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Colorectal Cancer
Screening
Matt Clausen, MS3
Diagnostic Radiology Elective, December 2007
Clinical Significance
• Disease Burden—Estimates for 20071
– Colorectal Cancer is the third leading cause of
cancer death in the U.S. in both men and
women. It passes breast/prostate cancer for
2nd place if both sexes are considered
together.
– 112,000 new cases in 2007.
– 52,000 deaths in 2007.
– Approximately 10% of cancer deaths.
More Disease Burden6
• A person at age 50 has a…
– 5% lifetime risk of being diagnosed with
colorectal cancer.
– 2.5% chance of dying from it.
• The average patient dying of colorectal cancer
loses 13 years of life.
Colorectal Cancer Epidemiology5
• Peak incidence between ages 60 and 79.
• Less than 20% of cases occur before age 50.
• Worldwide distribution, but dramatic
geographical differences in incidence and death
rates thought to be due to environmental
differences, particularly dietary practices.
• Aspirin and other NSAIDS may be protective.
Hyperplastic Polyps3
• Constitute 90% of all
polyps in the GI tract.
• Found in ½ of all
people 60 years or
older.
• Small, usually < 5
mm.
• Non-neoplastic, with
virtually no malignant
potential.
Adenomas (Adenomatous Polyps) 3
•
•
•
•
•
•
•
Intraepithelial neoplasms
Range from small, often
pedunculated lesions to large,
usually sessile, neoplasms.
Prevalence 20-30% before age 40,
rising to 40-50% after age 60.
Adenomas are precursor lesions for
invasive colorectal
adenocarcinomas.
Malignant risk depends on size,
histologic architecture, and severity
of epithelial dysplasia.
Often asymptomatic.
The goal of screening programs is
to detect asymptomatic adenomas
before they progress to malignancy.
Colorectal Carcinogenesis6
• More than 80% of colorectal cancers arise from
adenomatous polyps.
• Fewer than 1% of adenomatous polyps less than
1 cm will eventually develop into cancer.
• 10% of adenomatous polyps greater than 1 cm
– become malignant within 10 years.
– about 25% become malignant after 20 years.
Colorectal Carcinogenesis3
• Most colorectal cancers occur sporadically in the
absence of well-defined familial syndromes.
• There are conditions associated with risk of
tumor development.
• There is a well-described set of genetic
alterations that occur ultimately leading from
adenoma to colorectal carcinoma.
Pathologic Basis for The Adenoma-Carcinoma
Sequence3
• Populations that have a high prevalence of adenomas have a high
prevalence of colorectal cancer, and vice versa.
• The distribution of adenomas within the colorectum is more or less
comparable to that of colorectal cancer.
• The peak incidence of adenomatous polyps antedates by some
years the peak for colorectal cancer.
• When invasive carcinoma is identified at an early stage, surrounding
adenomatous tissue is often present
• The risk of cancer is directly related to the number of adenomas,
and hence the virtual certainty of cancer in patients with familial
polyposis syndromes.
• Programs that follow patients for the development of adenomas and
remove all that are suspicious reduce the incidence of colorectal
cancer.
The Adenoma-Carcinoma Sequence3
•
•
•
•
•
“First hit.” Loss of one normal copy of the tumor suppressor gatekeeper gene APC occurs
early.
“Second hit.” The loss of the remaining normal copy of the APC gene follows.
Mutations of the oncogene K-RAS occur next.
Additional mutations or losses of heterozygosity inactivate the tumor suppressor gene p53
and SMAD2 and SMAD4, leading finally to the emergence of carcinoma, in which
additional mutations occur.
The accumulation of mutations, rather than their occurrence in a specific order, is more
important than the temporal sequence of changes.
Distribution of Cancers in the Colorectum3
Anatomic Site
Percentage
Cecum/ascending colon
22%
Transverse colon
11%
Descending colon
6%
Rectosigmoid colon
55%
Other
6%
Gross Morphology3
• All colorectal carcinomas begin
as in situ lesions, but evolve
into different morphologic
patterns.
• Tumors in the proximal colon
tend to grow as polypoid,
exophytic masses.
Obstruction is uncommon.
