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Clinical Practice

CarenG. Solomon, M.D., M.P.H., Editor

Screening for Colorectal Neoplasia


JohnM. Inadomi, M.D.

This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence
supporting various strategies is then presented, followed by a review of formal guidelines, when they exist.
The article ends with the authors clinical recommendations.

A 79-year-old woman visits your office for routine health maintenance. She has nor- From the Division of Gastroenterology,
mal daily bowel movements without rectal bleeding. Her medical history is notable Department of Medicine, University of
Washington School of Medicine, and the
for osteoarthritis but no other medical conditions. She takes nonsteroidal anti Department of Health Services, Univer-
inflammatory medication and multivitamins. Her maternal uncle received a diagno- sity of Washington School of Public
sis of colorectal cancer at 65 years of age, but she has never undergone screening for Health both in Seattle. Address reprint
requests to Dr. Inadomi at the Division of
colorectal cancer. Would you advise this patient to undergo screening for colorectal Gastroenterology, Department of Medi-
cancer, and if so, which screening strategy would you recommend? cine, University of Washington School of
Medicine, 1959 N.E. Pacific St., Seattle,
WA 98195, or at jinadomi@uw.edu.
The Cl inic a l Probl em N Engl J Med 2017;376:149-56.

C
DOI: 10.1056/NEJMcp1512286
olorectal cancer is the third most commonly diagnosed can- Copyright 2017 Massachusetts Medical Society.
cer and cause of death from cancer in the United States1; however, it can
be detected in asymptomatic patients at a curable stage, and several ran-
domized, controlled trials have shown lower mortality among patients who undergo
screening than among those who do not. Screening can also detect precancerous
polyps that can be removed during colonoscopy, thereby reducing the incidence of
cancer. This review focuses on screening patients at average risk for the develop-
ment of colorectal cancer.
An audio version
of this article
S t r ategie s a nd E v idence is available at
NEJM.org
Screening Options
Multiple strategies are available to screen patients who are at average risk for the
development of colorectal cancer, including fecal occult blood testing (with the use
of guaiac-based or immunochemical tests) alone or in combination with stool
DNA examination, endoscopy (flexible sigmoidoscopy or colonoscopy), radiologic
examination (computed tomographic [CT] colonography), and testing for blood-
based molecular markers, such as circulating methylated septin 9 gene (SEPT9)
DNA. Each strategy has differing characteristics with respect to accuracy, invasive-
ness, interval, costs, and quality of evidence supporting its use. The advantages
and disadvantages associated with each screening strategy are summarized in
Table1. Colorectal cancer screening involves not only the one-time use of a screen-
ing test, but also repeated testing over a persons lifetime (programmatic screening).
In addition, if colonoscopy is not performed as the primary screening test, all
other screening strategies require colonoscopy as follow-up to a positive test.

n engl j med 376;2nejm.org January 12, 2017 149


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The n e w e ng l a n d j o u r na l of m e dic i n e

Key Clinical Points

Colorectal Cancer Screening


Patients at average risk for the development of colorectal cancer should begin screening at 50 years of age.
Screening between 76 and 85 years of age should be tailored, and screening should stop after 85 years
of age.
There is no best strategy for colorectal cancer screening; therefore, the most effective strategy is the
one that a patient can adhere to consistently.
Screening strategies for colorectal cancer among patients at average risk include annual fecal occult blood
testing (with the use of highly sensitive guaiac-based or immunochemical tests) or colonoscopy every
10 years. If these strategies are declined, other screening options may include flexible sigmoidoscopy,
computed tomographic colonography, or blood or stool DNA testing.
Although the harms of specific tests vary greatly, the overall risks of complications from screening are
related mainly to colonoscopies (performed up front or as follow-up to other positive screening tests)
and polypectomies; these risks are low and similar among all strategies.

