Colorectal Cancer Screening (PDQ®): Screening - Health Professional Information [NCI]

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Colorectal Cancer Screening

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about colorectal cancer (CRC) screening. This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board.

Information about the following is included in this summary:

  • CRC incidence and mortality statistics and information about CRC risk factors.
  • CRC screening modalities.
  • Benefits and harms of CRC screening.

This summary is intended as a resource to inform clinicians and other health professionals about currently available CRC screening modalities. The PDQ Screening and Prevention Editorial Board uses a formal evidence ranking system in reporting the evidence of benefit and potential harms associated with each screening modality. It does not provide formal guidelines or recommendations for making health care decisions. Information in this summary should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version, which is written in less technical language.

Summary of Evidence

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.

Table 1. Effect of Screening Intervention on Reducing Mortality from Colorectal Cancera

a There are no data on the effect of other screening interventions (i.e., fecal occult blood test combined with sigmoidoscopy, barium enema, colonoscopy, computed tomographic colonography, and stool DNA mutation tests) on mortality from colorectal cancer.
  Fecal Occult Blood Test Sigmoidoscopy Digital Rectal Exam
STUDY DESIGN Randomized controlled trials Case-control studies, randomized controlled trials in progress Case-control studies
INTERNAL VALIDITY Good Fair Fair
CONSISTENCY Good Fair Good
MAGNITUDE OF EFFECTS 15%–33% About 50% for left colon No effect
EXTERNAL VALIDITY Fair Poor Poor

Table 2. Effect of Screening Intervention on Surrogate Endpoints (e.g., stage at diagnosis, adenoma detection)

CT = computed tomography; FOBT = fecal occult blood test; N/A = not available.
  Sigmoidoscopy [1,2] FOBT/ Sigmoidoscopy [3,4] Barium Enema [5] Colonoscopy [6,7] CT Colonography [8,9,10] Stool DNA Mutation Tests [11]
STUDY DESIGN Case-control studies Randomized controlled studies Ecologic and descriptive studies Ecologic and descriptive studies Ecologic and descriptive studies Studies in progress
INTERNAL VALIDITY Poor Fair Fair Fair Fair Unknown
CONSISTENCY Fair Poor Poor Poor Poor Unknown
MAGNITUDE OF EFFECTS ON SURROGATE ENDPOINTS About 45% decrease in detection rate of cancers compared with colonoscopy No difference in diagnostic yield between sigmoidoscopy + FOBT vs. sigmoidoscopy alone Barium enema detects about 30%–50% of cancers detected by colonoscopy About 3% of patients with no distal adenomas have advanced proximal neoplasia. There is a threefold increase in this rate in patients with distal adenomas. CT colonography may have similar sensitivity to colonoscopy in certain centers. Unknown
EXTERNAL VALIDITY Poor N/A N/A N/A Poor Unknown

References:

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. Mulhall BP, Veerappan GR, Jackson JL: Meta-analysis: computed tomographic colonography. Ann Intern Med 142 (8): 635-50, 2005.
11. 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.

Significance

Colorectal cancer (CRC) is the third most common malignant neoplasm worldwide [1] and the second leading cause of cancer deaths in the United States.[2] It is estimated that there will be 146,970 new cases diagnosed in the United States in 2009 and 50,630 deaths due to this disease.[2] Between 1973 and 1995, mortality from CRC declined by 20.5%, and incidence declined by 7.4% in the United States. The incidence is higher in men than in women. It ranges from 48.3 per 100,000 per year in Hispanic men to 72.5 per 100,000 per year in African American men. In women it ranges from 32.3 per 100,000 per year in Hispanics to 56.0 per 100,000 per year in African Americans. The age-adjusted mortality rates for men and women are 24.8 per 100,000 per year in men and 17.4 per 100,000 per year in women.[3,4] About 6% of Americans are expected to develop the disease within their lifetime.[3] Age-specific incidence and mortality rates show that most cases are diagnosed after age 50 years.[3]

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; first-degree relative with adenomas diagnosed before age 60 years;[5] a personal history of ovarian, endometrial, or breast cancer; and a personal history of long-standing chronic ulcerative colitis or Crohn colitis.[6,7,8] 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.[9]