• Tumors in the distal colon tend
to be annular, encircling
lesions that produce so-called
napkin-ring constrictions of the
bowel. The lumen may be
markedly narrowed, and the
proximal bowel may be
distended.
Clinical Features5
• Colorectal cancers remain asymptomatic for years.
• Symptoms develop insidiously and frequently have been
present for months, and sometimes years, before
diagnosis.
• Cecal and right colonic cancers most often present with
fatigue, weakness, and iron-deficiency anemia.
• Left-sided lesions present with occult bleeding, changes
in bowel habit, or crampy left lower quadrant discomfort.
• Cancers of the rectum and sigmoid tend to be more
infiltrative at the time of diagnosis than proximal lesions,
and therefore have a somewhat poorer prognosis.
Prognosis5
• The single most important prognostic
indicator of colorectal carcinoma is the
extent of the tumor at the time of diagnosis
(ie stage).
Stage at Diagnosis
5-year Survival
Localized (confined to bowel wall)
91%
Regional spread (lymph node involvement)
66%
Metastases
9%
Characteristics of a Good Screening Test2
1.
2.
3.
4.
5.
6.
The condition must have a significant effect on the quality and
quantity of life.
Acceptable methods of treatment must be available.
The condition must have an asymptomatic period during which
detection and treatment significantly reduce morbidity and
mortality.
Treatment in the asymptomatic phase must yield a therapeutic
result superior to that obtained by delaying treatment until
symptoms appear.
Tests that are acceptable to patients must be available, at a
reasonable cost, to detect the condition in the asymptomatic
period.
The incidence of the condition must be sufficient to justify the cost
of screening.
Screening Modalities for Colorectal Cancer
•
•
•
•
•
•
Fecal occult blood testing (FOBT)
Sigmoidoscopy
FOBT combined with sigmoidoscopy
Double Contrast Barium Enema (DCBE)
Colonoscopy
CT Colonoscopy
U.S. Preventive Services Task Force
Recommendations6
• Strongly recommends (Grade A
recommendation) screening men and women
over 50 years of age for colorectal cancer.
• Acceptable methods of screening include…
–
–
–
–
–
FOBT
Flexible sigmoidoscopy
Combined FOBT and flexible sigmoidoscopy
DCBE
Colonoscopy
USPSTF Waffling6
“There are insufficient data to determine which strategy is best in
terms of the balance of benefits and potential harms or costeffectiveness. Studies reviewed by the USPSTF indicate that
colorectal cancer screening is likely to be cost-effective (less than
$30,000 per additional year of life gained) regardless of the strategy
chosen.
“It is unclear whether the increased accuracy of colonoscopy
compared with alternative screening methods (for example, the
identification of lesions that FOBT and flexible sigmoidoscopy would
not detect) offsets the procedure's additional complications,
inconvenience, and costs.”
Screening Goals6
• The goals of screening for colorectal cancer are
to detect and remove early stage
adenocarcinomas and adenomatous polyps, the
precursor lesions to colorectal cancer.
• Reduction in colorectal cancer morbidity and
mortality through screening is achieved by…
– Detecting disease at a more favorable stage.
– Removing precursor lesions.
Fecal Occult Blood Test (FOBT)5
• Performed annually.
• Detects the presence of blood
in stool that my derive from
colorectal cancer or from large
polyps (>2 cm).
• Small polyps tend not to bleed.
• Bleeding from cancers tends to
be intermittent.
• Therefore annual testing
recommended that involves
obtaining serial specimens.
• Positive result warrants further
workup with DCBE or
colonoscopy.
• A one sample FOBT with stool
collected on DRE, while
convenient, has very poor
sensitivity and is susceptible to
false positive results due to
DRE-related trauma.
FOBT Operating Characteristics6
• Reported sensitivities range from 50-90%.
• Specificity 96-98%.
• Hydration of specimen increases sensitivity to
60%, but reduces specificity to 90%.
• In patients who have a positive FOBT
– Using rehydrated slides
• 2% will have cancer
• 6-8% will have a large polyp
– Using unrehydrated specimens
• 5-18% will have cancer
• 20-40% will have a large polyp
FOBT Screening Interval6
Annual FOBT
with hydrated
specimen
Unhydrated
specimen or
biennial FOBT
Detected
colorectal
carcinomas
49%
27-39%
Colonoscopies
performed due
to positive test
results
38%
5-28%
FOBT Effectiveness6
• Three randomized controlled trials show reductions in
risk of death from colorectal cancer from 15-33% from
periodic FOBT screening.