Fecal Screening Tests studies used guaiac-based testing, almost all cur-
Fecal screening can be divided into two broad rent population-based screening programs use
categories: those that detect blood from ulcerated immunochemical tests because their accuracy is
colonic mucosa resulting from cancer or large greater and dietary restrictions are not required.
polyps and those that detect molecular markers Molecular markers including abnormal DNA
that are shed from cancerous epithelial cells. from cancerous cells can be detected in stool.
Fecal occult blood tests include guaiac-based FIT combined with a stool DNA test (FIT-DNA)
tests and immunochemical tests that use anti- has been approved by the Food and Drug Ad-
bodies to detect human blood. The fecal immu- ministration (FDA) for colorectal cancer screen-
nochemical test (FIT) has the advantage of not ing. One study showed that one-time FIT-DNA
requiring dietary restrictions; such restrictions had a higher sensitivity for detection of colorec-
are necessary with guaiac-based tests because tal cancer than one-time FIT alone (92.3% vs.
they may be falsely positive in the presence of 73.8%), but specificity was lower (86.6% vs.
blood from red meat or food that reacts with the 94.9%).11 The screening interval differs between
guaiac (e.g., raw horseradish, turnips, or broccoli). FIT (annual) and FIT-DNA (interval unknown,
FIT should be performed at home on successive although the U.S. Preventive Services Task Force
bowel movements; digital rectal examination in recommends 1 or 3 years), which makes a com-
the clinic does not provide an adequate stool parison of the effectiveness of programmatic
sample for testing. One-time FIT has been re- screening difficult. Data from studies evaluating
ported to have a sensitivity of 79% (95% confi- the colorectal cancer mortality benefit of screen-
dence interval [CI], 69 to 86) and a specificity of ing FIT-DNA are lacking.
94% (95% CI, 92 to 95) for detection of cancer,
and two or three samples do not significantly Endoscopic Screening
increase the accuracy over a single sample.2 Flexible Sigmoidoscopy
However, many types of immunochemical tests Randomized trials have shown that screening
are available, and their test characteristics vary with flexible sigmoidoscopy, followed by colonos-
widely. copy if precancerous polyps are detected, reduces
High-quality evidence supports a strategy of colorectal cancer mortality. Although not all tri-
fecal occult blood testing every year or every als have shown a significant benefit with respect
2years to screen for colorectal cancer, with colo- to reducing mortality (mortality benefit),15,16 the
noscopy used as follow-up to a positive test. intention-to-treat analyses in several large, ran-
Several randomized, controlled trials have shown domized, controlled trials have confirmed the
up to 32% lower mortality from colorectal can- effectiveness of one-time and periodic (every 3 to
cer with this strategy than with no screening, 5 years) sigmoidoscopy, with a 26 to 31% lower
with up to 30 years of follow-up (Table S1 in the mortality from colorectal cancer among patients
Supplementary Appendix, available with the full who underwent flexible sigmoidoscopy screening
text of this article at NEJM.org).3-7 Although these than among those who underwent no screening

150 n engl j med 376;2nejm.org January 12, 2017

The New England Journal of Medicine


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Table 1. Comparison of Key Features of Screening Strategies.*

Strategy and Effect Detection of Precancerous


on Cancer Mortality Quality of Evidence Interval Cost-Effectiveness Convenience and Requirements Neoplasia
Guaiac FOBT and FIT: Multiple RCTs have shown a mortali- Annual May be more effective and Performed at home Does not reliably detect
32% lower mortality ty benefit (reduction in mortality) less expensive than no precancerous neoplasia
for guaiac FOBT2-7; although FIT screening; total costs
is more accurate than guaiac lower than no screen-
FOBT, RCTs evaluating FIT are ing, because of the high
lacking expense of late-stage
cancer treatment with
biologic agents
Flexible sigmoidoscopy: RCTs have shown a mortality benefit8,9 Every 5 yr Cost-effective as compared Limited bowel preparation as Can detect precancerous
27% lower mortality with no screening and compared with colonoscopy neoplasia
other strategies
Flexible sigmoidoscopy plus A single RCT showed that flexible Annual (FIT) and Cost-effective as compared Strategy that combines endo- Can detect precancerous
FIT: 38% lower mortality sigmoidoscopy plus FIT reduces every 10 yr (sig- with no screening and scopic and stool testing neoplasia
cancer mortality more than sig- moidoscopy) other strategies
moidoscopy alone10
FIT-DNA: unknown effect Data from studies showing a mortal- Every 1 or 3 yr Less effective and more Performed at home Does not reliably detect
on mortality ity benefit are lacking; studies costly than FOBT, FIT, precancerous neoplasia
were limited to the detection of or colonoscopy
cancer and precancerous polyps
Clinical Pr actice

