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Note: Separate PDQ summaries on Colorectal Cancer Prevention; Colon Cancer Treatment; and Rectal Cancer Treatment are also available.
Based on solid evidence, screening for colorectal cancer (CRC) reduces CRC mortality, but there is little evidence that it reduces all-cause mortality, possibly because of an observed increase in other causes of death.
Colorectal cancer (CRC) is the third most common malignant neoplasm worldwide  and the second leading cause of cancer deaths in the United States. It is estimated that there will be 142,820 new cases diagnosed in the United States in 2013 and 50,830 deaths due to this disease. From 2005 to 2009, CRC incidence declined by 4.1% per year among adults aged 50 years and older. However, in adults younger than 50 years, CRC incidence rates have been increasing by 1.1% per year. From 2005 to 2009, mortality from CRC declined by 2.4% per year in men and 3.1% per year in women. The incidence is higher in men than in women. It ranges from 46.1 per 100,000 per year in Hispanic men to 66.9 per 100,000 per year in African American men. In women it ranges from 31.9 per 100,000 per year in Hispanics to 50.3 per 100,000 per year in African Americans. The age-adjusted mortality rates for men and women are 20.2 per 100,000 per year in men and 14.1 per 100,000 per year in women. About 5% of Americans are expected to develop the disease within their lifetime and about half of those will die from it. Age-specific incidence and mortality rates show that the vast majority of cases are diagnosed after age 50 years; about 4% of CRCs occur younger than age 50 years.[3,4]
Among the groups that have a high incidence of CRC are those with hereditary conditions, such as familial adenomatous polyposis and hereditary nonpolyposis CRC (inherited in an autosomal dominant manner). Combined, the two groups account for no more than 6% of CRCs. More common conditions associated with an increased risk include a personal history of CRC or adenomas; first-degree relative with CRC; a personal history of ovarian, endometrial, or breast cancer; and a personal history of long-standing chronic ulcerative colitis or Crohn colitis.[5,6,7] These high-risk groups account for about a quarter of all CRCs. Limiting screening or early cancer detection to only these high-risk groups would miss the majority of CRCs.
Genetic, experimental, and epidemiologic studies suggest that CRC results from complex interactions between inherited susceptibility and environmental or lifestyle factors. Efforts to identify causes led to the hypothesis that adenomatous polyps (adenomas) are precursors for the vast majority of CRCs. In effect, measures that reduce the incidence and prevalence of adenomas may result in a subsequent decrease in the risk of CRCs ; however, some CRC mortality may be caused by fast-growing lesions and even lesions that do not pass through an adenomatous phase. Overall, the details of growth rates of adenomas and cancer are unknown; most likely there is a broad spectrum of growth patterns, including formation and spontaneous regression of adenomas.
Fecal Occult Blood Test (FOBT)
In FOBT testing, a person collects stool samples that are analyzed for the presence of small amounts of blood. Collection details vary somewhat for different tests, but typically involve collection of as many as three different specimens on 3 different days, with small amounts from one specimen smeared by a wooden stick on a card with two windows or otherwise placed in a specimen container.
The guaiac test identifies peroxidase-like activity that is characteristic of human and nonhuman hemoglobin. Thus, it will record blood from ingested meat, upper airway bleeding such as epistaxis, upper gastrointestinal (GI) bleeding, as well as colonic lesions.
Five controlled clinical trials have been completed or are in progress to evaluate the efficacy of screening utilizing the FOBT. The Swedish trial is a targeted study for individuals aged 60 to 64 years. The English trial selects candidates from lists of family practitioners. The Danish trial offers screening to a population aged 45 to 75 years randomly assigned to a control or study group.[3,4]
The Minnesota trial demonstrated that annual guaiac-based FOBT (gFOBT) testing using primarily rehydrated samples decreased mortality from colorectal cancer (CRC) by 33%  and that biennial testing developed a 21% relative mortality reduction. Some part of the reduction may have been attributed to chance detection of cancer by colonoscopies; rehydration of guaiac test slides greatly increased positivity and consequently increased the number of colonoscopies performed. Subsequent analyses by the Minnesota investigators using mathematical modeling suggested that for 75% to 84% of the patients mortality reduction was achieved because of sensitive detection of CRCs by the test; chance detection played a modest role (16%–25% of the reduction). Nearly 85% of patients with a positive test underwent diagnostic procedures that included colonoscopy or double-contrast barium enema plus flexible sigmoidoscopy (FS). After 18 years of follow-up, the incidence of CRC was reduced by 20% in the annually screened arm and 17% in the biennially screened arm.
The English trial allocated approximately 76,000 individuals to each arm. Those in the screened arm were offered nonrehydrated gFOBT testing every 2 years for three to six rounds from 1985 to 1995. At a median follow-up time of 7.8 years, 60% completed at least one test, and 38% completed all tests. Cumulative incidence of CRC was similar in both arms, and the trial reported a relative risk (RR) reduction of 15% in CRC mortality (odds ratio [OR] = 0.85; 95% confidence interval [CI], 0.74–0.98). The serious complication rate of colonoscopy was 0.5%. There were five deaths within 30 days of surgery for screen-detected CRC or adenoma in a total of 75,253 individuals screened. After a median follow-up of 11.8 years, no difference in CRC incidence between the intervention and control groups was observed. The disease-specific mortality rate ratio associated with screening was 0.87 (0.78–0.97; P = .01). The rate ratio for death from all causes was 1.00 (0.98–1.02; P = .79). When the median follow-up was extended to 19.5 years, there was a 9% reduction in CRC mortality (RR = 0.91; 95% CI, 0.84–0.98) but no reduction in CRC incidence (RR = 0.97; 95% CI, 0.91–1.03), or death from all causes (RR = 1.00; 95% CI, 0.99–1.02).