Genetic,[10] experimental, and epidemiologic [11] studies suggest that CRC results from complex interactions between inherited susceptibility and environmental or lifestyle factors. Efforts to identify causes and to develop effective preventive measures led to the hypothesis that adenomatous polyps (adenomas) are precursors for the vast majority of CRCs.[12] In effect, measures that reduce the incidence and prevalence of adenomas may result in a subsequent decrease in the risk of CRC.[13] In addition, the formation and spontaneous regression of adenomas may also be a dynamic process.[14]

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.
2. American Cancer Society.: Cancer Facts and Figures 2009. Atlanta, Ga: American Cancer Society, 2009. Also available online. Last accessed January 6, 2010.
3. Ries LAG, Eisner MP, Kosary CL, et al., eds.: SEER Cancer Statistics Review, 1975-2002. Bethesda, Md: National Cancer Institute, 2005. Also available online. Last accessed December 10, 2009.
4. Edwards BK, Howe HL, Ries LA, et al.: Annual report to the nation on the status of cancer, 1973-1999, featuring implications of age and aging on U.S. cancer burden. Cancer 94 (10): 2766-92, 2002.
5. Ahsan H, Neugut AI, Garbowski GC, et al.: Family history of colorectal adenomatous polyps and increased risk for colorectal cancer. Ann Intern Med 128 (11): 900-5, 1998.
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.
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.
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.
10. Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 61 (5): 759-67, 1990.
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.
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.
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.

Evidence of Benefit

Fecal Occult Blood Test

Five controlled clinical trials have been completed or are in progress to evaluate the efficacy of screening utilizing the fecal occult blood test (FOBT). The Swedish trial is a targeted study for individuals aged 60 to 64 years.[1] The English program selects candidates from lists of family practitioners.[2] The Danish trial offers screening to a population aged 45 to 75 years randomly assigned to a control or study group.[3,4] The Memorial Sloan-Kettering Cancer Center (MSKCC)-Strang Clinic trial, completed in 1985, was an evaluation of the FOBT as a supplement to annual rigid sigmoidoscopy.[5] The study and control groups were selected by calendar periods.

The Minnesota trial demonstrated that annual FOBT testing using primarily rehydrated samples decreased mortality from colorectal cancer (CRC) by 33% [6] and that biennial testing developed a 21% relative mortality reduction.[7] A large part of the reduction may be attributed to chance detection of cancer by colonoscopies; rehydration of guaiac test slides greatly increased positivity and consequently increased the number of colonoscopies performed.[8] 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 minor role (16%–25% of the reduction).[9] 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.[10]

The English trial allocated approximately 76,000 individuals to each arm. Those in the screened arm were offered nonrehydrated FOBT testing every 2 years for three to six rounds from 1985 to 1995. Median follow-up time was 7.8 years. Sixty percent completed at least one test, and 38% completed all tests. Cumulative incidence of CRC was similar in both arms. 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).[11] In this study, 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.[12] After a median follow-up of 11.8 years, a difference in CRC incidence between the intervention and control groups was not observed. Overall, 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).[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 FOBT 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 was 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 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, flexible sigmoidoscopy, 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).[17]

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.[14] A meta-analysis of all previously reported randomized trials using biennial FOBT showed no overall mortality reduction by FOBT screening (RR = 1.002; 95% CI, 0.989–1.085). The RR of CRC death in the FOBT arm was 0.87 (95% CI, 0.8–0.95), and the RR of non-CRC death in the FOBT group was 1.02 (95% CI, 1.00–1.04; P = .015).[18]

The MSKCC study evaluated compliance and effectiveness of using the FOBT in conjunction with sigmoidoscopy to screen for CRC in a setting of comprehensive medical examinations. From 1975 to 1979, a total of 21,756 patients (aged 40 years and older) who presented at the Preventive Medicine Institute-Strang Clinic for routine medical evaluations were enrolled by calendar period into study and control groups. Study patients were offered annually both rigid sigmoidoscopy examinations and FOBTs requiring two stool specimens per day for 3 days, while control patients were offered only annual sigmoidoscopy. Trial I was primarily a demonstration of feasibility of using the FOBT as a supplemental screening method. Trial II was an evaluation of effectiveness. In Trial II, CRC mortality was lower in the study group than in the control group (0.36 vs. 0.63 per 1,000), a nonstatistically significant result (P = .053).

