1. BACKGROUND
Colorectal cancer (CRC) remains the second leading cause of cancer death in the United States (1). It is estimated that approx 148,610 will be diagnosed with CRC and 55,170 will die from it in 2006 (1). However, mortality from CRC has been declining over the past 20 yr, felt largely to be due to earlier detection. The average lifetime risk is 6%, with men and women almost equally affected. Most cases are sporadic, apparently resulting from a combination of environmental and genetic factors (Fig. 1), although there are many known risk factors (Table 1). Screening for CRC has been advocated on the grounds that CRC is a major public health problem, it is preventable through removal of precursor lesions, it is curable if detected early (Fig. 2), and screening tests have been proven to impact disease outcomes. In fact, some screening strategies have been proven to reduce cancer mortality and many strategies are cost-effective (2,3). Unfortunately, CRC screening is under- utilized because of a variety of barriers to screening.
We now have a wide assortment of screening modalities to offer our patients, each with its own strengths and limitations.
It is important to keep in mind that screening should be viewed as a program that occurs over time, not as an individual test administered at one point in time. Therefore, there are costs associated with the original screening test, as well as with the evaluation of positive tests, surveillance, complications, and the cost of cancers not avoided. This chapter focuses on screen- ing for CRC among average-risk individuals, and follows the algorithm proposed by the Multisociety Task Force (Fig. 3) (4). Readers can find additional information on screening and surveillance of individuals at increased risk (e.g., prior per- sonal history of adenomatous polyps, CRC, or inflammatory
From: Endoscopic Oncology: Gastrointestinal Endoscopy and Cancer Management. Edited by: D. O. Faigel and M. L. Kochman © Humana Press, Totowa, NJ
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bowel disease,and family history of colonic neoplasia) covered in Chapters 18 and 19 of this text, as well as in published guidelines (4). Patients with signs or symptoms of CRC should undergo an appropriate diagnostic evaluation.
2. WHEN TO START AND WHEN TO STOP SCREENING
Based on data indicating a rapid rise in the incidence of CRC around age 50 (Fig. 4), screening for CRC should begin at age 50 for average-risk individuals. Those believed to be at increased risk (e.g., first-degree relative with CRC before 60 yr of age) should begin screening at an earlier age.
Although there are no clear guidelines for when to stop screening, one general principal is that screening should cease when the patient is unlikely to benefit from further screening. From a population perspective, the impact of CRC on life expectancy is rather minimal beyond age 80 (5) (Fig.
5). Therefore, it is reasonable to discontinue screening of
individuals whose age or comorbidity limits their life expectancy.
3. SCREENING TESTS
3.1. DIGITAL RECTAL EXAMAlthough there is no direct evidence of the effectiveness of
digital rectal examination (DRE) and only 5–10% of all can-
cers could be detected by DRE (6), its use is generally part of
other screening tests (i.e., sigmoidoscopy, colonoscopy, and
barium enema). Moreover, DRE is usually performed as part
of a routine physical exam in patients of appropriate age for
CRC screening (i.e., prostate evaluation in men, pelvic exami-
nation in women). Therefore, the additional effort required on
the part of providers and patients is minimal, and DRE can be
included as an adjunctive screening method in a CRC screen-
ing program.
3.2. FECAL OCCULT BLOOD TESTS 3.2.1. Guaiac-Based Stool Tests
The American College of Physicians has published com- prehensive guidelines for fecal occult blood testing (FOBT) and interpretation with review of the data (7,8). FOBT has been estimated to detect around 90% of cancers with repeated testing over several years (9). However, a one-time FOBT (three samples) has an estimated sensitivity for advanced neo- plasia of only 23.9% (10). FOBT is most commonly performed using a guaiac-based test for peroxidase activity. Therefore, it is important that patients avoid other substances with peroxi- dase or pseudoperoxidase activity, such as rare red meat and some fruits and vegetables (e.g., turnips and horseradish).
False-positive results can also occur as a result of other sources of gastrointestinal bleeding (e.g., hemorrhoids, peptic ulcer, and gum disease). False-negatives can result from tumors,
which do not bleed at the time the stool is sampled, or from vitamin C use, which can interfere with the test reaction.
Rehydration of the stool specimen with a drop of water has been demonstrated to increase the sensitivity at the expense of decreased specificity. The positive predictive value for cancer is 10–17% without rehydration, and 2–6% with rehydration.
Despite the apparent simplicity of the test, improper test inter- pretation can be a significant problem (11).
FOBT is the only screening modality that has been proven to reduce mortality from CRC in randomized controlled trials (Table 2) (9,12–14). FOBT has also been demonstrated to reduce CRC incidence (15). In the Minnesota Colorectal Cancer Control Trial, 46,551 people without symptoms of CRC were randomized to undergo either annual FOBT, bien- nial FOBT, or usual care (9). For most of the trial, FOBT was performed with rehydrated slides. Colonoscopy was recom- mended for those with a positive FOBT. Over 13 yr of follow- up, the annually screened group evidenced a 33% reduction in CRC mortality (see
Fig. 6). There was no significant reductionin mortality with biennial screening during 13 yr of follow-up, although after 18 yr, CRC mortality was reduced by 21% (16).
