SCREENING AND PREVENTION

The slow development of CRC from a benign polyp to an invasive cancer provides a window of

opportunity for the detection and removal of premalignant adenomatous polyps and early-stage cancers.

Removal of adenomatous polyps reduces the incidence of cancer, and the diagnosis of CRC at earlier

stages reduces mortality.62,63 A number of prospective studies have proven that screening for colorectal

polyps and cancer using a variety of methods reduces CRC mortality, and the reduction in mortality

persists long-term after screening.64–66 There is good evidence that screening has contributed

significantly to the drop in CRC mortality rates from a peak a few decades ago. Screening for CRC is

cost-effective, in terms of the quality-adjusted life-years gained, compared to nonscreening. In the

United States, screening for CRC is recommended for men and women over age 50, but compliance

remains suboptimal because more than one-third of Americans report not having participated in a

screening program.

Figure 68-6. Nomogram to predict 5-year and 10-year recurrence-free survival in colon cancer. Used by drawing a straight line up

to the Points axis to determine how many points toward recurrence the patient should receive. Sum of the points received from

each prognostic variable is then located along the total points axis. Then drawing a line down from the total Points axis to the 5-

year or 10-year freedom from recurrence axes provides the patient’s specific risk. RS, rectosigmoid colon; L, left colon; R, right

colon; Sig, sigmoid colon; TC, transverse colon. (From Weiser et al. 2008, J Clin Oncol 26:380–385.)

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Table 68-6 Tools for Colorectal Cancer Screening

Screening Tests

Numerous screening methods for CRC have been used over the years (Tables 68-6 and 68-7). These fall

into one of two categories: stool tests, which detect the presence of blood or altered DNA in the stool;

and structural tests, which identify polyps and cancers. Efficacy in detecting CRC, cost-effectiveness as a

screening tool, supporting evidence, and patient acceptability vary for each of these tests.67–69

Stool Tests

CRCs and polyps bleed more than the normal mucosa, and detecting occult blood in the stool is the basis

of the most widely used screening tests. Blood is detected by searching the stool for hemoglobin using

chemical or immunologic methods; patients found to have blood in the stool should then undergo

colonoscopy. The original fecal occult blood tests (FOBTs) relied on guaiac-based detection of the

pseudoperoxidase activity of hemoglobin. However, as pseudoperoxidase activity is not specific to

human hemoglobin, foods such as red meat can produce false positives. Medications such as aspirin and

nonsteroidal anti-inflammatory drugs can also cause a false-positive reaction. Other foods, in particular

those rich in vitamin C, can cause false-negative results and should also be avoided before a test. Thus,

for improved accuracy, a special diet and avoidance of these drugs should be followed for 2 to 3 days

before FOBT. As most tumors bleed slowly and intermittently, the sensitivity of this test remains low.

Rehydration of the test cards increases sensitivity, at the cost of reducing specificity. The sensitivity of

the test increases with the number of samples tested; testing two samples per stool on three consecutive

bowel movements is recommended. Several prospective, randomized trials have demonstrated that

screening by FOBT, followed by total colonic evaluation with colonoscopy in individuals with a positive

test, reduces mortality from CRC.70–72

Fecal immunochemical tests (FITs) rely on antibodies that are specific to human hemoglobin, and the

analysis of samples by automated quantification methods. FITs are as sensitive as the guaiac-based tests,

but more specific in detecting human hemoglobin in stool. They therefore avoid the false-negative

results in the presence of vitamin C, and the false positives obtained in guaiac-based testing from red

meats. The test does not require dietary modification beforehand, and the handling of the specimens is

less demanding. As with any fecal test, a positive result with FIT requires a complete colonoscopic

examination. Several studies have demonstrated that FIT has better screening performance, compared to

FOBT.73,74 As an additional consideration, FIT may be more easily implemented as a screening regimen,

compared with sole usage of colonoscopy.75 Based on this evidence, a number of countries have

introduced screening programs utilizing these tools.

Detection of altered DNA from exfoliated tumor cells has been investigated as a screening test for

CRC for years. Similar to the detection of hemoglobin, detection of altered DNA triggers patient referral

for colonoscopy. Large, prospective studies of this test show fair sensitivity in detecting CRC and low

sensitivity in detecting large adenomas, compared with colonoscopy.76,77 A more recent study using new

stabilizing buffers, more discriminating markers, and more sensitive analytical methods, has shown that

stool DNA testing is more sensitive than FIT in detecting CRC and advanced precancerous lesions.

