: The authors thank the patient for sharing her
story.
Grant Support: Beyond the Guidelines receives no external
support.
Disclosures: All relevant financial relationships have been miti-
gated. Disclosures can also be viewed at www.acponline.org/
authors/icmje/ConflictOfInterestForms.do?msNum=M22-1961.
Corresponding Author: Risa B. Burns, MD, MPH, Beth Israel
Deaconess Medical Center, 330 Brookline Avenue, Boston, MA
02215; e-mail, rburns@bidmc.harvard.edu.
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Annals.org
APPENDIX: COMMENTS AND QUESTIONS
Dr. Zahir Kanjee: I will ask the first question, and then
we have a few great questions from the audience. This
question is for both discussants. What strategies need to
be implemented to increase screening in underserved
populations? And we can start maybe with Dr. Mangione?
Dr. Carol Mangione: I think the strategies really
need to be multilevel. There are community strategies
that we should consider about educating patients about
the risk of colon cancer, the epidemiological shift, and
the importance of having discussions with your clinician
and getting screened. Not having a usual source of care
reduces the chance of getting screened for colorectal
cancer, and that is true across the age spectrum and def-
initely for people between the ages of 50 and 75 years.
Social policies and governmental policies that ensure
that all people who live in our nation have access to pri-
mary care would go a long way with helping to ensure
that all people who are eligible get screened. And then
finally, I think that we have to recognize that in some set-
tings we need to make sure that patients know about the
value of the fecal-based tests because, especially among
low-income populations, people may not have sick
leave, they may not be able to take a day off from work
to go have a colonoscopy unless they can get by without
being paid for that day, there may be childcare issues,
there are a lot of potential barriers to obtaining a colono-
scopy, and the important thing is that a FIT or other
stool-based test that can be done at home, and doesn't
require anesthesia and a bowel prep and missing work,
may be really the only feasible test. We don't want to dis-
count the value of using that test in settings where it's
really not going to be feasible for patients to have a
colonoscopy.
Dr. David Weinberg: It's education, education, edu-
cation. I find it still, having done this for 30 years, shock-
ing when I tell an average-risk patient that their lifetime
risk for colon cancer is 1 in 20. The look in their eyes is
mind boggling. Most women, not all, but most women
are motivated to get breast cancer screening where the
risk is roughly 1 in 10. We're not talking about an uncom-
mon cancer. The second challenge is setting up health
care systems that can, in fact, support FIT and other
fecal-based tests. This can be complicated. You need to
make sure a patient has a FIT test once a year, have
some system to make sure that every year they do it, and
understand that missing a year usually is not a good
idea, and finally a system to make sure that if the test is
positive that, A) the patient knows, and B) appropriate
follow-up is arranged. Each and every one of those steps
is a sieve where people fall through the cracks. So, it
starts with all of us, primary care on the frontlines particu-
larly, educating patients about what they need to do. I
think you'd be surprised how little most patients know
[about screening options]. There is a predilection in the
U.S. for colonoscopy, we should probably try to change
that if we could, and then we need systems that make
sure that everyone, regardless of their background, has
access to these tests and if and when they're positive
they're followed up.
Annals.org
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Dr. Kanjee: Great, thank you, that's actually a nice intro-
duction to a question from Dr. Carol Bates from the Division
of General Medicine here at Beth Israel. She says, “I believe
we are the only country that does screening colonoscopy.
Can you comment on Canadian, U.K., and other countries'
recommendations? And whether our outcomes are better
in the U.S.?”
Dr. Weinberg: You want me to take that one, Carol?
Dr. Mangione: Sure.
Dr. Weinberg: Okay. So, Canada for a few years
actually explicitly said they didn't want colonoscopies to
be their screening test of choice. Many European coun-
tries have organized, particularly in Scandinavia, organ-
ized fecal screening tests. There are parts of the U.S.—
the Kaiser system for northern California, at least, has
organized methods to get FIT screening into the hands
of all eligible persons. So, I don't know the answer off
the top of my head to Carol Bates' question about
whether the outcomes are different; I think there are so
many different things that would contribute to the out-
come that it would be hard to explain what the differen-
ces were, although I am sure they exist. But we could
have organized FIT screening programs in this country,
but so far we have chosen, generally speaking, not to do
that.