Of note, 38% of the annually screened subjects and 28% of the biennial group underwent colonoscopy at some point during the initial 13-yr study. Also of interest, patients in the annual FOBT group completed 75% of the screening offered and 90% com- pleted at least one screening.
In a second randomized controlled trial, conducted in the Nottingham, England area, more than 150,000 patients aged between 45 and 74 were randomly offered FOBT without hydration biennially or received usual care (12). Again, colono- scopy was recommended for those with a positive FOBT.
After a mean of 7.8 yr of follow-up, CRC mortality was reduced by 15% in the screened group (odds ratio [OR] 0.85, 95% confidence interval [CI] 0.74–0.98). Compliance with at least one FOBT was 59.6%. A similar study conducted of nearly 62,000 Danes aged 45–75 found an 18% reduction in CRC mortality 10 yr after the study began (OR 0.82, 95% CI 0.68–0.99) (13). In this study, 67% of the screening group completed the first screening round and more than 90% of those accepted repeated screening. Based on the above stud- ies, annual FOBT appears to be more effective than biennial screening. Complications of FOBT testing include the negative effects patients endure as a result of false-positive test results,
Fig. 1. Factors associated with annual new cases of CRC. Spor adic,men and women age 50 and older with no special risk factors. FH, positive family history; FAP, familial adenomatous polyposis;
HNPCC, hereditary nonpolyposis colorectal cancer; IBD, inflamma- tory bowel disease. (Reprinted with permission from ref. 91.)
Fig. 2. Correlation of survival with stage of CRC. Stage I (63); s, stage II (49); j, stage III (55); h, stage IV (32). (Reprinted with per- mission from ref. 92.)
Table 1
Risk Factors for Colorectal Cancer Inflammatory bowel disease
Chronic ulcerative colitis Crohn’s colitis
Adenomatous polyposis Familial polyposis MYH-associated polyposis Turcot’s syndrome
Oldfield’s syndrome Juvenile polyposis
Hereditary nonpolyposis colorectal cancer Family history
Colorectal adenomas younger than 60 yr Colorectal cancer
Past history
Colorectal adenomas Colorectal cancer
Breast, ovarian, and uterine cancer Adapted from ref. 85.
the danger of misleading reassurance in those with false- negative results, and complications related to the diagnostic evaluation of positive FOBT results.
3.2.2. Immunochemical-Based Stool Testing
Given concerns about the need for dietary restriction and detection of clinically insignificant bleeding from the upper gut with the guaiac-based FOBT, immunochemical tests for human hemoglobin have been developed. Immunochemical tests have performed well compared to guaiac-based tests in clinical studies, but commercially available tests have not been studied in large populations of average-risk individuals in order to clearly demonstrate their accuracy (17). Although immunochemical tests may be easier to interpret than guaiac- based tests, the processing of the available immunochemical tests must occur in a central lab. Also, the cost of immunochemical
tests is considerably higher than guaiac-based tests (e.g., $28 for InSure™ [18] compared to typically less than $4 for guaiac-based tests [19]). As noted by Levin et al. (20), these tests have not found wide usage for technical and commercial reasons. As a result, some immunochemical tests (e.g., FlexSureOBT™ and HemeSelect™) are no longer on the market. Our experience with immunochemical tests failed to show any clear benefit with respect to patient compliance and overall rate of positive results when compared with a guaiac- based test (21).
3.2.3. Fecal DNA-Based Molecular Marker Assays
Genetic and epigenetic alterations of DNA are a fundamental aspect of virtually all cancers, including CRC (Fig. 7). Conse- quently, testing of stool samples for altered DNA has been
Fig. 3. Algorithm for colorectal cancer screening. +, either colorectal cancer or adenomatous polyp; *, hereditary nonpolyposis colorectal can- cer; **, see text. FAP, familial adenomatous polyposis. (Reprinted with permission from ref. 4.)Fig. 4. Cumulative incidence of colorectal cancer according to age and the presence or absence of a family history of the disease.
(Reprinted with permission from ref. 93.)
Fig. 5. The impact of colorectal cancer on life expectancy. The x-axis depicts age in 5-yr groups; the y-axis indicates the decrease in life expectancy in days owing to colorectal cancer. (Reprinted with per- mission from ref. 5.)
proposed as a potential screening test for colon cancer. In 1992, Sidransky et al. (22) demonstrated the feasibility of this approach by detecting mutant KRAS2 DNA in stool samples from people with colon cancer. Since that time, a number of other investigators have demonstrated that other DNA alterations, including APC mutations, TP53 mutations, and microsatellite unstable DNA (i.e., BAT26 alterations), can be detected in fecal DNA and can serve as molecular markers for colon adenomas and colon cancer (23–26). Furthermore, with the recent demonstration of the com- mon occurrence of aberrantly methylated genes in colon adeno- mas and cancer and the development of a technique called methylation-specific polymerase chain reaction (PCR), consider- able interest in the use of aberrantly methylated genes as serum or stool-based molecular marker assays for colon cancer has devel- oped (27,28). As proof of principle, methylated SFRP2, the gene for secretory frizzled related protein 2, has been shown to be a potential stool-based molecular marker for colon cancer (29).