• Two European trials, using biennial screening and
unrehydrated test cards, found 15-18% reductions in
mortality.
• In a U.S. study, using rehydrated test cards, colorectal
cancer mortality after 18 years of follow-up was 33%
lower among persons advised to undergo annual FOBT
compared to controls who received usual care (9.46
versus 14.09 deaths per 1,000 patients screened).
– Biennial screening reduced mortality by 21%.
Sigmoidoscopy5
• Performed every 5 years.
• Most commonly used
sigmoidoscope is flexible
and 60 cm long.
• Minimal patient preparation
involving saline enema 1-2
hours before the procedure.
• Generally performed
without sedation.
• Skilled examiners can
complete the exam in 10
minutes or less.
• If positive, patient is usually
referred for colonoscopy.
• Biopsy during
sigmoidoscopy is rare
because…
– Polyps in the distal
bowel signal an
increased risk of cancer
in the proximal bowel.
– Biopsy with
electrocautery in the
incompletely prepared
bowel poses the risk of
explosion of ignited
hydrogen or methane.
Sigmoidoscopy Operating Characteristics6
• 1,000 first-time sigmoidoscopic screening examinations detect
– approximately 7 cancers and
– about 60 large or high-risk polyps
• Sigmoidoscopy only visualizes the lower half of the colon, but it has
been estimated to identify 80% of all patients with significant findings
in the colon, because findings on sigmoidoscopy will trigger
examination of the entire colon.
• Difficult to quantify the false-positive rate of endoscopic screening.
• Screening may lead to the removal of many polyps that are
– of low malignant potential or
– would not have caused clinical disease.
Sigmoidoscopy Effectiveness6
• Current evidence limited to several well-designed casecontrol studies, but 2 ongoing RCTs are expected to
report results within 5 years.
• A case-control study in a large health plan that had
implemented rigid sigmoidoscopy screening suggested
that screening reduced the risk of death from cancers
within reach of the rigid sigmoidoscope by 59%.
• A second case-control study in which 75% of the
examinations were performed with a flexible instrument
found similar protection.
Sigmoidoscopy plus FOBT6
• Combining FOBT and periodic sigmoidoscopy has been
advocated to improve the sensitivity of screening.
• In 3 randomized trials, performing flexible sigmoidoscopy
in addition to FOBT yielded approximately 7 additional
cancers or large polyps per 1,000 patients compared to
FOBT alone.
– Adding FOBT did not improve the yield over sigmoidoscopy
alone at the initial screening in these studies, which used flexible
sigmoidoscopy.
– An earlier study which used rigid sigmoidoscopy, however, did
show and improved yield.
Sigmoidoscopy plus FOBT Effectiveness6
• No randomized trials have examined whether combining
FOBT and sigmoidoscopy would lower mortality or
morbidity better than either test alone.
• In a nonrandomized, controlled study involving more
than 12,000 first-time attendees at a preventive health
clinic screened using rigid sigmoidoscopy, the addition of
FOBT
– detected more cancers on initial screening than sigmoidoscopy
alone
– but mortality after 9 years was not significantly lower (0.36 in
patients receiving both tests versus 0.63 per 1,000 patient-years
in controls; P =0.11).
– Uncertain whether results are generalizable to flexible
sigmoidoscopy.
Barium Enema5
• Performed every 5 years.
• Single contrast = barium
• Double contrast = barium +
instilled air
• DCBE is more sensitive than
single contrast.
• Bowel prep involves clear
liquid diet for 24 hours,
followed by liquid laxatives and
enemas.
• Bowel prep is critical as
residual stool can mask
lesions or lead to false-positive
results.
• If positive, the patient is
referred for colonoscopy.
Barium Enema Operating Characteristics and
Effectiveness6
• Some studies have reported high sensitivity (8690%) of DCBE for colorectal cancer and polyps,
and high specificity (95%).
• Others report a sensitivity of only 48% for polyps
>1 cm with a specificity of 85%.
