sábado, 6 de abril de 2019

Colorectal Cancer Screening (PDQ®)—Health Professional Version - National Cancer Institute

Colorectal Cancer Screening (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute

Colorectal Cancer Screening (PDQ®)–Health Professional Version

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Summary of Evidence

Note: Separate PDQ summaries on Colorectal Cancer Prevention; Colon Cancer Treatment; and Rectal Cancer Treatment are also available.

Evidence of Benefit Associated With Colorectal Cancer Screening

Based on solid evidence, screening for colorectal cancer (CRC) reduces CRC mortality. In addition, there is solid evidence that some CRC screening modalities also reduce CRC incidence. A meta-analysis of flexible sigmoidoscopy randomized controlled trials found that screening with sigmoidoscopy reduces all-cause mortality.
Table 1. Effect of Screening Intervention on Reducing Mortality from Colorectal Cancera
ENLARGE
Screening InterventionStudy DesignInternal ValidityConsistencyMagnitude of Effect on CRC IncidenceMagnitude of Effect on CRC MortalityExternal Validity
CRC = colorectal cancer; RCT = randomized controlled trial.
aThere are no data from RCTs 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 (guaiac-based)RCTs [1]GoodGoodLikely small to none15%–33%Fair
SigmoidoscopyRCTsGoodGood20%–25%About 25%; 50% for left colonFair
Digital Rectal ExamCase-control studiesFairGoodNo effectNo effectPoor
ColonoscopyCase-control studies; observational cohort studies that use historical/other controls; RCTs in progressPoorPoorAbout 60%–70% for left colon; uncertain for right colonAbout 60%–70% for left colon; uncertain for right colonFair
References
  1. Hewitson P, Glasziou P, Watson E, et al.: Cochrane systematic review of colorectal cancer screening using the fecal occult blood test (hemoccult): an update. Am J Gastroenterol 103 (6): 1541-9, 2008. [PUBMED Abstract]