DNA-based markers are a promising class of potential early detection markers because DNA is stable in the stool, is shed continuously, and can be detected in minute amounts through the use of PCR-based technologies (30). However, a substantial technical limitation to the use of DNA alterations as markers for colon cancer is the lack of a single alteration that can serve as a marker for all colon cancers. For example, APC muta- tions, which are believed to be the most common mutation in colon cancer, can be found in at most 70% of colon cancers using conventional mutation detection techniques (31). In fact, it is now well appreciated that colon cancers are genetically heterogeneous, which has led to the belief that assay panels that include tests that detect a variety of gene alterations will be needed to generate a clinically useful test (25). One of these assay panels is commercially available and marketed under the name PreGen-Plus (EXACT Sciences and LabCorp). This assay is a stool-based panel of 23 assays that targets known point mutations in APC, KRAS2, TP53, BAT26 and also tests for long fragments of DNA, which has been called the DNA Integrity Assay (DIA
®). Of note, the mechanism responsible for the long fragments of DNA found in individuals with colon neoplasms is not known but may be DNA from nonapoptotic cells. Data using this assay panel from a small pilot study of symptomatic patients undergoing colonoscopy (N = 61) found that the sensitivity for cancer was 91% (95% CI, 71–99%), the sensitivity for large adenomas was 82% (95% CI, 48–98%), and the specificity for adenomas or cancer was 93% (95% CI, 76–99%) (25). Exclusion of KRAS2 mutations in the assay panel increased the specificity to 100% (95% CI, 88–100%)
with a fall in sensitivity for adenomas to 73% (95% CI, 39–94%). In this highly selected sample, the positive predic- tive value was 100%, with a negative predictive value of 85%.
In this study, Hemoccult performed poorly at detecting adeno- mas (0/11 detected). Other studies of fecal-based DNA mark- ers have demonstrated similar levels of specificity and sensitivity for colon cancer and colon adenomas. For example, Traverso et al. demonstrated that an assay that detects APC mutations in DNA extracted from stool had a sensitivity of 57% (95% CI, 41–71%) for colon cancer or colon adenomas more than 1 cm in size and a specificity of 100% (95% CI, 88–100%) (23). Imperiale et al. demonstrated in a large prospective study of people undergoing colonoscopy for colon cancer screening that the PreGen Plus assay could detect indivi- duals with CRC (sensitivity 51.6%) and advanced adenomas (sensitivity 18.2%) with 95% specificity. Thus, these studies have demonstrated the feasibility of an approach using mole- cular markers for the early detection or prevention of colon cancer; however, their performance as screening assays in this large cross-sectional study demonstrated that the sensitivity of these assays using current technological approaches is not ideal because the sensitivity is less than that of other available CRC screening methods. Thus, studies are ongoing using
Table 2Evidence of the Effectiveness of Fecal Occult Blood Testing
Minn (9) Minn (16) UK (12) Denmark (13) France (14)
Frequency of testing Annual Biennial Biennial Biennial Biennial
Duration (yr) 13 18 8 10 11
Slide rehydration Yes Yes No No No
Colonoscopy 38 >28 5 4 4
performed (%)
Colorectal cancer 33 21 15 18 16
mortality reduction (%)
Fig. 6. Cumulative mortality by years since randomization (time on study) for each randomization group (annual, biennial, and control), with bars at 4, 8, 13, and 18 yr representing 95% confidence inter- vals. Early in the study, cumulative colorectal cancer mortality was greater in the biennial group than in the control group. The trend was reversed by the 11th year of follow-up and resulted in a 21% reduc- tion by year 18. (Reprinted with permission from ref. 16.)
second-generation molecular marker assays to improve on the performance of the first-generation assay panels. It is widely believed that the performance of the molecular marker assays will improve substantially with advances in sample collection methods, choice of targets for the assays, and target detection technology (32).