Dr. Mangione: I agree with that answer, and just to
remind everybody: the large foundational trials for
screening for colon cancer were done with fecal occult
blood testing, and when we think about the benefits and
harms for colonoscopy, that really is coming from well-
done observational studies. I think to answer your ques-
tion, Dr. Bates, I would say that the balance of benefits
and harms are so close in the eyes of the Task Force that
we felt really comfortable creating that table that allows
primary care doctors to present all of the testing options.
The sDNA-FIT option, as David mentioned, is not cost-
effective because it is a very expensive fecal test. It is
about $500 per test rather than about $30 per test for a
FIT, and we don't have randomized trial data to support
use of that test, we just know that it has similar accuracy
to other stool-based tests. Although it does have a
slightly higher false-positive rate, which is what you
would expect because it's two tests at once instead of
one.
Dr. Kanjee: Great, thank you, and our next question
comes from Mark Zeidel from the Department of Medicine
at Beth Israel Deaconess Medical Center. He says, “The pri-
mary care doctor speaking with an individual patient is not
focused on the allocation of resources, the ability to give a
colonoscopy is not greatly limited by a lack of facilities and
doctors, and, for the individual clinician, discussions about
resource allocation may not be relevant,” and so I will add a
little bit and combine a couple of questions here, but, in a
primary care visit where a primary care doctor has maybe 1
or 2 minutes to talk about screening, what key points do
you think they should be emphasizing in their visit to
address colon cancer screening? We will start with Dr.
Mangione.
Dr. Mangione: Thank you. First of all, I would say that
what you said about access and resources may be true
in an insured population, at a place like Beth Israel, but I
Annals of Internal Medicine
have to tell you, having volunteered for years in federally
qualified health centers, that we had a very limited num-
ber of colonoscopies that we could order a month and
they were often times “donated” from doctors in the
community. In that setting, we did use fecal occult blood
testing as the first-line screening. So, it really depends
on where you practice and whether obtaining a colono-
scopy is a limited resource or not. I think that the most
important messaging, if you have a minute or 2 in pri-
mary care, is first of all to let people know that colon can-
cer is real. A lot of women think colon cancer doesn't
happen in women, and a lot of younger people are not
aware about the epidemiologic shift. Then the second
thing is to really talk to your patients about what's going
to fit in their life, and which test are they going to be able
to follow through on. If you use a fecal-based test, peo-
ple need to know that if it is positive they are going to
have to proceed on to a colonoscopy, but I think letting
patients know that that is not a bad choice, especially if
someone really doesn't have sick leave or a way to man-
age the transportation and missing work. So, I think right
now, we tend to do the quick thing, which is to just order
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the colonoscopy—that certainly is the case where I prac-
tice—but we need to make sure that we let people know
their options and that we don't make them feel bad
about opting for a fecal-based test instead of colono-
scopy because, based on the evidence, this is a good
choice.
Dr. Kanjee: Dr. Weinberg?
Dr. Weinberg: Well, I tend to see people at the other
end. They've been referred for their colonoscopy or
they've had a stool test that was positive. I have done a
lot of colon cancer screening trials in my day, and I
remain completely and utterly impressed by the primary
care doctors who got patients to participate in those tri-
als, and I suspect it translates into clinical care successes
as well. They are the docs that take even that 1 or 2
minutes to say, “Hey, you've got to get screened for co-
lon cancer.” Hopefully there is a mechanism to make
sure that the people who say yes will do it, either
because you give them a FIT card on the way out the
door or you give them the appointment for a colono-
scopy, but the topic has to be raised even in that short
period of time.
Annals of Internal Medicine