Description of the Evidence

Incidence and Mortality

Colorectal cancer (CRC) is the third most common malignant neoplasm worldwide [1] and the third leading cause of cancer deaths in the United States.[2] It is estimated that there will be 145,600 new cases diagnosed in the United States in 2019 and 51,020 deaths due to this disease. From 2006 to 2015, CRC incidence declined by 3.7% per year among adults aged 55 years and older. However, from 2006 to 2015, in adults younger than 55 years, CRC incidence rates have been increasing by 1.8% per year. From 2007 to 2016, mortality from CRC declined by 2.7% per year among adults aged 55 years and older but increased by 1% per year among adults younger than 55 years.[2] Incidence is higher in men than in women. The incidence rates range from 43.3 per 100,000 per year in Hispanic men to 61.2 per 100,000 per year in African American men. In women, the incidence rates range from 30.0 per 100,000 per year in Hispanics to 46.0 per 100,000 per year in African Americans. The age-adjusted mortality rates are 18.6 per 100,000 per year in men and 13.1 per 100,000 per year in women. About 4.5% of Americans are expected to develop the disease within their lifetime, and the lifetime risk of dying from CRC is 1.9%.[3,4] Age-specific incidence and mortality rates show that most cases are diagnosed after age 50 years; about 4% of CRC cases occur in patients younger than age 50 years.[5,6]
Long-term trends in CRC were addressed in an analysis of national data for the period 1975 to 2010.[7] Incidence increased for men from 1975 to 1985, but there were marked declines from 1985 to 1995 for both men and women followed by a nonsignificant increase from 1995 to 1998, then marked declines from 1998 to 2010. Death rates from CRC have declined since 1984 in both men and women, with an accelerated rate of decline since 2002 for men and since 2001 for women. From 1997 to 2010, CRC incidence declined for all racial/ethnic groups. The fastest annual rate of decline occurred in men and women aged 65 years or older, but short-term incidence trends increased annually for individuals younger than 50 years in most population subgroups. Incidence rates of distal colon and rectal cancers decreased in men and women for all ages combined. Incidence rates of proximal colon cancer also decreased in men and women for all race/ethnicities combined.
The major factor that increases a person’s risk for CRC is increasing age. Risk increases dramatically after age 50 years with 90% of all CRCs diagnosed after this age. History of CRC in a first-degree relative, especially occurring before age 55, roughly doubles the risk. While a personal history of CRC or high-risk adenomas (i.e., large [>1cm] tubular adenomas, sessile serrated adenomas, or multiple adenomas) indicates increased future risk of cancer, follow-up of these individuals after they have undergone screening is considered surveillance, and not screening.[8]
Genetic,[9] experimental, and epidemiologic [10] 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 of most CRCs.[11] In effect, measures that reduce the incidence and prevalence of adenomas may result in a subsequent decrease in the risk of CRCs;[12] however, some CRC mortality may be caused by fast-growing lesions or lesions that do not pass through an adenomatous phase. Overall, details about the growth rates of adenomas and CRC are unknown; most likely, there is a broad spectrum of growth patterns, including formation and spontaneous regression of adenomas.[13,14]
References
  1. Ferlay J, Soerjomataram I, Ervik M, et al.: GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide. Lyon, France: International Agency for Research on Cancer, 2013. IARC CancerBase No. 11. Available online. Last accessed February 1, 2019.
  2. American Cancer Society: Cancer Facts and Figures 2019. Atlanta, Ga: American Cancer Society, 2019. Available online. Last accessed January 23, 2019.
  3. Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2012. Bethesda, Md: National Cancer Institute, 2015. Also available online. Last accessed January 31, 2019.
  4. 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 February 22, 2019.
  5. 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 December 19, 2018.
  6. 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 Abstract]
  7. Edwards BK, Noone AM, Mariotto AB, et al.: Annual Report to the Nation on the status of cancer, 1975-2010, featuring prevalence of comorbidity and impact on survival among persons with lung, colorectal, breast, or prostate cancer. Cancer 120 (9): 1290-314, 2014. [PUBMED Abstract]
  8. Lieberman DA, Rex DK, Winawer SJ, et al.: Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 143 (3): 844-57, 2012. [PUBMED Abstract]
  9. Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 61 (5): 759-67, 1990. [PUBMED Abstract]
  10. 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.
  11. Muto T, Bussey HJ, Morson BC: The evolution of cancer of the colon and rectum. Cancer 36 (6): 2251-70, 1975. [PUBMED Abstract]
  12. 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 Abstract]
  13. 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 Abstract]
  14. Tutein Nolthenius CJ, Boellaard TN, de Haan MC, et al.: Evolution of Screen-Detected Small (6-9 mm) Polyps After a 3-Year Surveillance Interval: Assessment of Growth With CT Colonography Compared With Histopathology. Am J Gastroenterol 110 (12): 1682-90, 2015. [PUBMED Abstract]

Evidence of Benefit

Fecal Occult Blood Test (FOBT)

In FOBT testing, stool samples are collected and analyzed for the presence of small amounts of blood. The first generation of FOBTs used guaiac-based assays to detect blood, which are less sensitive and less specific than immunochemical-based testing. The now-classic randomized controlled trials (RCTs) that assessed colorectal cancer (CRC) mortality reduction all used guaiac-based testing. The finding of decreased CRC mortality provided a major foundation for recommendations to do CRC screening. The first-generation guaiac-based tests are being replaced by more sensitive and more specific immunochemical tests that have not been—and likely will never be—assessed in RCTs in a no-screening control group.
In this setting, the RCT evidence about guaiac-based testing is reviewed briefly here, with further discussion of how immunochemical FOBT (iFOBT or FIT) may provide improved sensitivity and specificity. Generally, if guaiac FOBT (gFOBT) is acceptable as a screening test (as shown in RCTs), then a strong case can be made for using a more sensitive and more specific test like FIT.
gFOBT 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.
A systematic review regarding evidence of benefit was conducted through the Cochrane Collaboration. It examined all CRC screening randomized trials that involved gFOBT testing done on more than one occasion. The combined results showed that trial participants allocated to screening had a 16% lower CRC mortality (relative risk [RR], 0.84; 95% confidence interval [CI], 0.78–0.90). There was no difference in all-cause mortality between the screened groups and the control groups (RR, 1.00; 95% CI, 0.99–1.02). The trials reported a low positive predictive value (PPV) for the FOBT test, suggesting that most positive tests were false positives. The PPV was 5.0% to 18.7% in the trials using nonrehydrated slides (Funen and Nottingham), and it was 0.9% to 6.1% in the trials using rehydrated slides (Goteborg and Minnesota). The report contained no discussion about contamination in the control arms of the trials and no information about treatment by disease stage.[1,2]
On initial (prevalence) examinations, 1% to 5% of unselected persons tested with gFOBT have positive test results. Of those who tested positive, approximately 2% to 10% had cancer and approximately 20% to 30% had adenomas,[3,4] depending on how the test was done. Data from RCTs of gFOBT testing are summarized in Table 2.
Four controlled clinical trials have been completed or are in progress to evaluate the efficacy of screening utilizing gFOBT. While more sensitive stool blood tests based on measuring human hemoglobin have been developed (and are discussed later in this summary), results about their performance in RCTs have not been yet reported. For gFOBT, the Swedish trial was a targeted study for individuals aged 60 to 64 years.[5] The English trial selected candidates from lists of family practitioners.[6] The Danish trial offered screening to a population aged 45 to 75 years who were randomly assigned to a control or study group.[7,8]
The Minnesota trial randomly assigned 46,551 men and women aged 50 to 80 years to one of three arms: colorectal cancer screening with gFOBT, rehydrated (with some small percentage of unrehydrated) FOBT every year (n = 15,570), every 2 years (n = 15,587), or control (n = 15,394). This trial demonstrated that annual FOBT screening decreased mortality from CRC by 33% after 18 years of follow-up (RR, 0.67; 95% 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).[9] 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.[10] 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).[11] 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).[12] 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.[12,13]
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 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).[14] 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.[15] 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).[16] 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).[17]
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,[18] 15% at 13 years of follow-up (RR, 0.85; 95% CI, 0.73–1.00),[19] and 11% at 17 years of follow-up (RR, 0.89; 95% CI, 0.78–1.01).[20] 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. Follow-up ranged 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).[5]