The potential advantages and disadvantages of stool-based DNA mutation testing have been discussed in some detail by Levin et al. (20) and are summarized below. These advantages include the following: (1) a high specificity for neoplasia, because the mutation assays developed to date do not appear to generate false-positive results from other causes of gastro- intestinal bleeding as occurs with fecal occult blood; (2) a theoretical ability to detect cancers proximal to the colon (e.g., aerodigestive cancers); (3) the noninvasive nature of the assay, which requires no preparation; and (4) the potential for high accuracy for the early detection of colon cancer. However, as noted earlier, there are still major limitations currently to the application of these assays as colon cancer screening tests, including the lack of data of the performance characteristics of most of these assays when run on screening populations, the need for test refinement to improve sensitivity without sacri- ficing specificity, the high cost (currently >$600 per test), and
finally concerns about adherence because an entire bowel movement must be expeditiously delivered to the laboratory to perform the assays. In addition, these tests can theoretically identify clinical and pre-clinical disease because they detect DNA alterations that may precede the onset of histologically evident disease, which raises issues about how these “false- positive” results will be evaluated. It is not clear what should be done if the test is positive but the colonoscopic exam does not reveal any adenomas or cancer, especially in light of the fact that at least some of these assays can detect aerodigestive tract cancers. Thus, molecular marker assays for colon cancer show considerable promise to be inexpensive and accurate noninvasive screening tests, however, their performance as colon cancer screening assays in comparison to other currently available screening tests remains to be determined.
3.3. FLEXIBLE SIGMOIDOSCOPY
The advantages of sigmoidoscopy over FOBT include
direct visualization of the bowel lumen and the ability to
biopsy lesions at the time of the procedure, thereby increasing
the sensitivity and specificity for detecting cancer within the
limits of the length of the scope. Moreover, there may be an
indirect benefit of screening with sigmoidoscopy through
two mechanisms. First, removal of small polyps during
Fig. 7. Schematic representation of the adenoma–carcinoma progression sequence that highlights histological stages that are believed to repre- sent critical steps in the evolution of normal colon epithelial cells to adenocarcinomas cells. Genetic and epigenetic events that have been iden- tified at these different histological steps are shown above and below the histological representations of the steps. Colon cancers are believed to be heterogeneous in regards to the genetic and epigenetic events they acquire during this progression sequence, and this figure is not intended to imply that all colon cancers will have all of the alterations listed. In addition, there are at least two different types of colon cancers that can be defined by the type of genomic DNA instability they display, and these have been called chromosome unstable (CIN) tumors and micro- satellite unstable (MSI) tumors. The genetic and epigenetic alterations observed in these two types of colon cancers vary as shown above.sigmoidoscopy may prevent progression of these polyps to future CRC. Second, adenomas found during sigmoidoscopy often prompt full colonoscopy with subsequent detection of premalignant or malignant lesions in the portion of the colon not seen with the sigmoidoscope. It is estimated that approxi- mately half of all polyps and cancers are within reach of a stan- dard 60-cm flexible sigmoidoscope. Several studies have evaluated the proportion of patients with advanced proximal neoplasia according to the findings in the distal colon (Table 3).
There is still controversy as to the necessity for full colono- scopy if only one or two small adenomas are detected and removed at sigmoidoscopy (33). The prevalence of proximal advanced neoplasia in patients without distal adenomas is under 5%.
To date, no randomized controlled trials have been com- pleted that evaluate the effectiveness of screening sigmoid- oscopy, although studies are underway (34). Nonetheless, there is good evidence of the effectiveness from four case–control studies (35–38) (Table 4). Selby et al. (36) performed a case–
control study of the effect of rigid sigmoidoscopy on CRC mortality using enrollees of Kaiser Permanente of Northern California (261 cases and 868 controls). They found a 59%
reduction in CRC mortality for those cancers within reach of the sigmoidoscope (OR 0.41, 95% CI 0.25–0.69). Importantly, they found no benefit of sigmoidoscopy with respect to mor- tality from cancers beyond the reach of the sigmoidoscope (OR 0.96, 95% CI 0.61–1.50). This internal control helps to adjust for potential unmeasured differences between the cases and controls with respect to other cancer risk factors.
The correct interval at which to screen with sigmoidoscopy is unknown. From the study by Selby et al., it appears as though the benefit of screening persists for as much as 10 yr. The Muller and Sonnenberg study suggests that the benefit persists for at least 6 yr (35). A repeat colonoscopy 5 yr after a negative colonoscopy will infrequently identify advanced neoplasia (39), although the quality of the preparation and completeness of the exam may be less for sigmoidoscopy than for colonoscopy. The current recommendation is to offer flexible sigmoidoscopy (FS) every 5 yr. The decision to perform colonoscopy after a small polyp is found on sigmoidoscopy is controversial.
3.4. FS COMBINED WITH FOBT
The rationale behind combining FOBT and sigmoidoscopy stems from a belief that each test offers some benefit to counter the limitations of the other. Although sigmoidoscopy fails to screen above the reach of the sigmoidoscope, FOBT can detect proximal lesions that bleed. Although FOBT fails to detect many nonbleeding cancers, sigmoidoscopy directly visualizes the bowel and offers the possibility of reducing cancer inci- dence through polyp removal. In fact, in the Nottingham trial of FOBT, two-thirds of the cancers missed by FOBT were in the rectosigmoid region (40). There has been one controlled trial of more than 12,000 people in the Sloan-Kettering Institute and Strang Clinic in New York, which compared annual rigid sigmoidoscopy to annual rigid sigmoidoscopy with FOBT (41). CRC mortality was reduced by 43% in the group receiving combination screening after 5–11 yr of follow-up.