The Danish trial in Funen, Denmark, entered approximately 31,000 individuals into two arms, in which individuals in the screened arm were offered nonrehydrated gFOBT testing every 2 years for nine rounds over a 17-year period. Sixty-seven percent completed the first screen, and more than 90% of individuals invited to each subsequent screen underwent FOBT testing. This trial demonstrated an 18% reduction in CRC mortality at 10 years of follow-up, 15% at 13 years of follow-up (RR = 0.85; 95% CI, 0.73–1.00), and 11% at 17 years of follow-up (RR = 0.89; 95% CI, 0.78–1.01). CRC incidence and overall mortality were virtually identical in both arms.
The Swedish trial in Goteborg enrolled all 68,308 citizens in the city born between 1918 and 1931 that were aged 60 to 64 years, and randomly assigned them to screening and control groups of nearly equal size. Participants in the control group were not contacted and were unaware they were part of the trial. Screening was offered at different frequencies to three different cohorts according to year of birth. Screening was done using the gFOBT Hemoccult-II test after dietary restriction. Nearly 92% of tests were rehydrated. Individuals with a positive test result were invited to an examination consisting of a case history, FS, and double-contrast barium enema. The range of follow-up times was from 6 years 7 months to 19 years 5 months, depending on the date of enrollment. The primary endpoint was CRC-specific mortality. The overall screening compliance rate was 70%, and 47.2% of participants completed all screenings. Of the 2,180 participants with a positive test, 1,890 (86.7%) underwent a complete diagnostic evaluation with 104 cancers and 305 adenomas of at least 10 mm detected. In total, there were 721 CRCs (152 Dukes D, 184 Dukes C) in the screening group and 754 CRCs (161 Dukes D, 221 Dukes C) in the control group, with an incidence ratio of 0.96 (95% CI, 0.86–1.06). Deaths from CRC were 252 in the screening group and 300 in the control group, with a mortality ratio of 0.84 (95% CI, 0.71–0.99). This CRC mortality difference emerged after 9 years of follow-up. Deaths from all causes were very similar in the two groups, with a mortality ratio of 1.02 (95% CI, 0.99–1.06).
All trials have shown a more favorable stage distribution in the screened population compared with controls (Table 3). Data from the Danish trial indicate that while the cumulative incidence of CRC was similar in the screened and control groups, a higher percentage of CRCs and adenomas were Dukes A and B lesions in the screened group. A meta-analysis of all previously reported randomized trials using biennial FOBT showed no overall mortality reduction by gFOBT screening (RR = 1.002; 95% CI, 0.989–1.085). The RR of CRC death in the gFOBT arm was 0.87 (95% CI, 0.8–0.95), and the RR of non-CRC death in the gFOBT group was 1.02 (95% CI, 1.00–1.04; P = .015).
Mathematical models have been constructed to extrapolate the results of screening trials to screening programs for the general population in community health care delivery settings. These models project a reduction in CRC mortality or an increase in life expectancy using currently available screening methodology.[18,19,20,21] The anticipated success of such methodology is critically dependent on the appropriate use of the FOBT and an effective clinical management plan.[22,23]
A systematic review done through the Cochrane Collaboration examined all CRC screening randomized trials that involved gFOBT testing on more than one occasion. The combined results showed that trial participants allocated to screening had a 16% lower CRC mortality (RR = 0.84; 95% CI, 0.78–0.90). There was, however, no difference in all-cause mortality between the screened and control groups (RR = 1.00; 95% CI, 0.99–1.02). Furthermore, the trials reported a low positive predictive value (PPV) for the FOBT test, suggesting that most positive tests were false positives. From the trials with nonrehydrated slides (Funen and Nottingham), the PPV was 5.0% to 18.7%, while the PPV in the trials using rehydrated slides (Goteborg and Minnesota) was 0.9% to 6.1%. The report contains no discussion on contamination in the control arms of the trials and no information on treatment by stage.[24,25]
On initial (prevalence) examinations, from 1% to 5% of unselected persons tested with gFOBT have positive test results. Of those persons with positive test results, approximately 2% to 10% have cancer and approximately 20% to 30% have adenomas,[26,27] depending on how the test is done. Data from randomized controlled trials (RCT) are summarized in Table 3.
Newer FOBTs: Nonrandomized Controlled Trial Evidence
The immunochemical FOBT (iFOBT) was developed to detect intact human hemoglobin. The advantage of iFOBT over guaiac FOBT (gFOBT) is that it does not detect hemoglobin from nonhuman dietary sources. It also does not detect partly digested human hemoglobin that comes from the upper respiratory or GI tract. Preliminary studies of several commercially developed iFOBT tests define their sensitivity and specificity compared with concurrently performed colonoscopy. These studies also examine these outcomes for different cut points, and the benefit of multiple versus single stool samples. Generally, iFOBT testing is more sensitive for cancers than for benign neoplasias. As expected, higher cut points decrease sensitivity and increase specificity.