Stage distribution

All trials have shown a more favorable stage distribution in the screened population than in controls (refer to Table 2). Data from the Danish trial indicated 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 Dukes B lesions in the screened group.[18] 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).[21]

Mathematical modeling

Mathematical models have been constructed to extrapolate the results of screening trials and screening programs for benefit of the general population in community health care delivery settings. These models project that using currently available screening methodology can reduce CRC mortality or increase life expectancy.[22]
Table 2. Randomized Controlled Screening Trials to Assess Outcome: Guaiac-Based Fecal Occult Blood Testing
ENLARGE
SitePopulation SizePositivity Rate (%)% Cancers LocalizedaTesting IntervalCRC Mortality Relative Risk (95% CI)CRC Incidence RR (95% CI)
CI = confidence interval; CRC = colorectal cancer; RR = risk ratio.
a% Localized = T1–3 N0 M0.
 ScreenedControl  
Minnesota [9,23]48,000Unrehydrated: 2.4%5953Annual0.67 (0.51–0.83)0.80 (0.70–0.90)
 Rehydrated: 9.8%  Biennial0.79 (0.62–0.97)0.83 (0.73–0.94)
United Kingdom [14]150,000Unrehydrated: 2.1%5244Biennial0.85 (0.74–0.98)1.04 (0.95–1.14)
Denmark [18]62,000Unrehydrated: 1.0%5648Biennial0.82 (0.68–0.99)1.00 (0.87–1.13)
Sweden [24]68,308Unrehydrated: 1.9%5250Varied0.84 (0.71–0.99)0.96 (0.86–1.06)
 Rehydrated: 5.8%     

Immunochemical FOBTs (iFOBT or FIT): Nonrandomized Controlled Trial Evidence to Assess Lesion Detection