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.[19,20,21,22] The anticipated success of such methodology is critically dependent on the appropriate use of the FOBT and an effective clinical management plan.[23,24]

A systematic review done through the Cochrane Collaboration examined all CRC screening randomized trials that involved FOBT 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. In 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 of contamination in the control arms of the trials and no information on treatment by stage.[25,26]

On initial (prevalence) examinations, from 1% to 5% of unselected persons tested with FOBT have positive test results. Of those with positive test results, approximately 2% to 10% have cancer and approximately 20% to 30% have adenomas,[27,28] depending on how the test is done. Data from randomized controlled trials are summarized in Table 3.

Table 3. Randomized Controlled Screening Trials: Fecal Occult Blood Testing

N/A = not available.
a % Localized = T1–3 N0 M0.
Site Population Size Positivity Rate (%) % Localizeda Testing Interval Relative Mortality Reduction
  SCREENED CONTROL  
Minnesota [6,7] 48,000 Unrehydrated: 2.4% 59 53 Annual 33%
  Rehydrated: 9.8%     Biennial 21%
United Kingdom [11] 150,000 Unrehydrated: 2.1% 52 44 Biennial 15%
Denmark [14] 62,000 Unrehydrated: 1.0% 56 48 Biennial 18%
Sweden [1] 27,000 Unrehydrated: 1.9% 65 33   N/A
  Rehydrated: 5.8%        

Newer FOBTs: Nonrandomized Controlled Trial Evidence

Newer FOBTs have been developed to detect human hemoglobin (immunochemical FOBT [iFOBT]) in contrast to the peroxidase-like activity that is detected by the guaiac-based FOBT (gFOBT) studied in the randomized controlled trials above.

In a study of 1,000 persons at high risk of CRC who had colonoscopy and iFOBT done on three bowel movements, the sensitivity and specificity for CRC was 94% and 87%; for advanced adenoma and CRC, it was 67% and 91%.The results were only slightly changed after removing seven patients with cancer who had been referred because of guaiac-positive FOBT or anemia.[29] In another study using a different iFOBT, which was tested in one bowel movement, the sensitivity for CRC was 66% and for advanced adenoma and CRC, the sensitivity was 27%, and specificity was 95%.[30] These sensitivities are much higher than the 13% to 39% sensitivity for CRC using gFOBT when studied in a similar way. A systematic review of gFOBTs and iFOBTs commissioned to evaluate the comparative diagnostic performance of the two test types to inform a decision to introduce screening for CRC in the United Kingdom found no clear performance superiority of either type and significant sensitivity variability among types in different clinical settings.[31]

Sigmoidoscopy

The flexible fiberoptic sigmoidoscope was introduced in 1969. The 60 cm flexible sigmoidoscope became available in 1976.[32] 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.[33,34] 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.[35] Removal of adenomas is associated with a decreased risk of subsequent CRC.[36] While most of these adenomas are polypoid, flat and depressed lesions may be more prevalent than previously recognized. Large flat and depressed lesions are more likely to be severely dysplastic. Specialized techniques may be needed to identify, biopsy, and remove such lesions.[37]

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 Memorial-Strang Clinic sigmoidoscopy study was conducted between 1946 and 1954 in 26,124 patients.[38] The survival rate in the 58 patients found to have cancer was 90% after a follow-up period of 15 years. There were, however, neither controls nor adjustment for biases.

One study was conducted over a 25-year period with 18,158 patients who underwent periodic rigid sigmoidoscopy with removal of polyps.[39] This study showed a significant reduction in the incidence of cancer in the rectosigmoid colon when compared with statewide data. There were 14 rectal cancers in the study group, which was only 15% of the expected incidence in that state. This study, however, was not controlled and provided minimal follow-up data.

The Kaiser-Permanente Multiphasic Health Checkup was a randomized study of 10,713 health plan members between the ages of 35 and 54 years; after 16 years, the study reported a more favorable stage distribution and survival rate and a reduction in mortality between the study and control groups (12 vs. 29 deaths, respectively), which was statistically significant.[40] In a re-evaluation considering only those cancers within reach of the sigmoidoscope, no statistical difference, however, could be demonstrated.