In one study, 2,188 patients scheduled for colonoscopy because of an elevated risk due to personal or family history of colorectal neoplasm, positive gFOBT result, change in bowel habits, anemia, abdominal pain with weight loss, or anal symptoms were invited to participate in a comparative assessment of iFOBT against colonoscopy findings. After exclusions for health and cognitive reasons, 1,859 patients were offered iFOBT, 1,116 patients adhered to the protocol, and 1,000 patients completed the procedure. Sensitivity and specificity were calculated at various cut-points. At a cut-point of 100 ng/mL, sensitivity and specificity were, respectively, 88.2% and 89.7% for cancer and 61.5% and 91.4% for any clinically significant neoplasia (cancer and advanced polyps). At 150 ng/mL the respective sensitivities and specificities were 82.4% and 91.9% for cancer and 53.8% and 95% for any clinically significant neoplasia. Calculations were based on the most severe pathologic finding from colonoscopy and the highest fecal-hemoglobin concentration measured by iFOBT applied to three stool samples collected prior to the colonoscopy. Stool samples were collected by patients following iFOBT kit instructions and analyzed by the OC-MICRO analyzer (from the Eiken Chemical Company in Tokyo, Japan).
In another study, 21,805 asymptomatic patients received iFOBT based on one stool sample collected by patients following the kit instructions on the day of or the day before the colonoscopy. Stool samples were analyzed using the Magstream 1,000/Hem SP automated system (from Fujirebio Incorporated, Tokyo, Japan), which is based on the HemeSelect system (from Beckman Coulter, Palo Alto, California). Sensitivity and specificity based on subsequent colonoscopy were, respectively, 65.8% and 94.6% for cancer and 27.1% and 95.1% for advanced neoplasm.
Fecal immunochemical tests may vary with regard to numbers of stools tested and cut-off values for a positive result.[29,32,33]
A systematic review to evaluate the comparative diagnostic performance of gFOBT and iFOBT in the context of a decision to introduce screening for CRC in the United Kingdom, included 33 studies evaluating gFOBT and 35 studies evaluating iFOBT, including nine that evaluated both gFOBT and iFOBT. There was no clear evidence for superiority of either gFOBT or iFOBT. Sensitivities for the detection of all neoplasms ranged from 6.2% (specificity 98%) to 83.3% (specificity 98.4%) for gFOBTs and 5.4% (specificity 98.5%) to 62.6% (specificity 94.3%) for iFOBT. Increasing sensitivity entailed adjusting cut-points to decrease specificity. Sensitivities were higher for the detection of CRC and lower for adenomas.
Some studies have utilized the quantitative ability of iFOBT to consider detection and specificity at various test cut-points for defining a positive test. One study  found that reducing the cut-point from the standard 100 ng/mL to 50 ng/mL increased the detection of advanced adenomas but had little impact on the detection of cancer. The number of colonoscopies required to detect a single advanced adenoma or cancer increased from 1.9 to 2.3; a 20% increase. Specificity declined from 97.8% to 96%.
Potential false-positive test results due to an increased risk of upper GI bleeding are of concern with FOBT testing and pretest protocols, therefore; low-dose aspirin regimens should be discontinued for a week or more prior to FOBT. The performance of iFOBT was tested in an ongoing diagnostic study (2005–2009) at 20 internal medicine GI practices in southern Germany. Nineteen hundred seventy-nine patients (233 regular low-dose aspirin users and 1,746 never users) were identified in the records for inclusion in the analysis. All patients provided one stool sample taken within a week before colonoscopy preparation, which was collected according to instructions in a container that was kept refrigerated or frozen until rendered to the clinic on the day of colonoscopy, and the patients agreed to complete a standard questionnaire regarding the use of analgesics and low-dose aspirin (for prevention of cardiovascular disease). Stool samples were thawed within a median of 4 days after arrival at the central laboratory (shipped frozen from the recipient clinics). Fecal occult blood levels were measured by two automated iFOBT tests according to the manufacturer's instructions (RIDASCREEN Haemoglobin and RIDASCREEN Haemo-/Haptoglobin Complex, r-biopharm, Bensheim, Germany) following clinical procedures and blinded to colonoscopy results. Advanced neoplasms were found in 24 aspirin users (10.3%) and in 181 nonusers (10.4%). At the cut-point recommended by the manufacturer, sensitivities for the two tests were 70.8% (95% CI, 48.9%–87.4%) for users compared with 35.9% (95% CI, 28.9%–43.4%) for nonusers and 58.3% (95% CI, 36.6%–77.9%) for users compared with 32% (95% CI, 25.3%–39.4%) for nonusers (P = .001 and P = .01, respectively). Specificities were 85.7% (95% CI, 80.2–90.1%) for users compared with 89.2% (95% CI, 87.6%–90.7%) for nonusers and 85.7% (95% CI, 80.2%–90.1%) for users compared with 91.1% (95% CI, 89.5%–92.4%) for nonusers (P = .13 and P = .01, respectively). For these iFOBTs, sensitivity for advanced neoplasms was notably higher with the use of low-dose aspirin while specificity was only slightly reduced, suggesting that there might be an advantage to aspirin use to increase sensitivity without much decrease in specificity.