• No trial has examined the ability of screening
barium enema to reduce the incidence or
mortality from colorectal cancer.
Colonoscopy5
• Performed every 10 years.
• Requires extensive bowel prep
involving 24 hour liquid diet
followed by bowel stimulants
and an 8-10 hour fast.
• Exam terminates at cecum.
• Patient is usually sedated for
the procedure.
• Usually performed in a
hospital, but can be done in an
outpatient setting.
• Higher risk of complications
compared to sigmoidoscopy.
• Skilled operator can complete
exam in approximately 30
minutes.
Colonoscopy Operating Characteristics6
• Accuracy difficult to determine as colonoscopy is
generally considered to be the gold standard for
detecting lesions in the colon.
• Estimated sensitivity of a single exam is
– 90% for large polyps and
– 75% for small polyps (<1 cm).
• As with sigmoidoscopy, many patients will have
polyps detected or removed on colonoscopy, but
only a minority of those would have developed
cancer.
Colonoscopy Effectiveness6
•
•
The effectiveness of colonoscopy to prevent colorectal cancer or mortality
has not been tested in a randomized clinical trial.
The National Polyp Study, a randomized trial of different intervals of
surveillance after polypectomy
– estimated that 76-90% of cancers could be prevented by regular colonoscopic
surveillance exams.
– These results should be interpreted with caution.
• They are based on historical controls.
• Trial participants had more complete polyp removal than may occur in the screening
setting.
•
A single case-control study suggests that colonoscopy is associated with
– Lower incidence of colon cancer (OR, 0.47; 95% CI, 0.37 to 0.58).
– Lower mortality from colorectal cancer (OR, 0.43; 95% CI, 0.30 to 0.63).
•
Slightly greater benefits of colonoscopy have been predicted in models that
project benefits based on sensitivity of screening and rates of polyp
progression.
Virtual Colonoscopy/CT Colography5,6
• Requires similar bowel prep to
conventional colonoscopy,
followed by instillation of air
through a rectal tube.
• Exam takes 10-15 minutes.
• Relatively sensitive and
specific in research settings
(85% to 90%).
• May have less accuracy in
clinical application.
• Small and flat polyps are less
well visualized than cancers
and large polyps.
Virtual Colonoscopy Debate4
• No studies yet examining
clinical outcomes.
• Optimists feel virtual
colonoscopy may be a costeffective filter for therapeutic
colonoscopy and improve
patient compliance with
screening programs.
• Pessimists (primarily
gastroenterologists who have
a substantial financial stake in
the outcome of the debate)
counter that it is not known
whether leaving small polyps
behind is safe.
They didn’t
tell me about
the rectal
tube!
Potential Harms of Screening6
• False-positive tests can lead to invasive
procedures such as colonoscopy.
• Sigmoidoscopy
– Perforation 1-2 per 10,000 examinations.
– Pain (14%), anxiety, bleeding (3%), gas or flatus
(25%).
• Barium Enema
– important complications of any type occurred in 1 in
10,000 examinations.
– perforation occurred in 1 in 25,000 examinations.
– death in 1 in 55,000 examinations.
Colonoscopy Risks6
•
Screening colonoscopy poses higher risks than FOBT or sigmoidoscopy.
– It is a more invasive procedure.
– It is generally used with conscious sedation.
•
Risks depend on whether it is used simply for screening and diagnosis, or
whether it is also used for therapeutic procedures.
– In 2 studies of screening colonoscopies in more than 5,000 patients, 0.2-0.3%
had major complications during or immediately after the procedures, the most
common being bleeding.
– Rates of perforation for diagnostic procedures in 16 published studies range from
0.03-0.61%.
– The complication rates for therapeutic procedures are higher in some studies:
0.07- 0.72% for perforations and 0.2- 2.67% for bleeding.
– Death is rare (between 1 in 16,000 to 1 in 27,000) and more likely in patients with
comorbid conditions.
• Complication rates could increase, if widespread adoption of colonoscopy leads to more
procedures by less skilled endoscopists.
•
No data on complications for virtual colonoscopy.
Patient Adherence6
• Some patients may find FOBT unpleasant
to perform, but 50-70% will complete
FOBT when advised to do so by a doctor.
