References

1. Thiis-Evensen E, Hoff GS, Sauar J, et al.: Population-based surveillance by colonoscopy: effect on the incidence of colorectal cancer. Telemark Polyp Study I. Scand J Gastroenterol 34 (4): 414-20, 1999. [PubMed: 10365903]
2. Cotterchio M, Manno M, Klar N, et al.: Colorectal screening is associated with reduced colorectal cancer risk: a case-control study within the population-based Ontario Familial Colorectal Cancer Registry. Cancer Causes Control 16 (7): 865-75, 2005. [PubMed: 16132797]
3. Schoenfeld P, Cash B, Flood A, et al.: Colonoscopic screening of average-risk women for colorectal neoplasia. N Engl J Med 352 (20): 2061-8, 2005. [PubMed: 15901859]
4. Segnan N, Senore C, Andreoni B, et al.: Randomized trial of different screening strategies for colorectal cancer: patient response and detection rates. J Natl Cancer Inst 97 (5): 347-57, 2005. [PubMed: 15741571]
5. Gondal G, Grotmol T, Hofstad B, et al.: The Norwegian Colorectal Cancer Prevention (NORCCAP) screening study: baseline findings and implementations for clinical work-up in age groups 50-64 years. Scand J Gastroenterol 38 (6): 635-42, 2003. [PubMed: 12825872]
6. Winawer SJ, Stewart ET, Zauber AG, et al.: A comparison of colonoscopy and double-contrast barium enema for surveillance after polypectomy. National Polyp Study Work Group. N Engl J Med 342 (24): 1766-72, 2000. [PubMed: 10852998]
7. Lieberman DA, Weiss DG, Bond JH, et al.: Use of colonoscopy to screen asymptomatic adults for colorectal cancer. Veterans Affairs Cooperative Study Group 380. N Engl J Med 343 (3): 162-8, 2000. [PubMed: 10900274]
8. Imperiale TF, Wagner DR, Lin CY, et al.: Risk of advanced proximal neoplasms in asymptomatic adults according to the distal colorectal findings. N Engl J Med 343 (3): 169-74, 2000. [PubMed: 10900275]
9. Pickhardt PJ, Choi JR, Hwang I, et al.: Computed tomographic virtual colonoscopy to screen for colorectal neoplasia in asymptomatic adults. N Engl J Med 349 (23): 2191-200, 2003. [PubMed: 14657426]
10. Cotton PB, Durkalski VL, Pineau BC, et al.: Computed tomographic colonography (virtual colonoscopy): a multicenter comparison with standard colonoscopy for detection of colorectal neoplasia. JAMA 291 (14): 1713-9, 2004. [PubMed: 15082698]
11. Mulhall BP, Veerappan GR, Jackson JL: Meta-analysis: computed tomographic colonography. Ann Intern Med 142 (8): 635-50, 2005. [PubMed: 15838071]
12. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al.: Fecal DNA versus fecal occult blood for colorectal-cancer screening in an average-risk population. N Engl J Med 351 (26): 2704-14, 2004. [PubMed: 15616205]