by FIT-DNA as compared with


colonoscopy11
Colonoscopy: 68% lower A prospective cohort study showed Every 10 yr Cost-effective as compared Requires full bowel preparation; Can detect precancerous
mortality a mortality benefit12 with no screening and usually requires sedation neoplasia

The New England Journal of Medicine


n engl j med 376;2nejm.org January 12, 2017
other strategies and an escort
CT colonography: unknown Data from studies showing a mortal- Every 5 yr Less effective and more No sedation required but re- Can detect precancerous
effect on mortality ity benefit are lacking; studies costly than FOBT, FIT, quires bowel preparation neoplasia
were limited to the detection of or colonoscopy
cancer by CT colonography as
compared with colonoscopy13

Copyright 2017 Massachusetts Medical Society. All rights reserved.


Circulating methylated Data from studies showing a mortal- Unknown Unknown A blood test may be associated Does not reliably detect
SEPT9 DNA: unknown ity benefit are lacking; studies with greater adherence than precancerous neoplasia
effect on mortality were limited to the detection of that with other screening
cancer by circulating methylated tests
SEPT9 DNA as compared with
colonoscopy14

* CT denotes computed tomography, FIT fecal immunochemical test, FIT-DNA fecal immunochemical test combined with stool DNA test, FOBT fecal occult blood test, and RCT randomized,
controlled trial.
The effect on mortality represents a comparison of the strategy with either no screening or other strategies.
Cost-effectiveness was determined as the cost per quality-adjusted life-year gained.

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151
The n e w e ng l a n d j o u r na l of m e dic i n e