The immunochemical FOBT (iFOBT or FIT) was developed to detect intact human hemoglobin. The advantage of FIT over gFOBT is that it does not detect hemoglobin from nonhuman dietary sources. Also, FIT does not detect partly digested human hemoglobin that comes from the upper respiratory or GI tract. Preliminary studies of several commercially developed FIT tests define their sensitivity and specificity compared with concurrently performed colonoscopy. The studies also examine these outcomes for different cutpoints, and the benefit of multiple versus single stool samples.[25,26]
Overall, FIT testing is much more sensitive than gFOBT, and it is more sensitive for cancers than for benign neoplasias. As expected, higher cutpoints decrease sensitivity and increase specificity.
A meta-analysis of FIT testing [27] assessed the diagnostic accuracy of FITs in asymptomatic average-risk adults. The pooled sensitivity and specificity were 0.71 (95% CI, 0.58–0.81) and 0.94 (95% CI, 0.91–0.96) from studies using colonoscopy in persons with negative and positive FITs. Because FITs are quantitative, selection of different cut-off values results in different sensitivities and specificities, with sensitivities reaching 96% or 100% and specificities declining to about 88%, in small studies. Variations in sample preparation and in numbers of samples analyzed (one, two, or three) suggest that this is a developing field. Overall, FIT provides a substantially improved sensitivity compared with gFOBT, although with some compromise in 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 FIT result, change in bowel habits, anemia, abdominal pain with weight loss, or anal symptoms were invited to participate in a comparative assessment of FIT against colonoscopy findings. After exclusions for health and cognitive reasons, 1,859 patients were offered FIT, 1,116 patients adhered to the protocol, and 1,000 patients completed the procedure. Sensitivity and specificity were calculated at various cutpoints. At a cutpoint 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 FIT applied to three stool samples collected before the colonoscopy. Stool samples were collected by patients following FIT kit instructions and analyzed by the OC-MICRO analyzer (from the Eiken Chemical Company in Tokyo, Japan).[28]
In another study, 21,805 asymptomatic patients received FIT 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.[29]
Fecal immunochemical tests may vary with regard to numbers of stools tested and cut-off values for a positive result.[26]
The performance and acceptability of FIT over time was assessed by Kaiser-Permanente of Northern and Southern California in a screening program. A retrospective cohort of 323,349 persons aged 50 to 70 years was followed for up to four screening rounds over 4 years. Of patients invited, participation in round one was 48.2%, and of those remaining eligible, 75.3% to 86.1% participated in subsequent rounds. The authors reported that “programmatic FIT screening detected 80.4% of patients with CRC diagnosed within 1 year of testing, including 84.5% in round one and 73.4% to 78.0% in subsequent rounds.” An important observation was the degree of participation found. One limitation of the study is that it was not clear how work-up bias was addressed; e.g., when individuals with a positive test result are preferentially worked up to ascertain the presence or absence of CRC, while individuals with a negative test, but who might have CRC, are not. Although a look-backmethod was used to ascertain whether an individual had cancer, it is not clear that the duration of follow-up was long enough to discover everyone who should have been included in the denominator of the sensitivity calculation. Nevertheless, the results suggested that subsequent FIT results were at least partially independent of previous results. Longer follow-up may help clarify this issue. Mortality reduction could not be assessed in this study.[30]
A systematic review to evaluate the comparative diagnostic performance of gFOBT and FIT in the context of a decision to introduce screening for CRC in the United Kingdom, included 33 studies evaluating gFOBT and 35 studies evaluating FIT, including nine that evaluated both gFOBT and FIT. There was no clear evidence of superiority of either gFOBT or FIT. 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 FIT. Increasing sensitivity entailed adjusting cut-points to decrease specificity. Sensitivities were higher for the detection of CRC and lower for adenomas.[31]
Some studies have utilized the quantitative ability of FIT to consider detection and specificity at various cutpoints for defining a positive test. One study [32] found that reducing the cutpoint 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 20%, from 1.9 to 2.3. Specificity declined from 97.8% to 96%. Another study found that programmatic sensitivity of FIT increased from 66.0% with a positivity threshold of 30 μg/g to 79.3% with a threshold of 10 μg/g; correspondingly, programmatic specificity decreased from 94.7% using a 30 μg/g threshold to 87.0% using a 10 μg/g threshold.[33] Reducing the threshold from 20 μg/g to 15 μg/g would detect 3% more cancer cases and would require 23% more colonoscopies.
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 are discontinued for a week or more before FOBT. The performance of FIT 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 FIT 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 cutpoint 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 FITs, 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.[34]