References

1. Shike M, Winawer SJ, Greenwald PH, et al.: Primary prevention of colorectal cancer. The WHO Collaborating Centre for the Prevention of Colorectal Cancer. Bull World Health Organ 68 (3): 377-85, 1990. [PMC free article: PMC2393072] [PubMed: 2203551]
2. American Cancer Society: Cancer Facts and Figures 2016. Atlanta, Ga: American Cancer Society, 2016. Available online. Last accessed July 11, 2016.
3. Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2011. Bethesda, Md: National Cancer Institute, 2014. Also available online. Last accessed June 3, 2016.
4. Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations). Bethesda, Md: National Cancer Institute, 2012. Also available online. Last accessed September 29, 2016.
5. Imperiale TF, Wagner DR, Lin CY, et al.: Results of screening colonoscopy among persons 40 to 49 years of age. N Engl J Med 346 (23): 1781-5, 2002. [PubMed: 12050337]
6. Fuchs CS, Giovannucci EL, Colditz GA, et al.: A prospective study of family history and the risk of colorectal cancer. N Engl J Med 331 (25): 1669-74, 1994. [PubMed: 7969357]
7. Smith RA, von Eschenbach AC, Wender R, et al.: American Cancer Society guidelines for the early detection of cancer: update of early detection guidelines for prostate, colorectal, and endometrial cancers. Also: update 2001--testing for early lung cancer detection. CA Cancer J Clin 51 (1): 38-75; quiz 77-80, 2001 Jan-Feb. [PubMed: 11577479]
8. Levin B, Rozen P, Young GP: How should we follow up colorectal premalignant conditions? In: Rozen P, Young G, Levin B, et al.: Colorectal Cancer in Clinical Practice: Prevention, Early Detection, and Management. London, UK: Martin Dunitz, 2002, pp 67-76.
9. Winawer SJ, Fletcher RH, Miller L, et al.: Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 112 (2): 594-642, 1997. [PubMed: 9024315]
10. Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 61 (5): 759-67, 1990. [PubMed: 2188735]
11. Young GP, Rozen P, Levin B: How does colorectal cancer develop? In: Rozen P, Young G, Levin B, et al.: Colorectal Cancer in Clinical Practice: Prevention, Early Detection, and Management. London, UK: Martin Dunitz, 2002, pp 23-37.
12. Muto T, Bussey HJ, Morson BC: The evolution of cancer of the colon and rectum. Cancer 36 (6): 2251-70, 1975. [PubMed: 1203876]
13. Winawer SJ, Zauber AG, Ho MN, et al.: Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med 329 (27): 1977-81, 1993. [PubMed: 8247072]
14. Loeve F, Boer R, Zauber AG, et al.: National Polyp Study data: evidence for regression of adenomas. Int J Cancer 111 (4): 633-9, 2004. [PubMed: 15239144]

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 they 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, the test records blood from ingested meat, upper airway bleeding such as epistaxis, upper gastrointestinal (GI) bleeding, and 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.[1] The English trial selects candidates from lists of family practitioners.[2] The Danish trial offers screening to a population aged 45 to 75 years who were randomly assigned to a control or study group.[3,4]

The Minnesota trial randomly assigned 46,551 men and women aged 50 to 80 years to one of three arms: colorectal cancer screening with guaiac-based, rehydrated FOBT every year (15,570), every 2 years (15,587), or control (15,394). This trial demonstrated that annual FOBT screening decreased mortality from colorectal cancer (CRC) by 33% after 18 years of follow-up (relative risk [RR], 0.67; 95% confidence interval [CI], 0.51–0.83, compared with the control group) and that biennial testing resulted in a 21% relative mortality reduction (RR, 0.79; 95% CI, 0.62–0.97).[5] 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.[6] 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).[7] 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. With follow-up through 30 years, there was a sustained reduction in CRC mortality of 32% in the annually screened arm (RR, 0.68; 95% CI, 0.56–0.82) and 22% in the biennially screened arm (RR, 0.78; 95% CI, 0.65–0.93). There was no reduction in all-cause mortality in either screened arm (RR, 1.00; 95% CI, 0.99–1.01 for the annually screened arm; and RR, 0.99; 95% CI, 0.98–1.01 for the biennially screened arm).[8] Important information that was not reported includes the treatment of CRC cases by stage by arm and the extent of CRC screening in each arm by FOBT, sigmoidoscopy, or colonoscopy after the completion of the trial protocol.[8,9]

The English trial allocated approximately 76,000 individuals to each arm. Those in the screened arm were offered nonrehydrated guaiac FOBT (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 RR reduction of 15% in CRC mortality (odds ratio [OR], 0.85; 95% CI, 0.74–0.98).[10] 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.[11] 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).[12] 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).[13]

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,[14] 15% at 13 years of follow-up (RR, 0.85; 95% CI, 0.73–1.00),[15] and 11% at 17 years of follow-up (RR, 0.89; 95% CI, 0.78–1.01).[16] CRC incidence and overall mortality were virtually identical in both arms.