(Table S1 in the Supplementary Appendix).8-10,13,17 lesions outside the colon that were discovered
However, the benefit of sigmoidoscopy is limited incidentally.
to cancer in the distal colon (rectum, sigmoid,
and descending colon), for which the reduction Blood-Based Tests
in mortality was reported to be 46%.17 The FDA has approved a blood-based colorectal
Colonoscopy cancer screening test that detects circulating
Case-control and prospective cohort studies have methylated SEPT9 DNA. Data from studies evalu-
estimated cancer mortality to be 68 to 88% ating the colorectal cancer mortality benefit of
lower among persons who undergo screening blood-based screening are lacking. In a prospec-
colonoscopy than among those who do not tive study conducted in a screening population,
(Table S1 in the Supplementary Appendix).12,17-19 in which colonoscopy was used as the reference
A meta-analysis of observational studies showed standard, the presence of circulating methylated
that despite a 68% lower mortality overall, no SEPT9 DNA was shown to have a sensitivity of
significant mortality benefit from colonoscopy 48.2% (95% CI, 32.4 to 63.6), a specificity of
was seen with respect to cancer in the proximal 91.5% (95% CI, 89.7 to 93.1), a positive predic-
colon.17 This discrepancy may be explained by tive value of 5.2% (95% CI, 3.5 to 7.5), and a
the quality of colonoscopy (i.e., incomplete colo- negative predictive value of 99.5% (95% CI, 99.2
noscopy, poorer bowel preparation, or more dif- to 99.6) for detection of colorectal cancer.14
ficult polyp removal in the proximal colon) or
differences in the biologic characteristics of prox- When to Start and Stop Screening
imal and distal colorectal cancer. The mechanism The U.S. Preventive Services Task Force used com-
underlying the majority of colorectal cancers is parative effectiveness modeling to examine dif-
chromosomal instability with early mutations ferent ages at which to initiate screening. Start-
in APC followed by KRAS and late mutations in ing screening at 45 years of age instead of 50
P53.20 Sessile serrated polyps are more commonly years could increase life-years and reduce cancer
associated with early KRAS or BRAF mutations mortality but could also increase the potential
that may lead to chromosomal or microsatellite harms due to the increased burden of colonos-
instability than are adenomatous polyps.21 Ses- copy; for this reason, the recommendations are
sile serrated polyps are often flat or minimally to begin screening at 50 years of age in patients
raised, making them more difficult than other at average risk for colorectal cancer.23 Although
polyps to detect by colonoscopy, and are more the risk of colorectal cancer increases with age,
common in the proximal colon, which may con- the competing risk of death from other diseases
tribute to the higher risk of proximal cancer and the risk of serious complications from colo-
than distal cancer after colonoscopy.22 noscopy also increase with age.24,25 Several na-
tional organizations recommend that screening
Radiographic Tests for patients between 76 and 85 years of age
Published data from studies evaluating the effect should be tailored on the basis of the presence
of CT colonography on colorectal cancer inci- of coexisting illnesses and that screening should
dence and mortality are lacking. The reported be stopped after patients reach 85 years of age.23,26
sensitivity and specificity of CT colonography to A microsimulation model suggested that the
detect adenomas 1 cm in diameter or larger have intensity of prior screening and the individual
ranged from 66.7 to 93.5% and from 86.0 to risk of colorectal cancer should also be consid-
97.9%, respectively.13 Because sessile serrated ered in determining the age at which to stop
polyps are flat, CT colonography is inferior to screening. Patients without a notable coexisting
colonoscopy for detection of these polyps.22 A illness who are at average or higher risk for
polyp 6 mm in diameter or larger typically colorectal cancer and have had no prior screen-
prompts a referral for optical colonoscopy, al- ing would be expected to benefit from screening
though the most useful size cutoff is controver- into their 80s.27
sial. Disadvantages of CT colonography include
exposure to radiation and associated concerns Adherence
regarding radiation-induced cancers and the po- The percentage of U.S. residents with up-to-date
tential need for additional testing and care for screening for colorectal cancer has not increased