However, the specificity of stool DNA testing was found to be inferior to FIT, with roughly 10% of the

screened individuals having a false-positive result.78 There are concerns that a positive stool DNA test

and negative colonoscopy may lead to additional and unnecessary work-up for malignancy. Therefore,

screening guidelines of the U.S. Preventive Services Task Force do not currently recommend the fecal

DNA test as a screening option.

Structural Tests

Two-thirds of CRCs and polyps are located in the sigmoid colon and rectum, and can be reached with a

60-cm flexible sigmoidoscope. The presence of adenomatous polyps in the rectosigmoid colon increases

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the probability of finding additional polyps or cancers in more proximal segments of the large bowel. If

an adenomatous polyp is found during flexible sigmoidoscopy, the patient should undergo a complete

colonoscopy. Flexible sigmoidoscopy is safe, fast, requires minimal preparation, and can be performed

in an office-based setting, as conscious sedation is not needed. The risk of perforation with flexible

sigmoidoscopy is approximately 1 in 20,000, but the lack of sedation can occasionally be associated

with discomfort, deterring some patients from undergoing future examinations. The effectiveness of

flexible sigmoidoscopy as a screening modality requires examination to at least 40 cm from the anal

verge, and the ability of the endoscopist to biopsy-suspected adenomas. The main limitation of flexible

sigmoidoscopy is that it does not examine the entire colon. However, as distal tubular adenomas are

often indicative of proximal advanced neoplasia, the efficacy of flexible sigmoidoscopy is greatest when

patients with distal adenomas are subsequently referred for colonoscopy. Due to differences in the

distribution of colorectal neoplasia in patients of different age, gender, and racial groups, the efficacy of

flexible sigmoidoscopy may vary. Several case-control studies have demonstrated that screening by

sigmoidoscopy reduces mortality from CRC by two-thirds in the setting of tumors located within reach

of the sigmoidoscope.79,80 More recently, several prospective studies have demonstrated that screening

with flexible sigmoidoscopy reduced CRC incidence and mortality by approximately 25%.81–83 The

reduction in incidence occurs in both the proximal and distal colon, while the reduction in mortality

applies mainly to tumors in the distal colon. The optimal interval between tests is still controversial. In

some studies, flexible sigmoidoscopy was performed every 3 to 5 years. At least two prospective trials

demonstrated a reduction in CRC incidence and mortality with only one flexible sigmoidoscopy

screening between 55 and 64 years of age.83,84

Although the evidence for combining FOBT and flexible sigmoidoscopy is weak, some studies have

shown that the combination of these two screening methods is more effective in detecting colorectal

neoplasia than each method used individually.85 The combined approach has a theoretical advantage of

detecting lesions located throughout the colon, but its impact on mortality from CRC is unknown. In the

United States, annual FOBT combined with flexible sigmoidoscopy every 5 years is a common screening

method for the average-risk population.

Colonoscopy is considered the most accurate test for the early diagnosis and prevention of CRC. It

allows direct visualization of the mucosa of the entire colon and rectum, simultaneously allowing the

biopsy or removal of suspicious lesions. Colonoscopy is also used to evaluate patients who have tested

positive on other screening tests. However, colonoscopy is inconvenient, requires dietary modification

and bowel preparation beforehand, is usually performed under conscious sedation, and carries a risk of

complications of 1–2 per 1,000. Colonoscopy is also more expensive compared to other screening

methods. Overall, patient acceptability of colonoscopy seems to be higher compared to other invasive

screening methods, and it is now the most commonly used screening method in the United States. There

is indirect evidence from microsimulation and case-control studies that colonoscopy reduces mortality.86

However, randomized controlled trials proving that screening with colonoscopy reduces CRC mortality

are lacking. Comparative studies show that colonoscopy is more effective in detecting advanced colonic

neoplasia, in both men and women, than a single FOBT combined with sigmoidoscopy. Colonoscopy is

more likely to detect preneoplastic polyps, but just as likely to detect invasive CRC as FITs. In addition,

colonoscopy provides the protective benefit of screening the proximal colon.87 For average-risk

individuals colonoscopy screening should start at 50 years of age and be repeated every 10 years.

Table 68-7 Screening and Surveillance for Colorectal Cancer According to Risk7

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