In addition, this study demonstrated a shift toward earlier stage
of cancer diagnosis in the combination group (70 vs 48%). In an ongoing randomized trial of sigmoidoscopy with or without FOBT, there is no evidence from their preliminary report that FOBT adds to the proportion of patients found to have high- risk neoplasia compared with sigmoidoscopy alone (42). A recommendation of the Multisociety Task Force is to offer screening including both FOBT and sigmoidoscopy (as described in the earlier recommendations for the individual tests) together, although FOBT should be done first (as a posi- tive test will result in a colonoscopy and obviate the need for sigmoidoscopy) (4).
3.5. BARIUM ENEMA
Barium enemas can be used to visualize the entire colon in most patients. An air-contrast, or double-contrast barium enema (DCBE) is better at identifying small mucosal lesions than a single-contrast study. The performance characteristics of DCBE are difficult to determine precisely owing to methodological problems in the available studies. However, it is estimated that the sensitivity of DCBE is 53% for polyps 6–10 mm in size and 48% for polyps larger than 1 cm (43). False-negative tests result from inadequate visualization of the bowel or improper inter- pretation. False-positive tests result from adherent stool and other non-neoplastic mucosal lesions. One case–control study suggested there might be some association with reduced CRC mortality, although the confidence interval was wide (44).
There are no controlled trials that show that barium enema is effective in reducing adverse health outcomes related to CRC.
Therefore, any recommendation for screening with barium enema is based on indirect evidence stemming from the ability of barium enema to detect colonic neoplasms. Furthermore, there are no studies that help us to determine the appropriate frequency of screening with DCBE. Complications relating to barium enema include perforation (estimated 1/25,000), radiation exposure (300–500 mrem) and minor complications directly attributable to the test, as well as complications from colonoscopy resulting from positive screening tests.
The Multisociety Task Force clinical guidelines recommend that DCBE be offered every 5 yr (4). This recommendation is based on evidence that screening DCBE is better at detecting cancers and large polyps than FOBT and is probably safer than sigmoidoscopy or colonoscopy. DCBE is less sensitive to small polyps than endoscopy, can result in false-positives that require colonoscopic evaluation, and involves patient discomfort and inconvenience. Although adding FS will increase the sensitiv- ity, the clinical benefit of such an approach for colon cancer screening has not been demonstrated and may not justify the additional effort.
3.6. COLONOSCOPY
Colonoscopy is attractive for CRC screening for several rea- sons. First, unlike sigmoidoscopy, colonoscopy offers the abil- ity to visualize the entire colon in most patients. Second, it allows for one to both detect, biopsy, and/or remove mucosal lesions in one setting. Moreover, colonoscopy does not rely on polyps or cancers to bleed in order for them to be detected.
Finally, as colonoscopy is the final common pathway for the
evaluation of positive screening tests (e.g., FOBT, barium
enema), it is reasonable to attribute much of the benefits of
other screening strategies to the colonoscopy itself. Two large, cross-sectional screening colonoscopy studies have been pub- lished showing that approximately half of those patients with advanced proximal neoplasia have no distal adenomas (45,46).
The sensitivity and specificity of colonoscopy are difficult to measure, because colonoscopy is often considered to be the gold standard. Tandem colonoscopy studies have shown that 0–6% of large polyps (≥1 cm) are missed and up to 27% of smaller lesions are missed (47,48). In the Office of Technology Assessment study of the cost-effectiveness of CRC screening, the sensitivity of colonoscopy for polyps and cancer was esti- mated at 90% (49). Given that lesions can be biopsied at the time of colonoscopy, the specificity is near 100%.
There are no controlled studies that directly assess the effectiveness of screening colonoscopy in reducing CRC mor- tality. There are case–control studies, which demonstrate that colonoscopy with or without polypectomy decreases the inci- dence of CRC (50). The National Polyp Study found that colonoscopy with polypectomy reduces the incidence of CRC (51) (Fig. 8). Similar results were seen in a cohort study from Italy (52). Moreover, a randomized, controlled study of sig- moidoscopy with follow-up colonoscopy did show a signifi- cant reduction in CRC incidence in screened subjects (53). It is not known how often screening colonoscopy should be performed. However, given that polyps usually require many years to progress to CRC, the high accuracy of colonoscopy for detecting advanced neoplasia (47), and the evidence of protection from cancer mortality for many years following
proctosigmoidoscopy, recent data on the low yield of colonoscopy 5 yr after a negative colonoscopy support the recommendation for screening colonoscopy every 10 yr in the absence of neoplasia.