The flexible fiberoptic sigmoidoscope was introduced in 1969. The 60 cm flexible sigmoidoscope became available in 1976. The flexible sigmoidoscope permits a more complete examination of the distal colon with more acceptable patient tolerance than the older rigid sigmoidoscope. The rigid instrument can discover 25% of polyps, and the 60 cm scope can find as many as 65%. The finding of an adenoma by FS may warrant colonoscopy to evaluate the more proximal portion of the colon.[38,39] The prevalence of advanced proximal neoplasia is increased in patients with a villous or tubulovillous adenoma distally and is also increased in those aged 65 years or older with a positive family history of CRC and with multiple distal adenomas. Most of these adenomas are polypoid, flat and depressed lesions, which may be somewhat more prevalent than previously recognized.
Virtually all screening studies using these types of sigmoidoscopes have demonstrated an increase in the proportion of early cases and a corresponding increase in survival compared with cases diagnosed in a nonscreening environment. Most of these studies, however, lack appropriate comparison groups, and their interpretation is unclear because of screening biases.
The first incidence and mortality results from a randomized trial of sigmoidoscopy were reported in the Norwegian Colorectal Cancer Prevention (NORCCAP) trial. This trial randomly assigned 41,913 men and women aged 55 to 64 years to a usual-care control group and 13,823 individuals to a screening group, 6,915 of whom received one-time FS and 6,908 of whom received both FS and iFOBT. Screening was conducted from January 1999 to December 2000. Follow-up was through national registries in Norway and ended December 31, 2006 for incidence and December 31, 2005 for mortality. The primary endpoint was incidence of CRC after 5, 10, and 15 years of follow-up based on an intention-to-screen analysis. The two randomly assigned groups had the same median age of 59 years and equal gender distribution. The attendance rate for screening was 65%. Mean insertion depth of the endoscope was 48.9 cm for men and 44.0 cm for women, with no severe complications. A neoplastic lesion was found in 19% of people screened, and 5% had a high-risk adenoma or invasive cancer. There were 33 prevalent CRCs, 17 in the subgroup invited for sigmoidoscopy only and 16 in the subgroup invited to both tests. Compliance for colonoscopy work-up was 97%. There was no difference in the cumulative hazard of CRC between the screened and control groups; 134.5 versus 131.9 cases per 100,000 person years, after a median follow-up of 7 years. The hazard ratio (HR) for CRC mortality was 0.73 (95% CI, 0.47–1.13) and for rectosigmoidal cancer mortality was 0.63 (95% CI, 0.34–1.18) after a median follow-up of 6 years. The HR for all-cause mortality was 1.02 (95% CI, 0.98–1.07). Additional follow-up is planned.
In the Telemark Study in Norway, 400 people aged 50 to 59 years were offered FS in 1983 and, if polyps were found, a colonoscopy was available to them at that time, and again 2 years later, and also 6 years later (the intervention was more aggressive than the one-time sigmoidoscopy currently being tested in the United Kingdom). A nonrandomized control group was selected that did not have a baseline examination. In 1996, all persons were invited to have a colonoscopy. The result was that ten persons in the control group and two in the screening group developed CRC (RR = 0.2; 95% CI, 0.03–0.95). The screening group, however, had a higher overall mortality compared with the control group.
A RCT of sigmoidoscopy screening in the United Kingdom suggests that the impact of endoscopic screening, at least on the left side of the colon, is substantial and prolonged. In this RCT, 170,000 persons were randomly assigned to one-time sigmoidoscopy versus usual care. At sigmoidoscopy, polyps were removed and patients with cancer were referred for treatment. Based on sigmoidoscopy findings, persons were considered to be low risk if they had normal exams or only one or two small (<1 cm) tubular adenomas; such persons were not referred for either colonoscopy workup or colonoscopic surveillance. In a follow-up of 10 years, the left-sided CRC incidence in the low-risk group (about 95% of attendees were low risk) was 0.02% to 0.04% per year—a very low risk of CRC compared with average risk. The cause of reduced risk—whether due to detection and removal of large or small polyps, or selection of individuals at lower risk—is yet unclear, but may be assessed in further analysis. The natural history of large polyps is not well known, but some evidence suggests that such lesions become clinical CRC at a rate of approximately 1% per year. Evidence from multiple studies has raised questions about the ability of endoscopy to reduce CRC mortality in the right colon.[46,47,48] Thus, it is unclear what the overall impact of endoscopy (e.g., colonoscopy screening) is, and whether there may be a large difference in impact on the left side of the colon compared with the right side.
The SCORE RCT from Italy randomly assigned 34,272 participants aged 55 to 64 years to either one-time FS or control. About 58% of FS group participants actually had an FS. After 10.5 years of follow-up, CRC incidence was reduced in the FS group by 18% (RR, 0.82; 95% CI, 0.69–0.96), with the reduction beginning about 5 years after randomization. CRC mortality in the FS group was also lower than in the control group, but not to a statistically significant degree (RR, 0.78; 95% CI, 0.56–1.08). Overall, these results are consistent with the United Kingdom results.
Sigmoidoscopy screening was also evaluated in the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) screening randomized trial. Results were very similar to those of the United Kingdom trial. In PLCO, 77,445 men and women aged 55 to 74 years were randomly assigned to receive 60 cm flexible sigmoidoscopy screening at baseline and again at 3 or 5 years from 1993 to 2001 depending on their date of entry into the trial. The 77,455 men and women randomly allocated to the control arm received usual medical care. An examination was considered positive if a polyp or mass was detected. Participants were then referred to their primary care physicians for diagnostic follow-up. A total of 86.6% of participants underwent at least one sigmoidoscopy screening and 28.5% were positive. Of these, 80.5% had a diagnostic evaluation, of which 95.6% underwent colonoscopy. Thus 21.9% of participants in the intervention arm had a colonoscopy. Colorectal cancer screening in the control arm (contamination) was assessed by a questionnaire in a small sample of participants. The rate was estimated as 46.5%. In addition, the rate of colonoscopy after the screening phase was estimated as 47.7% in the intervention arm and 48.0% in the control arm.