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Clinical Pr actice

appreciably since 2010 and remains at approxi- implementing screening strategies. The quality of
mately 60%.28 Currently, the percentage of U.S. a screening program should be measured by its
adults undergoing colonoscopy screening greatly ability to identify patients who are due for screen-
exceeds the percentage screened by fecal occult ing, provide access to screening, assess adherence
blood testing, and less than 1% undergo flexible to the screening test and to follow-up colonos-
sigmoidoscopy.29 Barriers to screening include copy if a noncolonoscopy screening test is posi-
costs, lack of knowledge of colorectal cancer and tive, document test outcomes and disseminate
screening, underappreciation of the effect or se- accurate follow-up recommendations, identify
verity of colorectal cancer, fatalism, and a per- patients with a negative test to follow them for
ceived lack of importance or fear of screening repeat screening at the appropriate intervals, and
tests.30 Costs remain a barrier despite the man- provide timely surgery for cancers. The rate of
date in the Affordable Care Act that health plans adenoma detection (the percentage of patients in
cover colorectal cancer screening with no patient whom precancerous polyps are detected during
cost-sharing, because Medicare and other insur- screening colonoscopy) differs substantially among
ers impose a cost-sharing requirement when a endoscopists and may be used as a measure of
colonoscopy is performed to evaluate a positive the ability of screening to prevent colorectal
screening test or when a screening colonoscopy cancer.36 A retrospective study showed that for
becomes a therapeutic procedure with the inclu- every 1% increase in the rate of adenoma detec-
sion of polypectomy.31 tion, there is a 3% decrease in the rate of cancer
Various interventions used in randomized, developing after colonoscopy.37
controlled trials have been shown to increase pa-
tient participation in screening; such interventions Harms and Cost-Effectiveness
include sending patients invitations from their
The harms of noncolonoscopy screening tests are
primary care provider, sending reminder letters
low; however, all strategies require colonoscopy
and making telephone calls, and mailing fecal as follow-up to a positive test. As a result, the
occult blood test kits to patients homes. Theprogrammatic harms of screening are propor-
most successful programs use patient navigators
tional to the number of colonoscopies and in
to reduce logistic barriers, address cultural issues,
particular polypectomies that are performed over
and encourage participants to undergo screen- the lifetime of the screened population. The tech-
ing; the use of patient navigators is especially
nical report from the Cancer Intervention and
important in underserved populations.32,33 Surveillance Modeling Network (CISNET) Colorec-
The National Colorectal Cancer Roundtable has
tal Cancer Working Group estimated the number
established a goal of 80% adherence to colorec-
of complications (perforations, gastrointestinal
tal cancer screening by the year 2018. Kaiser bleeding, nausea and vomiting, ileus, dehydration,
Permanente has implemented a comprehensive abdominal pain, myocardial infarction, angina,
strategy focused on FIT screening, with colonos-
arrhythmias, congestive heart failure, respira-
copy performed as follow-up to a positive test,
tory arrest, syncope, hypotension, or shock) in a
and has reached and maintained the goal of 80%population of 1000 persons screened between 50
adherence through four rounds of screening.34 and 75 years of age to be 14 to 15 with colonos-
Adherence to screening tests varies among strat-
copy at 10-year intervals, 9 to 12 with flexible
egies, and preference of strategy varies by race
sigmoidoscopy at 5-year intervals, 9 to 10 with
and ethnic group; white participants more com-FIT-DNA at 3-year intervals, and 10 to 11 with
monly prefer colonoscopy, and nonwhite partici-
annual FIT.38
pants tend to prefer fecal testing.30,35 To achieve
Cost-effectiveness models more than a decade
the highest level of adherence to colorectal can-
ago suggested that programmatic screening with
cer screening, it may be best to provide partici-
fecal occult blood testing, flexible sigmoidoscopy,
pants a choice, because the best strategy is the
or colonoscopy reduced colorectal cancer mor-
one that they will adhere to consistently. tality at a cost society was willing to pay.39 Find-
ings from a more recent analysis suggest that
Quality of Screening given the high expense of late-stage cancer treat-
Maximizing the benefit of colorectal cancer ment with biologic agents, FIT screening may be
screening requires a programmatic approach to cost-saving, with reductions in both cancer mor-

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The n e w e ng l a n d j o u r na l of m e dic i n e

Table 2. U.S. Guideline Recommendations for Screening and Screening Intervals to Reduce Mortality from Colorectal Cancer in Patients at
Average Risk.

U.S. Preventive National Comprehensive Multi-Society American College


Services Task Force Cancer Network Task Force of Gastroenterology
Strategy (2016)23* (2015)43 (2008)50 (2009)51
Sensitive guaiac FOBT Annually Recommended Recommended Recommended
(annually) (annually) (annually)
FIT Annually Recommended Recommended Recommended
(annually) (annually) (annually)
Stool DNA test Annually or every Not recommended Recommended Recommended
3 yr (interval (every 3 yr)
unknown)
Flexible sigmoidoscopy Every 5 yr Recommended Recommended Recommended
(every 5 yr) (every 5 yr) (every 5 yr)
Flexible sigmoidoscopy Every 10 yr, with Not recommended Not recommended Not recommended
plus FIT annual FIT or
sensitive FOBT
Colonoscopy Every 10 yr Recommended Recommended Preferred
(every 10 yr) (every 10 yr) (every 10 yr)
CT colonography Every 5 yr Not recommended Recommended Recommended
(every 5 yr) (every 5 yr)
Circulating methylated Not specified Unavailable for Unavailable for Unavailable for
SEPT9 DNA guideline guideline guideline

* No recommended strategy was provided.