Two case-control studies have been reported that evaluate the efficacy of screening sigmoidoscopy in preventing CRC mortality;[41,42] 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. In a multicenter study of colon cancer in northern California and Utah, sigmoidoscopic screening was associated with a decreased incidence of colon cancer in both men (OR = 0.56; 95% CI, 0.44–0.77) and women (OR = 0.53; 95% CI, 0.33–0.77) after adjusting for other risk factors for colon cancer.[43] A population-based mass screening program with proctoscopy for CRC in one Chinese province was associated with a reduction in incidence and mortality from rectal cancer. Mortality decreased from 4.20 (in 1974–1976) per 100,000 to 2.98 (in 1992–1996) per 100,000.[44]

In a population-based, case-control study in Germany, 39%, 77%, and 64% of proximal, distal, and total CRCs, respectively, were estimated to be preventable by colonoscopy. The estimated proportion of total CRCs preventable by sigmoidoscopy was 45% among both women and men, assuming that sigmoidoscopy reaches the junction of the descending and sigmoid colon only and that findings of distal polyps are not followed by colonoscopy. Assuming that sigmoidoscopy reaches the splenic flexure and colonoscopy is done after detection of distal polyps, estimated proportions of total CRCs preventable by sigmoidoscopy increased to 50% and 55% (73% and 91% of total CRCs preventable by primary colonoscopy) among women and men, respectively.

Based on an extensive evidence-based review, guidelines have been formulated by representatives from a consortium of medical societies for screening and surveillance of those at average risk and those at increased risk for CRC because of a family history of CRC or genetic syndromes or a personal history of adenomatous polyps, inflammatory bowel disease, or curative-intent resection of CRC.[45] Adherence to screening by FOBT and sigmoidoscopy is below 50% in unselected population studies.[46] Among research patients in a large-scale randomized clinical trial of screening, more than 85% accepted repeat sigmoidoscopy after 3 years. An uncomfortable or technically inadequate initial examination, which may be more common in women, had an adverse effect on subsequent adherence.[47,48]

An optimal frequency for CRC screening has not been rigorously established. Various organizations have recommended a 5-year interval for repeat sigmoidoscopy based on data from observational studies.[49,50] One case-control study found a negative association between sigmoidoscopy and mortality that persisted for as many as 10 years,[41] while another case-control study of endoscopy found an effect only for as many as 6 years. Other studies have examined the yield of adenomas [51] and cancers [51,52] in the distal colon 3 years after a negative sigmoidoscopy.[51] After only 3 years, potentially dangerous neoplasms were discovered; 72 advanced adenomas and six cancers were identified among 9,317 individuals examined.

Combination of FOBT and Flexible Sigmoidoscopy

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 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.[53] One-time use of FOBT differs from the annual or biennial application reported in those studies summarized in Table 1.

The Norwegian Colorectal Cancer Prevention 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.[54] A positive FS was defined as a finding of any neoplasia or any polyp at least 10.0 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 prior colonoscopic polypectomy.[55] 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 5.0 mm, 53% for those in which the largest adenomas detected were 6.0 mm to 10.0 mm, and 48% for those in which the largest adenomas detected were larger than 10.0 mm. In patients who have undergone colonoscopic polypectomy, colonoscopic examination is a more sensitive method of surveillance than double-contrast barium enema.

Colonoscopy

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.[56] 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.[57] 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.[58]

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; 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).[59]

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 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).[60] 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.[61] However, because the definition of flat or "nonpolypoid" was "height less than ½ 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.[62] Flat lesions may play a role in the phenomenon of "missed cancers."[63]

Virtual Colonoscopy (Computed Tomographic Colonography)

Virtual colonoscopy (also known as computed tomographic [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.[64]

The performance of virtual colonoscopy depends heavily on the size of the target lesion. In a series of 300 patients who were referred for CRC screening or the evaluation of symptoms and who underwent CT colonography followed by conventional colonoscopy, investigators obtained sensitivities for CT colonography of 90% for 83 polyps measuring larger than 10.0 mm and 80% for 141 polyps measuring 5.0 to 9.9 mm. The per patient sensitivity for the 10.0 mm lesion size was 94% (64 of 68), and it was 66.9% (95 of 142) for adenomas smaller than 5.0 mm. CT colonography led to false identification of 45 polyps ranging in size from 3.0 mm to 17.0 mm in patients who had normal colonoscopic results. Overall performance characteristics for CT colonography were similar when comparing results for the 96 individuals without symptoms to results for the 204 symptomatic individuals.[65]