• A reminder system can increase
adherence by an average of 14%.
• Adherence for sigmoidoscopy is 25-50%
for the initial test.
– No data on adherence to repeat
examinations.
Patient Preferences6
• When given information about screening options and offered the
choice of FOBT alone, sigmoidoscopy alone, or both tests together
– Most patients preferred both tests or FOBT alone.
– Only 8% to 13% preferred sigmoidoscopy alone.
• Patient adherence to combined testing is lower than it is for
sigmoidoscopy or FOBT alone.
• Patients’ acceptance of barium enema screening has not been
evaluated.
• Studies examining the relative discomfort of barium enema and
colonoscopy have produced inconsistent results.
• The acceptability of virtual colonoscopy has not been examined.
Cost Effectiveness6
•
•
•
The USPSTF has found that screening for colorectal cancer by any of the standard
screening strategies reduced colorectal cancer mortality for adults older than age 50
at average risk of colorectal cancer.
Most strategies have an average cost-effectiveness of $10-25 thousand per year of
life saved.
– compares favorably with other commonly endorsed preventive health care
interventions, such as screening mammography or treatment of moderate
hypertension.
The most “cost-effective” strategy depends on the cost threshold beyond which one
no longer wishes to “pay” for additional years of life saved.
– Assuming one does not wish to pay more than $20,000 per life-year saved, at
least 1 analysis found annual FOBT, sigmoidoscopy every 5 years, or
colonoscopy every 10 years to be the optimal method of screening.
– As one’s willingness to pay to save more life-years increases, either colonoscopy
every 10 years, or the combination of annual FOBT and sigmoidoscopy every 5
years, becomes favored.
– No study has examined the cost of patient time missed from work for screening
and treatment.
Screening Test Cost Estimates Used in Cost
Effectiveness Studies6
Test
Cost Estimate
Diagnostic colonoscopy
$150-1,000
Colonoscopy with polypectomy
$250-1,300
Flexible sigmoidoscopy
$100-500
FOBT
$5-30
• No data for DCBE given.
• Real world costs to patients and 3rd party payers likely
greater than reported here.
Take Home Points
• The vast majority of colonic polyps are benign.
• Most colorectal carcinomas start as adenomatous polyps, but
<1% of small adenomas (<1cm) progress to cancer.
• Prognosis depends heavily on extent of disease at diagnosis.
• Screening programs aim to detect early stage cancers or
adenomas before malignant transformation.
• FOBT, flexible sigmoidoscopy, FOBT + flexible
sigmoidoscopy, DCBE, and colonoscopy screening programs
all reduce colorectal cancer mortality.
• Colonoscopy carries more risks than other screening
methods.
• It is not yet clear which screening strategy is the most costeffective.
Selected References
1.
2.
3.
4.
5.
6.
American Cancer Society. Cancer Facts and Figures 2007. Available at:
www.cancer.org/docroot/STT/content/STT_1x_Cancer_Facts__Figures_2007.asp.
Accessed December 12, 2007.
Dickey LL. Health Promotion and Disease Prevention. In: Mengel MB, Holleman
WL, Fields SA, eds. Fundamentals of Clinical Practice, 2nd ed. New York: Kluwer
Academic; 2002:364-365.
Liu C, Crawfor JM. The Gastrointestinal Tract. In: Kumar V, Abbas AK, Fausto N,
eds. Robbins and Cotran Pathologic Basis of Disease, 7th ed. Philadelphia:
Elsevier Saunders; 2005:856-867.
Isselbacher KJ. 10/11/2007: Hot Topic: CT Colonography vs. Colonoscopy in the
Detection of Colon Cancer. In: Harrison’s Online. Available at:
www.accessmedicine.com. Accessed December 12, 2007.
Smith RA, Mettlin CJ. Cancer Detection. In: Lenhard RE, Osteen RT, Gansler T,
eds. Clinical Oncology. Williston, VT: Blackwell Publishing; 2001:93-99.
U.S. Preventive Services Task Force. Screening for Colorectal Cancer. Agency
for Healthcare Research and Quality. Recommendations and supporting
documents available at: http://ahrq.gov/clinic/uspstf/uspscolo.htm. Accessed
December 12, 2007.