The primary endpoint was colorectal cancer mortality, with colorectal cancer incidence a key secondary endpoint. All cancers and deaths were ascertained primarily by means of an annual questionnaire. Median follow-up time was 11.9 years and vital status within a year of the cutoff date was known for 99.9% of participants. The incidence rate of colorectal cancer was 11.9 per 10,000 person years in the intervention arm (1,012 cases) versus 15.2 in the usual care arm (1,287 cases) yielding a statistically significant RR of 0.79 (95% CI, 0.72–0.85). The absolute colorectal cancer risk reduction was 0.35%. In the distal colon the RR was 0.71 (95% CI, 0.64–0.80) while in the proximal colon the RR was 0.86 (95% CI, 0.76–0.97). The colorectal cancer mortality rate was 2.9 deaths per 10,000 person-years in the intervention arm (252 deaths) versus 3.9 deaths in the usual care arm (341 deaths) for a statistically significant RR of 0.74 (95% CI, 0.63–0.87). The absolute reduction in risk of colorectal cancer death was 0.11%. The mortality RR for the distal colon was 0.50 (95% CI, 0.38–0.64) while that for the proximal colon was 0.97 (95% CI, 0.77–1.22). Treatment of diagnosed colorectal cancers was very similar by arm within each stage. The rate of bowel perforations was 2.8 per 100,000 sigmoidoscopies. False positive screening results were observed in 20% of men and 13% of women. The RR for deaths from all causes excluding prostate, lung, colorectal, and ovarian cancers was 0.98 (95% CI, 0.96–1.01).
Two case-control studies have been reported that evaluate the efficacy of screening sigmoidoscopy in preventing CRC mortality;[51,52] one study used rigid sigmoidoscopy, and the other used rigid and FS. Both studies were conducted in prepaid health plans and suggested a significantly decreased risk (70%–90%) of fatal cancer of the distal colon or rectum among individuals with a history of one or more sigmoidoscopic examinations compared with nonscreened patients.
There are no strong direct data to determine frequency of screening tests in programs of screening.
Combination of FOBT and Flexible Sigmoidoscopy
A combination of FOBT and sigmoidoscopy might increase the detection of lesions in the left colon (compared with sigmoidoscopy alone) while also increasing the detection of lesions in the right colon. Sigmoidoscopy detects lesions in the left colon directly but detects lesions in the right colon only indirectly when a positive sigmoidoscopy (that may variously be defined as a finding of advanced adenoma, any adenoma, or any polyp) is used to trigger a colonoscopic examination of the whole colon.
In 2,885 veterans (97% male; mean age 63 years), the prevalence of advanced adenoma at colonoscopy was 10.6%. It was estimated that combined screening with one-time FOBT and sigmoidoscopy would detect 75.8% (95% CI, 71.0%–80.6%) of advanced neoplasms. Examination of the rectum and sigmoid colon during colonoscopy was defined as a surrogate for sigmoidoscopy. This represented a small but statistically insignificant increase in the rate of detection of advanced neoplasia when compared with FS alone (70.3%; 95% CI, 65.2%–75.4%). The latter result could be achieved assuming that all patients with an adenoma in the distal colon undergo complete colonoscopy. Advanced neoplasia was defined as a lesion measuring at least 10 mm in diameter, containing 25% or more villous histology, high-grade dysplasia, or invasive cancer. One-time use of FOBT differs from the annual or biennial application reported in those studies summarized in Table 1.
A study of 21,794 asymptomatic persons (72% were men) who had both colonoscopy and fecal immunochemical testing (FIT) for occult blood compared the detection of right-sided cancers as triggered by different test results. FIT alone resulted in a sensitivity of 58.3% and a specificity of 94.5% for proximal cancer diagnosis. FIT plus the finding of advanced neoplasia in the rectosigmoid colon yielded a sensitivity of 62.5% and a specificity of 93%. Thus, in this trial, the addition of sigmoidoscopy to FIT did not substantially improve the detection of right-sided colon cancers, compared with FIT alone.
The NORCCAP once-only screening study randomly assigned 20,780 men and women, aged 50 to 64 years, to FS only or a combination of FS and FOBT with FlexSure OBT. A positive FS was defined as a finding of any neoplasia or any polyp at least 10 mm. A positive FS or FOBT qualified for colonoscopy. Attendance in this study was 65%. Forty-one cases of CRC were detected (0.3% of screened individuals). Adenomas were found in 2,208 participants (17%), and 545 (4.2%) had high-risk adenomas. There was no difference in diagnosis yield between the FS only and the FS and FOBT groups regarding CRC or high-risk adenoma. There were no serious complications after FS, but there were six perforations after therapeutic colonoscopy (1:336).
As part of the National Polyp Study, colonoscopic examination and barium enema were compared in paired surveillance examinations in those who had undergone a prior colonoscopic polypectomy. The proportion of examinations in which adenomatous polyps were detected by barium enema was related to the size of the adenoma (P = .009); the rate was 32% for colonoscopic examinations in which the largest adenomas detected were no larger than 5 mm, 53% for those in which the largest adenomas detected were 6 mm to 10 mm, and 48% for those in which the largest adenomas detected were larger than 10 mm. In patients who have undergone colonoscopic polypectomy, colonoscopic examination is a more sensitive method of surveillance than double-contrast barium enema.