The Swedish trial in Goteborg enrolled all of its 68,308 citizens in the city, who were born between 1918 and 1931 and 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).[1]

All trials have shown a more favorable stage distribution in the screened population compared with controls (see 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.[14] 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).[17]

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.[18-21] 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 gFOBT is that it does not detect hemoglobin from nonhuman dietary sources. iFOBT 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. The studies also examine these outcomes for different cut-points, and the benefit of multiple versus single stool samples.[30] 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 before 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).[31]

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.[32]

Fecal immunochemical tests may vary with regard to numbers of stools tested and cut-off values for a positive result.[30,33,34]

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.[35]

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 [36] 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 before 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.[37]

Sigmoidoscopy

The flexible fiberoptic sigmoidoscope was introduced in 1969. The 60 cm flexible sigmoidoscope became available in 1976.[38] 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% of them. The finding of an adenoma by FS may warrant a colonoscopy to evaluate the more proximal portion of the colon.[39,40] 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.[41] Most of these adenomas are polypoid, flat and depressed lesions, which may be somewhat more prevalent than previously recognized.[42]

Five sigmoidoscopy screening RCTs have reported incidence and mortality results. These are the Norwegian Colorectal Cancer Prevention (NORCCAP) trial; the Telemark trial in Norway; the United Kingdom trial; the SCORE trial in Italy; and the U.S. Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Participants were aged 50 to 59 years in the Telemark trial, aged 55 to 74 years in PLCO, and aged 55 to 64 years in the other three trials. Together the trials enrolled 166,000 participants in the screened groups and 250,000 participants in the control groups. Follow-up ranged from 6 to 13 years. Results were summarized in two systematic reviews. There was an overall 28% relative reduction in CRC mortality (RR, 0.72; 95% CI, 0.65–0.80), an 18% relative reduction in CRC incidence (RR, 0.82; 95% CI, 0.73–0.91), and a 33% relative reduction in the incidence of left-sided CRC (RR, 0.67; 95% CI, 0.59–0.76). There was no effect on all-cause mortality.[43,44]

Two case-control studies have been reported that evaluate the efficacy of screening sigmoidoscopy in preventing CRC mortality;[45,46] 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%. The estimate was 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.[47] 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.[48]

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.[49] 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).

Barium Enema

As part of the National Polyp Study, colonoscopic examination and barium enema were compared in paired surveillance examinations in those who had undergone a previous colonoscopic polypectomy.[50] 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.

Colonoscopy

Because there are no completed 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.[51]

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 before radiographic examination.[67]

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 ≥10 mm, 98 (90%) were detected by CTC (referring everyone with a CTC lesion of ≥5 mm). Specificity was 86%, and PPV was 23%. There are several concerns from this study, including the following:

• Most, but not all, lesions found by CTC and not by OC were followed up with repeat OC.
• The design itself did not allow for following patients, thus potentially missing lesions that grow rapidly and would only be seen after follow-up.
• Because the centers conducting the screening were primarily academic centers and the radiologists and endoscopists were carefully trained, the generalizability of the findings is not clear.
• Sixteen percent of people had an extracolonic finding that required further evaluation.

Unknowns from the study include the following for either OC or CTC:[68]

• The number of detected polyps that would have progressed to invasive cancer.
• The number of people harmed by the screening process.

Another study reported similar sensitivity and specificity in persons with an increased risk of CRC.[69] 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 before the procedure, investigators in one study were able to detect lesions larger than 8 mm with 95% sensitivity and 92% specificity.[70] The particular tagging material used in this study caused about 10% of patients to become nauseated; however, other materials are being assessed.

Another study [71] 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 OC preferred CTC to OC (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 CTC. 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.[72] 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 CTC. CTC was performed immediately before a colonoscopy and these findings required further evaluation. The extent to which follow-up of these incidental findings benefited patients is unknown.[73]

Sixty-nine percent of 681 asymptomatic patients in Minnesota had extracolonic findings, of which 10% were considered to be highly important by the investigators, and required further medical workup. Suspected abnormalities involved kidney (34), chest (22), liver (8), ovary (6), renal or splenic arteries (4), retroperitoneum (3), and pancreas (1);[74] 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 [75] found that 8.6% of patients had an extracolonic finding of at least moderate importance, while 24% of patients in the smaller study [76] 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 the expertise of radiologists.[77]