However, there are several problems with colonoscopy as a screening test. First, its performance is operator-dependent,
Reference Normal Hyperplastic polyp adenoma <1 cm adenomas <1 cmb Advanced neoplasm10 2.7 (48/1765) 2.8 (13/464) 6.4 (35/543) 9.1 (4/44) 11.7 (32/274)
86 Not reported Not reported 0.8 (1/124) Not reported 11.8 (12/102)
87 Not reported Not reported 6.9 (13/189)c Not reported 28.6 (4/14)
88 Not reported Not reported 2.9 (15/521) 2.4 (2/85) 5.9 (27/460)
89 Not reported Not reported 1.6 (3/90) 10.4 (5/48) 7.4 (5/63)
90 5.3 (29/544) Not reported 5.0 (22/444) 6.3 (20/319) 8.8 (147/1665)
45 1.5 (23/1564) 4.0 (8/201) 7.1 (12/168) Not reported 11.5 (7/61)d
Modified from ref. 33.
aDefined as invasive cancer of adenoma 1 cm or larger in diameter or with villous features or high-grade dysplasia.
bDefined as three of more adenomas.
cIncludes adenomas with villous features.
dDoes not include adenomas 1 cm or larger.
Table 4
Case–Control Studies of Mortality Reduction Associated With Sigmoidoscopy Screening
Study characteristics Selby et al. (36) Newcomb et al. (37) Muller and Sonnenberg (35)
No. of cases of colorectal cancer 261 66 4411
Type of sigmoidoscope Rigid Rigid and flexible Rigid and flexible
Odds ratio (95% CI) for colorectal 0.41 (0.25–0.69) 0.21 (0.08–0.52) 0.41 (0.33–0.5) cancer death
Interval of apparent protective effect (yr) 9–10 Not specified 5
Modified from ref. 33. CI, confidence interval.
Fig. 8. Observed and expected CRC incidence in National Polyp Study cohort after colonoscopic polypectomy. (Reprinted with permission ref. 51.)
with the endoscopist’s experience playing a role in how often an adequate exam is obtained. It is estimated that the cecum can be reached in 98.6% of screening colonoscopies (54).
Colonoscopy performed by nongastroenterologists, however, has been shown to be less sensitive for detecting cancer than colonoscopy by gastroenterologists (55). Therefore, screen- ing colonoscopy should only be performed by well-trained providers. Second, patient discomfort or embarrassment may limit acceptance, although the use of conscious sedation dur- ing most colonoscopies can alleviate most patient discomfort.
In fact, many patients prefer colonoscopy to barium enema (56). Third, colonoscopy is the most expensive screening test under consideration when viewed from the perspective of cost per test. However, inclusion of downstream costs in the analy- sis alters this assessment. Finally, colonoscopy can result in complications such as perforation, bleeding, infection, and reactions to medications used for conscious sedation (57).
Commonly used estimates of the risk of perforation and bleed- ing are probably overstated, as these data often include patients undergoing therapeutic procedures, patients with comorbidity which would usually exclude screening, or they include com- plications during early experience with colonoscopy. In the Minnesota Colon Cancer Control Study, 12,246 colonoscopies were performed at the university hospital, resulting in 4 perforations (all requiring surgery) and 11 serious bleeding episodes (3 requiring surgery) (9). There were no perforations among more than 5000 patients in the two large screening colonoscopy studies (45,46).
3.7. COMPUTED TOMOGRAPHIC COLONOGRAPHY
Computed tomographic colonography (CTC) is performed using a spiral CT scan. Magnetic resonance imaging techniques are also under development. Computer software generates a virtual image of the bowel lumen, allowing one to perform a
“fly-through” examination of the bowel looking for polyps and cancer. This non-invasive technique for total colonic evaluation is rapidly evolving. If CTC can accurately distinguish patients with polyps or cancer from those without, then the cost and risks of colonoscopy can be limited to those most likely to benefit and overall screening rates may improve.
Unfortunately, there is considerable variability in the reported sensitivity and specificity of CTC, with most stud- ies reporting results that indicate further improvements are needed before widespread clinical application (58–60).
There is one study that stands out for its impressive results (61). In this study, Pickhardt et al. performed CTC followed by colonoscopy in 1233 subjects. Unlike other studies, these investigators employed software techniques to electronically
“cleanse” the bowel mucosa and utilized primary three- dimensional reconstruction for review of the images. Although they demonstrated that CTC sensitivity was similar to optical colonoscopy (88.7 vs 92.3% for polyps >5 mm), their results have yet to be reproduced. Other investigators have reported markedly lower sensitivities, although differences in tech- nique, hardware, and radiologist training may contribute to these differences.
For example, the study reported by Cotton et al. (58) uti- lized widely available CT technology, whereas the Pickhardt
study used only more state-of-the-art four- or eight-section CT scanners. Interestingly, subsequent three-dimensional imaging in the Cotton study did not dramatically improve the test charac- teristics. Radiologist experience may play a role, because the Cotton study required 10 prior CTC cases and the Pickhardt study required 25 prior CTC cases. The previously documented very poor interobserver variation of CTC interpretation among experienced radiologists raises concerns about the perform- ance of CTC in routine clinical practice (60). Further studies are needed to confirm the findings of Pickhardt et al. before CTC is endorsed as a screening test for CRC. Clearly, the technique is still evolving and the role of CTC in clinical care is yet to be fully defined.