The Multi-Society Task Force included the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy,
the American College of Gastroenterology, the American Cancer Society, and the American College of Radiology.
Sensitivity for detection of colorectal cancer is higher than 70%.
The screening interval is for multitarget FIT-DNA.
Stool-based testing may be added at year 3.
Colonoscopy was identified as the preferred strategy.

tality and overall costs even if one includes A r e a s of Uncer ta in t y


program support costs to increase screening
uptake.40 Moreover, screening with colonosco- Data from completed randomized, controlled
py or FIT is more effective in reducing cancer trials of screening colonoscopy are lacking, al-
mortality and less expensive than screening with though several studies are under way. The Colo-
FIT-DNA41 or CT colonography.42 From an eco- noscopy versus Fecal Immunochemical Test in
nomic perspective, FIT-DNA or CT colonography Reducing Mortality from Colorectal Cancer
should not be recommended unless screening (CONFIRM) trial (ClinicalTrials.gov number,
with FIT, sigmoidoscopy, or colonoscopy has NCT01239082) is a randomized comparison of
been declined. one-time colonoscopy with annual FIT plus colo-
noscopy as follow-up to a positive test, to exam-
Patients at Elevated Risk for Colorectal ine colorectal cancer incidence and mortality
Cancer over 10 years.44 A similar trial comparing colo-
Earlier and more frequent screening is recom- noscopy with FIT is being conducted in Spain
mended for patients at higher risk (Table S2 in (COLONPREV).45 Two additional European stud-
the Supplementary Appendix). Patients with a ies are comparing screening colonoscopy with
first-degree relative in whom colorectal cancer no screening (the Nordic-European Initiative on
developed before 60 years of age should undergo Colorectal Cancer [NordICC])4647 or with FIT or
colonoscopy at 40 years of age or an age 10 years no screening (Screening of Swedish Colons
younger than the relatives age when cancer de- [SCREESCO], NCT02078804) with respect to mor-
veloped, whichever is earlier.52 tality from colorectal cancer.

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Clinical Pr actice

Additional factors that might influence colorec- 50 and 75 years of age, with tailored screening for
tal screening strategies include race, lifestyle fac- those between 76 and 85 years of age.23
tors, or aspirin use. For example, among black
men and women, the rates of death from colorec- C onclusions a nd
tal cancer are 28.4 and 18.9 per 100,000 popula- R ec om mendat ions
tion, respectively; among white men and women,
the corresponding rates are 18.7 and 13.2 per Although the patient described in the vignette is
100,000 population.48 Obesity, tobacco smoking, 79 years of age, she has not previously under-
low physical activity, high intake of alcohol, high gone screening for colorectal cancer. Because of
intake of red or processed meat, and low intake her limited coexisting illnesses, she is expected
of fruits and vegetables are associated with in- to derive an overall benefit from a first screening
creased risk of colorectal cancer, and regular use for colorectal cancer, and thus I would recom-
of aspirin has been associated with reduced risk. mend screening for this patient. I would explore
However, none of these factors are currently her reasons for not previously pursuing screen-
used to differentiate screening strategy, age of ing and review with her the benefits and harms
screening initiation, or surveillance intervals.49 of different strategies. Because it is not feasible
to summarize the entire menu of options dur-
ing the span of a routine health maintenance
Guidel ine s
visit, I would initially focus the discussion on
Several national organizations have published colonoscopy or on annual FIT, followed by
guidelines on strategies to reduce colorectal colonoscopy if the test was positive, and engage
cancer mortality, including the National Com- the patient in shared decision making. If she
prehensive Cancer Network,43 the U.S. Multi-Society declined colonoscopy and FIT, I would discuss
Task Force,50 and the American College of Gas- additional screening options, with the under-
troenterology.51 Whereas these organizations rec- standing that insurance coverage, cost-sharing,
ommend certain screening strategies over others and other barriers may affect the feasibility of
(Table2), the 2016 U.S. Preventive Services Task some options.
Force recommendations do not support any spe- Dr. Inadomi reports receiving consulting fees from ChemImage.
cific testing strategy or strategies over others, but No other potential conflict of interest relevant to this article was
reported.
rather highlight the importance of screening pa- Disclosure forms provided by the author are available with the
tients at average risk for colorectal cancer between full text of this article at NEJM.org.

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