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.[78]

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.[79] Advanced techniques have been developed to detect several of these gene mutations that have been shed into the stool.[80-83] 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.[84,85]

A subsequent study of stool DNA markers utilized a new multitargeted stool test that combined methylation markers for NDRG4 and BMP3, several KRAS mutations, and a human hemoglobin immunoassay. The markers, each quantitated separately, were combined using an algorithm in a prespecified multivariable analysis. The assay’s sensitivity and specificity were compared with a commercial FIT test (OC FIT-CHEK Polymedco), using colonoscopy as the gold standard. Among 12,776 participants who had colonoscopy screening, were enrolled from 2011 through 2012 at 90 sites in the United States and Canada, and were aged 50 to 84 years (and weighted toward >65 years), 9,989 had fully evaluable results. There were 65 CRC and 757 advanced adenomas or sessile serrated polyps 1 cm or greater. The sensitivity for CRC was 92.3% (60 of 65 CRC) for the multitargeted test and 73.8% for FIT. Sensitivity for advanced lesions was 42.4% for the multitargeted test and 23.8% for FIT. Sensitivity for high-grade dysplasia was 69.2% for the multitarget test and 46.2% for FIT. Sensitivity for serrated sessile polyps 1 cm or greater was 42.4% for the multitargeted test and 5.1% for FIT. Specificities were 86.6% for the multitargeted test and 94.9% for FIT, using nonadvanced or negative colonoscopy results, and were 89.8% and 96.4% for totally negative colonoscopy results. A receiver operating characteristic (ROC) analysis showed that the multitargeted test has higher sensitivity than FIT alone, even if the FIT “cut-off” is reduced to try to increase sensitivity. A limitation is that there were no data about performance of repeated testing over time and what may be an appropriate testing interval.[86]

Overall, the multitargeted test was more sensitive than FIT for both CRC and advanced precancerous lesions, but the test was less specific.[86]

Adherence to Screening

Benefit from CRC screening can only occur if eligible people are actually screened. There have been problems with screening adherence, particularly for low income and uninsured people. There has also been concern that some people may adhere less to screening with a colonoscopy than with fecal tests. One well-conducted RCT found that, among an uninsured population, mailed FIT-kit outreach and follow-up reminder phone calls resulted in an adherence rate of 40.7%. Mailed colonoscopy invitations and follow-up phone reminders resulted in a 24.6% adherence rate. The usual-care adherence rate in this trial was 12.1%.[87]

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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.[1] A positive test can lead to further diagnostic procedures that include colonoscopy or double-contrast barium enema plus flexible sigmoidoscopy.

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.

Colonoscopy

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.[2]

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.[3] 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 before colonoscopy, and these findings required further evaluation. The extent to which the follow-up of these incidental findings benefited patients is unknown.[4]

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).[5]

References

1. Hewitson P, Glasziou P, Irwig L, et al.: Screening for colorectal cancer using the faecal occult blood test, Hemoccult. Cochrane Database Syst Rev (1): CD001216, 2007. [PMC free article: PMC6769059] [PubMed: 17253456]
2. Warren JL, Klabunde CN, Mariotto AB, et al.: Adverse events after outpatient colonoscopy in the Medicare population. Ann Intern Med 150 (12): 849-57, W152, 2009. [PubMed: 19528563]
3. Edwards JT, Wood CJ, Mendelson RM, et al.: Extracolonic findings at virtual colonoscopy: implications for screening programs. Am J Gastroenterol 96 (10): 3009-12, 2001. [PubMed: 11693340]
4. Hellström M, Svensson MH, Lasson A: Extracolonic and incidental findings on CT colonography (virtual colonoscopy). AJR Am J Roentgenol 182 (3): 631-8, 2004. [PubMed: 14975961]
5. Gluecker TM, Johnson CD, Wilson LA, et al.: Extracolonic findings at CT colonography: evaluation of prevalence and cost in a screening population. Gastroenterology 124 (4): 911-6, 2003. [PubMed: 12671887]

Purpose of This Summary

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