4. COST-EFFECTIVENESS OF SCREENING
It is critical to understand that the cost of screening for CRC entails more than just the cost of the initial screening test.
Other costs include those associated with the evaluation of true- and false-positive results, costs of complications, and costs of cancer care. Some costs are very difficult to measure and are usually not included in cost-effectiveness models.
These include the costs of time lost from work and early mor- tality with loss of income for the patient’s family.
There have been several formal analyses of the cost- effectiveness of CRC screening (3,49,62,63). In Lieberman’s model of the cost-effectiveness of preventing death from CRC, several key points were highlighted (63). Although FOBT achieves reduction in CRC mortality through detection of early stage cancer, it prevents the fewest cancers when com- pared with other screening modalities. One-time colonoscopy achieves the greatest reduction in CRC and mortality from CRC. The model assumed that 100% of patients with a posi- tive FOBT would undergo colonoscopy. This assumption is unlikely to be met in clinical practice, as the Minnesota Colon Cancer Control Study only had 81% compliance with follow- up colonoscopy. Importantly, the cost of cancer care is a key variable in the cost-effectiveness analysis, for when the cost of cancer care exceeds $45,000, the cost per death prevented is similar for FOBT, FS/FOBT, and colonoscopy. Failure to screen will result in additional costs to provide care for the cancers, which could have been prevented. As the cost of can- cer care rises, therefore, screening becomes increasingly cost- effective, and potentially cost-saving. When the cost of colonoscopy falls below $750, then one-time colonoscopy is more cost-effective than the other strategies studied. Finally, compliance is a key factor in determining the relative cost- effectiveness of the screening strategies. When compliance is 100% for all strategies, FOBT ($225,000 per death prevented) appears much more cost-effective than colonoscopy ($274,000 per death prevented). However, when compliance falls to 50%
for all tests, FOBT ($331,000 per death prevented) is negligi-
bly more cost-effective than colonoscopy ($337,000 per death
prevented). Because FOBT requires annual testing, whereas
colonoscopy is modeled as a one-time procedure, one could
speculate that compliance may actually be higher for
colonoscopy. Clearly, compliance is critical to any discussion
of cost-effectiveness. A program of FOBT testing would
require 80% compliance to achieve the same mortality reduc- tion seen when screening colonoscopy is performed with 50%
compliance. Unfortunately, we lack good data on reasonable compliance rates for colonoscopy. Although there is some evi- dence of poor participation in screening colonoscopy studies (64), participation may be dramatically improved if physicians, professional organizations and third-party payers strongly rec- ommend and support screening colonoscopy.
The model performed by the Office of Technology Assessment of the Unites States Congress (49) studied the cost-effectiveness of FOBT, FS, DCBE and colonoscopy, both individually and in combination, for patients aged 50–85 yr (Fig. 9). Although it accounted for years of life lost as a result of detection and treatment of cancer, it did not account for imperfect compliance. The most striking finding of this study is that all strategies cost less than $20,000 per year of life saved. This is well within the commonly accepted range (<$40,000) of cost-effectiveness for US health care (dialysis costs approximately $35,000 per year of life saved).
5. COMPLIANCE
Compliance with screening for CRC in the United States and Canada has been disappointingly low (65–67). The Centers for Disease Control conducts a state-based, random-digit-dialed telephone survey of the civilian US population on a biennial basis (67). In 2001, 87,729 persons aged 50 yr or older responded. An estimated 44.6% had ever had FOBT, with 23.5%
indicating they had FOBT in the past 12 mo. Overall, 47.3%
had ever had lower endoscopy and 43.4% had lower endoscopy within 10 yr. An estimated 53.1% had FOBT in the past 12 mo and/or lower endoscopy in the past 10 yr. Comparison to similar surveys conducted in 1997 and 1999 indicates a trend toward increasing participation (Fig. 10). Recent data from Ontario sug- gests that screening participation is much lower in Canada (65).
In this study of nearly 1 million individuals aged 50–59 yr without
prior evidence of screening in administrative databases, less than 20.5% were screened during 6 yr of follow-up.
There is marked variation in screening participation rates in studies of CRC screening. Much of this variation in compli- ance is explained by study design, with studies of high-risk sub- jects and volunteers generally finding higher compliance than mass screening studies. One British study has found that refusal to undergo screening may be related to fear of further tests and surgery, feeling well, and unpleasantness of the screening pro- cedure (68). Myers et al. (69) have found that prior exposure to health education interventions is associated with increased compliance with screening. Thus, compliance may be associ- ated with positive attitudes toward screening and a willingness to risk the complications of the screening test in return for the assurance that is obtained for a negative test. Unwillingness to undergo screening may represent perceived lack of vulnerabi- lity to CRC, fear of discomfort or discovery of illness, or possibly belief that finding cancer will not impact on treatment and survival. Weller et al. (70) in an Australian population-based study, found that although awareness of FOBT is high, only 15% of subjects over age 40 had been tested. Moreover, only 28% stated that they intend to be tested. Many patients denied susceptibility to CRC, had knowledge deficits related to treat- ment success, or felt uncomfortable about taking the test. Kelly and Shank have shown that perceptions of discomfort with screening and perception of how well the physician explained the importance of the test are significant predictors of adherence to a screening program (71).