Because there are no RCTs of colonoscopy, evidence of benefit is indirect. Most indirect evidence is about detection rate of lesions that may be clinically important (like early CRC or advanced adenomas). Some case-control results are available. One RCT of colonoscopy has been initiated.
Evidence about lesion detection rate
In a colonoscopic study of 3,121 predominantly male U.S. veterans (mean age: 63 years), advanced neoplasia (defined as an adenoma that was ≥10.0 mm in diameter, a villous adenoma, an adenoma with high-grade dysplasia, or invasive cancer) was identified in 10.5% of the individuals. Among patients with no adenomas distal to the splenic flexure, 2.7% had advanced proximal neoplasia. Patients with large adenomas (≥10.0 mm) or small adenomas (<10.0 mm) in the distal colon were more likely to have advanced proximal neoplasia than were patients with no distal adenomas (OR = 3.4; 90% CI, 1.8–6.5 and OR = 2.6; 90% CI, 1.7–4.1, respectively). One-half of those with advanced proximal neoplasia, however, had no distal adenomas. In a study of 1,994 adults (aged 50 years or older) who underwent colonoscopic screening as part of a program sponsored by an employer, 5.6% had advanced neoplasms. Forty-six percent of those with advanced proximal neoplasms had no distal polyps (hyperplastic or adenomatous). If colonoscopic screening is performed only in patients with distal polyps, about half the cases of advanced proximal neoplasia will not be detected.
A study of colonoscopy in women compared the yield of sigmoidoscopy versus colonoscopy. Among 1,463 women, cancer was found in one woman and advanced colonic neoplasia in 72 women or 4.9% (about one-half the prevalence compared with men). The authors focused, however, on RR (i.e., RR of missing an advanced neoplasm) as the outcome, instead of absolute risk of such neoplasms, which is substantially lower in women. In addition, the natural history of advanced neoplasia is not known, so its importance as an outcome in studies of detection is not clear.
Analysis of data from a colonoscopy-based screening program in Warsaw, Poland demonstrated higher rates of advanced neoplasia in men than in women. The predominant age range of participants was 50 to 66 years. Of the 43,042 participants aged 50 to 66 years, advanced neoplasia was detected in 5.9% (5.7% among women with a family history of CRC, 4.3% among women without a family history of CRC, 12.2% among men with a family history of CRC, and 8.0% among men without a family history of CRC). Clinically significant complications requiring medical intervention were rare (0.1%) consisting of five perforations, 13 episodes of bleeding, 22 cardiovascular events, and 11 other events over the entire population of 50,148 screened persons. There were no deaths; however, the author reported that collection of 30-day complications data was not systematic (therefore, the data may not be reliable).
Detection rates in colonoscopy screening vary with the rate at which the endoscopist examines the colon while withdrawing the scope. Detection rates among gastroenterologists (mean number of lesions per patient screened, 0.10–1.05; range of the percentage of patients with adenomas, 9.4%–23.7%) and the times to withdraw (3.1–16.8 minutes for procedures not including polyp removal). Examiners whose mean withdrawal time was 6 minutes or more had higher detection rates than those with mean withdrawal times of less than 6 minutes (28.3% vs. 11.8%; P < .001 for any neoplasia) and (6.4% vs. 2.6%; P < .005 for advanced neoplasia). Overall detection rate of adenomas and cancer may be affected by how thoroughly endoscopists search for flat adenomas and flat cancer. While the phenomenon of flat neoplasms has been appreciated for years in Japan, it has more recently been described in the United States. In a study in which endoscopists used high-resolution white-light endoscopes, flat or nonpolypoid lesions were found to account for only 11% of all superficial colon lesions, but they were about 9.8 times as likely to contain cancer (in situ neoplasia or invasive cancer) compared with polypoid lesions. However, because the definition of flat or nonpolypoid was height less than one-half of the diameter, it is likely that many lesions classified as nonpolypoid in this study would be routinely found and described by U.S. endoscopists as sessile. At the same time, the existence of very flat or depressed lesions (depressed lesions are very uncommon but are highly likely to contain cancer) means that endoscopists will want to pay increasing attention to this problem. Flat lesions may play a role in the phenomenon of missed cancers.
Flat or difficult-to-detect lesions include "serrated polyps," which may be more common in the right colon than they are in the left. The term serrated polyp is currently used to include hyperplastic polyps, sessile serrated adenomas, traditional serrated adenomas, and mixed serrated polyps.[65,66] The clinical significance of these lesions is uncertain, because the natural history is so difficult to learn for any polypoid lesion. However, the histologic and molecular characteristics of some serrated lesions suggest possibly important malignant potential (mutations in the BRAF gene may be an early step toward carcinogenesis in serrated polyps). This potential, along with the challenges of detecting flat lesions, may partially account for recent reports of a colonoscopy's lesser protective effect in the right colon compared to the left.
In 2011, authors of one study reported variability of detection rates for proximal serrated polyps. They studied 15 colonoscopists on faculty at one university and showed, during the years 2000 to 2009, a wide variation in detection rate for proximal serrated polyps, ranging (per colonoscopy) from 0.01 to 0.26, suggesting that many proximal serrated lesions may be missed on routine exam. The overall proportion of polyps that are "serrated" is unknown, in part because these lesions have been unappreciated and/or difficult to identify.