In a separate series of 201 patients who had symptoms suggestive of colorectal disease or who were undergoing surveillance because of prior colorectal neoplasia, investigators found that CT colonography detected all 13 CRCs identified in 13 patients on (endoscopic) colonoscopy but only 20 (7 > 10.0 mm) of the 118 (14 > 10.0 mm) polyps in 63 patients. Sensitivity for detection of invasive carcinoma and/or polyps 10.0 mm or larger in diameter was 73% (95% CI, 56%–90%), and the specificity was 94% (95% CI, 91%–98%).[66]

At several U.S. institutions employing an identical state-of-the-art protocol, 1,233 asymptomatic adults (728 men and 505 women; mean age 57.8 years) underwent complete virtual and optical colonoscopic examinations between May 2002 and June 2003. Extraordinary care was given to bowel preparation, and stool tagging was employed to minimize artifacts. High-speed, thin-section, supine-position and prone-position, single breath-hold scans were reconstructed in both two dimensions (2-D) and three dimensions (3-D), but the 3-D data were relied upon for image interpretation, using commercially available software.

Polyps were measured with electronic calipers and recorded according to colonic segment. Extracolonic findings were also recorded. CT colonographic studies were prospectively interpreted by one of six board-certified radiologists, each previously trained on a minimum of 25 CT colonographic studies, immediately before optical colonoscopic examination. Optical colonoscopies (OC) were performed by 17 experienced gastroenterologists or colorectal surgeons who were initially unaware of the CT findings. Polyps were photographed and measured with a calibrated linear probe.

CT results were unblinded segment by segment to the colonoscopists to allow them to re-evaluate their findings in light of the additional CT information, and thereby create a reference standard against which both CT colonography and OC findings could be compared. Performance characteristics for CT (and optical) colonoscopy were calculated for adenomatous polyps. Sensitivity of CT colonography increased from 88.7% (149/168), for adenomas at least 6.0 mm, to 93.8% (45/48), for adenomas at least 10.0 mm, with respective specificities of 79.6% and 96.0%. (Sensitivities for OC in the absence of CT information were, respectively by size, 92.3% and 87.5%.)

Most of the polyps found on CT colonography, but not on the initial OC, were situated behind a colonic fold, that is "recognized as a relative blind spot" for OC. Interobserver agreement for independent double readings of CT colonography studies, segment by segment, was good, 99.6% for polyps at least 10.0 mm and 97.6% for polyps at least 6.0 mm. Only two cancers were detected in this asymptomatic population, one by OC and both by CT colonography. Fifty-six patients (4.5%) had extracolonic findings considered to be potentially clinically important and needing medical workup.[67]

Another study reported very different results. This study was a prospective evaluation of CT colonography among 600 participants who were seen at nine large medical centers. The participants were referred for routine clinically indicated colonoscopy, and CT colonography was performed immediately prior to the colonoscopy using multidetector scanning. The accuracy of CT colonography was substantially lower than previously reported; 39% of lesions less than 6 mm and 55% of lesions less than 1 cm were detected and six out of eight cancers were detected using CT colonography. Additionally, the accuracy of CT colonography varied substantially among centers and did not improve over time. Of note, some of the imaging techniques used in previously published reports were not used in this study, and that might explain, in part, the low sensitivity of the test in this report. The authors conclude, however, that techniques and training need to be improved before widespread use because most clinically significant polyps were missed.[68]

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 OC. The gold standard was 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: (1) most, but not all, lesions found by CTC and not by OC were followed up with repeat OC; (2) the design itself did not allow for following patients, thus potentially missing lesions that grow rapidly and would only be seen after follow-up; (3) 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; and (4) 16% of people had an extracolonic finding that required further evaluation. 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.[69]

A study has 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 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. While a number of hurdles remain to be overcome before virtual colonoscopy becomes popular and widely used,[71] this study provides important preliminary data suggesting that the problem of laxative preparation might be successfully addressed.

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, 11 needing 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 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.[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, 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);[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 CT colonography. 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 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 (2-D vs. 3-D and/or "fly-through"), and variability in 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.[80,81,82,83] 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]

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Date Last Modified: 2009-06-30

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