Although many of these factors are inherent to the patient, there are a number of system level barriers to CRC screening.
Although many professional societies have long endorsed CRC screening (72), screening guidelines from national task forces (e.g., US Preventive Services Task Force and Canadian Task Force on Preventive Health Care) have only endorsed many screening modalities relatively recently (2,73,74). As a result, physicians and other health care providers may not yet be convinced of the
Fig. 9. Effects and costs of CRC screening. S, sigmoidoscopy; B,DCBE; C, colonoscopy; F, annual fecal occult blood test (FOBT).
The number next to the letter indicates screening interval in years.
For example, S5F is sigmoidoscopy every 5 yr combined with annual FOBT. (Reprinted with permission from ref. 49.)
Fig. 10. Percentage of people aged 50 yr or older who reported receiv- ing a fecal occult blood test (FOBT) within 12 mo preceding survey and/or lower endoscopy within 5 yr* preceding survey, by test type and year—Behavioral Risk Factor Surveillance System (BRFSS), United States, 1997–2001.†(Reprinted with permission from ref. 67.)
benefits of screening. In addition, there are financial barriers to screening, especially because many insurance companies do not fully cover CRC screening. Nevertheless, screening participation is highest among those with health insurance, as well as those with higher education and recent routine doctors visits (75).
Although a CRC screening benefit was introduced for Medicare beneficiaries in 1998, early data suggests that this has not yet had measurable impact on test utilization (76).
Compliance with screening colonoscopy requires further study. When medical personnel and their spouses were invited to undergo a free screening colonoscopy, less than 15% accepted (64). Adherence to recommended follow-up colonoscopy after polypectomy was 80% in the National Polyp Study (77). How- ever, there is much interest in the idea of a one-time screening colonoscopy (78). This strategy may achieve a significant reduc- tion in CRC mortality without requiring longitudinal compli- ance, one of the most difficult problems with CRC screening.
This is especially important as the cost-effectiveness of screen- ing is reduced as compliance falls (Fig. 11).
6. PATIENT PREFERENCES FOR CRC SCREENING A variety of studies have assessed patient preferences for CRC screening. It is difficult to generalize findings from these studies, as the most defensible conclusion is that there is con- siderable variability in patient attitudes toward these screening modalities. In a survey of outpatients, Leard et al. (79) found that colonoscopic screening was preferred to sigmoidoscopy or barium enema. In a hospital-based randomized trial of screen- ing sigmoidoscopy vs screening colonoscopy, patients found the preparation for sigmoidoscopy easier (80). However, colonoscopy was less uncomfortable and less embarrassing than sigmoidoscopy, likely resulting from use of sedation with colonoscopy. In their study, colonoscopy was as acceptable to patients and only 20% more expensive. Patients clearly express anxiety and fear regarding endoscopy. McCarthy and Moskowitz found that although many patients undergoing screening sig- moidoscopy experienced pain and embarrassment, they reported significantly less pain and embarrassment than they had expected (81). In a study of veterans with and without CRC (82), substantial variation in attitudes toward screening
sigmoidoscopy and colonoscopy was demonstrated. Drossman et al. (83) have shown that younger patients, women, and patients without prior personal experience with endoscopic procedures were more likely to express concerns relating to endoscopy, including finding out what is wrong, experiencing pain, and finding cancer. These concerns may result in failure of the patient to undergo screening. Recent studies of CT colonogra- phy have assessed patient preferences for standard colonoscopy vs CT colonography. Unfortunately, there is no consistent pat- tern to the results, likely resulting from variation in how the subjects are queried about their preferences. One study has directly assessed preferences through the offering of either CT colonography or colonoscopy to 451 Australians in a commu- nity-based study. Of these, only 62 people chose to undergo screening, with 61% choosing colonoscopy and 39% choosing CT colonography (p = 0.075) (84).
Therefore, decisions regarding recommendations for CRC screening must take into account the variability in patient preferences. Ideally, patients should be offered a menu of test options from which to choose the test that best suits their preference. Although not all tests may be available in a given situation, patients should understand the advantages and lim- itations of each test in order to make an informed decision.
7. SUMMARY
CRC is a significant health care problem for which screen- ing has been shown to be effective in improving health related outcomes related to this cancer, as well as to be cost- effective. Unfortunately, participation rates in screening pro- grams have been disappointingly low. Given the availability of several good screening tests, it is incumbent on providers to educate their patients about the benefits of screening, and the test options. Efforts to remove barriers to screening should be supported.
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