Evidence about colorectal cancer mortality reduction
Although there is no RCT to assess reduction of CRC incidence or mortality by colonoscopy, some case-control evidence is available. Based on case-control data about sigmoidoscopy, noted above, it has been speculated in the past that protection for the right colon might be similar to that found for the left colon. However, a recent case-control study of colonoscopy raises questions about whether the impact of colonoscopy on right-sided lesions might be different than the impact on left-sided lesions. Using a province-wide administrative data base in Ontario, investigators compared cases of persons who had received a diagnosis of CRC from 1996 to 2001 and had died by 2003. Controls were selected from persons who did not die of CRC. Billing claims were used to assess exposure to previous colonoscopy. The OR for the association between complete colonoscopy and left-sided lesions was 0.33, suggesting a substantial mortality reduction. For right-sided lesions, however, the OR of 0.99 indicated virtually no mortality reduction.
This difference, which was striking and unexpected, might be explained in several possible ways and has been discussed extensively. It is possible that exams were incomplete and did not reach the cecum even though they were coded as complete. It is possible that poor prep or incomplete mucosal inspection caused important lesions to be missed. It is also possible that examination was complete but some right-sided lesions simply grow rapidly and are not detected and treated by periodic colonoscopy. In other words, it is impossible to determine the reason for the dramatically different results on the right side compared to the left side, which are either the result of physician-related and patient-related factors or are the result of the biology of cancer.
Even if it is not possible to determine which reasons may be responsible for the right side versus the left side difference, the findings beg the question, "What is the degree of mortality reduction from colonoscopy?" While a figure of 90% is sometimes cited as the degree of mortality reduction, the question will not be properly answered until the European study is completed. In the meantime, the results of the study mentioned above  question what is known about the degree of CRC mortality reduction provided by colonoscopy. Until there are more reliable results from RCTs, it may be prudent to expect an approximately 60% to 70% CRC mortality reduction, based on consideration of these studies and other data.
Evidence about colorectal cancer reduction
A case-control study assessed CRC reduction (not CRC mortality reduction) in the right side versus the left side. In a population-based study from Germany, data were obtained from administrative records and medical records; 1,688 case patients (with CRC) were compared with 1,932 participants (without CRC), aged 50 years or older. Data were collected about demographics, risk factors, and previous screening examinations. According to colonoscopy records, the cecum was reached 91% of the time. Colonoscopy in the previous 10 years was associated with an OR for any CRC of 0.23, for right-sided CRC of 0.44, and for left-sided CRC of 0.16. While this study does not assess CRC mortality, the results suggest that the magnitude of the right side versus the left side difference may be smaller than previously found. It would be extremely useful to assess right side versus left side differences in a RCT.
Virtual Colonoscopy (Computed Tomographic [CT] Colonography)
Virtual colonoscopy (also known as CT colonography or CT pneumocolon) refers to the examination of computer-generated images of the colon constructed from data obtained from an abdominal CT examination. These images simulate the effect of a conventional colonoscopy. Patients must take laxatives to clean the colon before the procedure, and the colon is insufflated with air (sometimes carbon dioxide) by insertion of a rectal tube just prior to radiographic examination.
A large, paired-design study was conducted by the American College of Radiology Imaging Network group, with 2,531 average-risk people (prevalence of polyps or cancer greater than or equal to 10 mm = 4%; mean age about 58 years) screened with both CT colonography and optical colonoscopy (OC). The gold standard was the OC, including repeat OC exams for people with lesions found by computed tomographic colonography (CTC) but not by OC. Of 109 people with at least one adenoma or cancer greater than or equal to 10 mm, 98 (90%) were detected by CTC (referring everyone with a CTC lesion of 5 mm or greater). Specificity was 86% and PPV was 23%. There are several concerns from this study, including the following:
Unknowns from the study include the following for either OC or CTC: the number of detected polyps that would have progressed to invasive cancer, and the number of people harmed by the screening process.
Another study reported similar sensitivity and specificity in persons with an increased risk of CRC. In this study, the sensitivity of OC could not be determined because it was done in an unblinded manner. This study suggests that virtual colonoscopy might be an acceptable screening or surveillance test for persons with a high risk of CRC, but this cross-sectional study does not address outcome or frequency of testing in high-risk persons.
Some studies have assessed how well virtual colonoscopy can detect colorectal polyps without a laxative prep. The question is of great importance for implementation because the laxative prep required by both conventional colonoscopy and virtual colonoscopy is considered a great disadvantage by patients. By tagging feces with iodinated contrast material ingested during several days prior to the procedure, investigators in one study were able to detect lesions larger than 8 mm with 95% sensitivity and 92% specificity. The particular tagging material used in this study caused about 10% of patients to become nauseated; however, other materials are being assessed.
Another study  utilized low fiber diet, orally ingested contrast, and 'electronic cleansing', a process that subtracts tagged feces. CTC identified 91% of persons with adenomas 10 mm or larger, but detected fewer (70%) lesions greater than or equal to 8 mm. Patients who received both CTC and optical colonoscopy preferred CTC to optical colonoscopy (290 vs. 175). This study shows that CTC without a laxative prep detects small 1 cm lesions with high sensitivity and is acceptable to patients. Long-term utilization of CTC will depend on several issues including the frequency of follow-up exams that would be needed to detect smaller lesions that were undetected and may grow over time.
Extracolonic abnormalities are common in CT colonography. Fifteen percent of patients in an Australian series of 100 patients, referred for colonography because of symptoms or family history, were found to have extracolonic findings, and 11% of the patients needed further medical workups for renal, splenic, uterine, liver, and gallbladder abnormalities. In another study, 59% of 111 symptomatic patients referred for clinical colonoscopy in a Swedish hospital between June 1998 and September 1999 were found to have moderate or major extracolonic conditions on CT colonography. CT colonography was performed immediately prior to colonoscopy and these findings required further evaluation. It is unstated to what extent the follow-up of these incidental findings benefited patients.
Sixty-nine percent of 681 asymptomatic patients in Minnesota had extracolonic findings, of which 10% were considered to be highly important by the investigators, requiring further medical workup. Suspected abnormalities involved kidney (34), chest (22), liver (8), ovary (6), renal or splenic arteries (4), retroperitoneum (3), and pancreas (1); however, the extent to which these findings will contribute to benefits or harms is uncertain. Two other studies, one large (n = 2,195) and one small (n = 136) examined the moderate or high importance of extracolonic findings from CTC. The larger study  found that 8.6% of patients had an extracolonic finding of at least moderate importance, while 24% of patients in the smaller study  required some evaluation for an extracolonic finding. The larger study found nine cancers from these evaluations, at a partial cost (they did not include all costs) of $98.56 per patient initially screened. The smaller study found no important lesions from evaluation, at a cost of $248 per person screened. Both of these estimates of cost are higher than previous studies have found. The extent to which any patients benefited from the detection of extracolonic findings is not clear. Because both of these studies were conducted in academic medical centers, the generalizability to other settings is also not clear. Neither of these studies examined the effect of extracolonic findings on patient anxiety and psychological function.
Technical improvements involving both the interpretation methodology, such as three dimensional (3-D) imaging, and bowel preparation are under study in many centers. While specificity for detection of polyps is homogeneously high in many studies, sensitivity can vary widely. These variations are attributable to a number of factors including characteristics of the CT scanner and detector, width of collimation, mode of imaging (two dimensional [2-D] vs. 3-D and/or "fly-through"), and variability in expertise of radiologists.
Digital Rectal Examination
A case-control study reported that routine digital rectal examination was not associated with any statistically significant reduction in mortality from distal rectal cancer.
Detection of DNA Mutations in the Stool
The molecular genetic changes that are associated with the development of colorectal adenomas and carcinoma have been well characterized. Advanced techniques have been developed to detect several of these gene mutations that have been shed into the stool.[82,83,84,85] Stool DNA testing was recently assessed in a prospective study of asymptomatic persons who received colonoscopy, three-card FOBT (Hemoccult II), and stool DNA testing based on a panel of markers assessing 21 mutations. Conducted in a blinded way with prestated hypotheses and analyses, the study found that among 4,404 patients, the DNA panel had a sensitivity for CRC of 51.6% (for all stages of CRC) versus 12.9% for Hemoccult II, while the false-positive rates were 5.6% and 4.8%, respectively. On this basis, the approach looks promising but would be improved, if possible, by increased sensitivity (perhaps by increasing the number of DNA markers) and by reduced cost.[86,87]
Harms are associated with the various modalities used to screen for colorectal cancer (CRC).
Fecal Occult Blood Testing (FOBT)
A systematic review done through the Cochrane Collaboration examined all CRC screening randomized trials that involved FOBT on more than one occasion. The trials reported a low positive predictive value for the FOBT, suggesting that more than 80% of all positive tests were false-positives. A positive test can lead to further diagnostic procedures that include colonoscopy or double-contrast barium enema plus flexible sigmoidoscopy.
Sigmoidoscopy can be an uncomfortable or painful procedure. Women may have more pain during the procedure, which may discourage them from returning for future screening sigmoidoscopies. Sigmoidoscopy can also cause perforation and bleeding, although this is rare.
Clinically significant complications requiring medical intervention are rare but can include the following: perforations, bleeding, cardiovascular events, and other adverse events. The rate of complications may increase among older persons.
Computed Tomographic (CT) Colonography
Extracolonic abnormalities are common in CT colonography. Fifteen percent of patients in an Australian series of 100 patients, referred for colonography because of symptoms or family history, were found to have extracolonic findings, and 11% of the patients needed further medical workups for renal, splenic, uterine, liver, and gallbladder abnormalities. Other areas of extracolonic findings include the chest, ovary, and pancreas. In another study, 59% of 111 symptomatic patients referred for clinical colonoscopy in a Swedish hospital between June 1998 and September 1999 were found to have moderate or major extracolonic conditions on CT colonography. CT colonography was performed immediately prior to colonoscopy, and these findings required further evaluation. It is unstated to what extent the follow-up of these incidental findings benefited patients.
Sixty-nine percent of 681 asymptomatic patients in Minnesota had extracolonic findings, of which 10% were considered to be highly important by the investigators, requiring further medical workup. Suspected abnormalities involved kidney (34), chest (22), liver (8), ovary (6), renal or splenic arteries (4), retroperitoneum (3), and pancreas (1).
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Updated statistics with estimated new cases and deaths for 2013 (cited American Cancer Society as reference 2 and Howlader et al. as reference 3).
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