Sigmoidoscopy

The flexible fiberoptic sigmoidoscope was introduced in 1969. The 60 cm flexible sigmoidoscope became available in 1976.[35] 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.[36,37] 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.[38] Most of these adenomas are polypoid, flat, and depressed lesions, which may be somewhat more prevalent than previously recognized.[39]
Four major sigmoidoscopy screening RCTs have reported incidence and mortality results (a fifth, the Telemark trial in Norway, was very small, with 800 total participants). These are the Norwegian Colorectal Cancer Prevention (NORCCAP) trial; the United Kingdom trial; the SCORE trial in Italy; and the U.S. Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial (refer to Table 3). Participants were 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. Median follow-up was approximately 11 years for each group. Results were summarized in three systematic reviews. There was an 18% relative reduction in CRC incidence (RR, 0.82; 95% CI, 0.75–0.89), an overall 28% relative reduction in CRC mortality (RR, 0.72; 95% CI, 0.65–0.80), a 31% relative reduction in the incidence of left-sided CRC (RR, 0.69; 95% CI, 0.63–0.74), and a 46% relative reduction in the mortality of left-sided CRC (RR, 0.54; 95% CI, 0.43–0.67).[40] A meta-analysis showed a statistically significant, although clinically small, effect on all-cause mortality (RR, 0.97; 95% CI, 0.96–0.99).[41]
The United Kingdom trial published an extended follow-up analysis in 2017, with median follow-up of 17.1 years. The RRs for CRC incidence and mortality were similar to those originally reported: RR of 0.70 (95% CI, 0.62–0.79) for CRC mortality and RR of 0.74 (95% CI, 0.70–0.80) for CRC incidence.
There are no strong direct data to determine frequency of screening tests in programs of screening.
Table 3. Randomized Controlled Screening Trials to Assess Outcome: Sigmoidoscopya
ENLARGE
SitePopulation Size (Intervention)FSG Rate (%)bColonoscopy Rate (%)cCumulative CRC Incidence (%)CRC Deaths per 100,000 Person-YearsCRC Mortality Relative Risk (95% CI)CRC Incidence Relative Risk (95% CI)
CI = confidence interval; CRC = colorectal cancer; FSG = flexible sigmoidoscopy; % = percent.
aAdapted from Lin et al.[26]
bThe FSG rate refers to the % of individuals who received FSG in the screened group.
cThe colonoscopy rate refers to the % of individuals who received a colonoscopy as a follow-up to a positive sigmoidoscopy among those who received a sigmoidoscopy. In the U.S. study, individuals with a polyp found at the time of a sigmoidoscopy were referred for diagnostic follow-up, which was generally done with a colonoscopy. In the other studies, the referral criteria for a colonoscopy depended on the histology of lesion(s) found at the time of the sigmoidoscopy.
d Half of the intervention group was also offered FOBT.
United Kingdom 2010Intervention: 57,09971.15.01.5Intervention: 300.69 (0.59–0.80)0.77 (0.70–0.84)
Control: 112,939Control: 44
Italy 2011Intervention: 17,13657.87.81.6Intervention: 350.78 (0.56–1.08)0.82 (0.69–0.96)
Control: 17,136Control: 44
United States 2012Intervention: 77,44586.625.31.5Intervention: 290.74 (0.63–0.87)0.79 (0.72–0.85)
Control: 77,455Control: 39
Norway 2014Intervention: 20,572d63.019.51.4Intervention: 310.73 (0.56–0.94)0.80 (0.70–0.92)
Control: 78,220Control: 43

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.[42] One-time use of FOBT differs from the annual or biennial application reported in those studies summarized in Table 2.
A study of 21,794 asymptomatic persons (72% were men), who had both colonoscopy and 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%. In this study, the addition of sigmoidoscopy to FIT did not substantially improve the detection of right-sided colon cancers, compared with FIT alone.[43]
The NORCCAP screening trial randomly assigned 20,780 men and women, aged 50 to 64 years, living in Oslo city or Telemark county, Norway, to a once-only, FS-only group (n = 10,392) or a once-only, combination of FS and FOBT with FlexSure OBT group (n = 10,388). The 79,430 remaining individuals in those areas were assigned as controls. After 11 years of follow up, in the total screening group compared with the controls, there was a 20% reduction in CRC incidence (RR, 0.80; 95% CI, 0.70–0.92) and a 27% reduction in CRC mortality (RR, 0.73; 95% CI, 0.56–0.94), with no difference in all-cause mortality (RR, 0.97; 95% CI, 0.93–1.02). The results in the two screening subgroups were not statistically different. The RRs for CRC incidence, compared with the controls, were 0.72 for the FS group and 0.88 for the FS with FOBT group, with overlapping CIs (P = .11 for heterogeneity). The corresponding RRs for CRC mortality were 0.84 and 0.62, with overlapping CIs (P = .20 for heterogeneity). The screening findings were very similar in these two subgroups with 17% adenomas, 4.5% advanced adenomas, and 20 versus 21 CRCs. About 20% of men and women in the two screening subgroups were referred for colonoscopy, and 95% of the referred attended colonoscopy.[44] Extended follow-up to a median of 14.8 years revealed a 22% reduction in CRC incidence (RR, 0.78; 95% CI, 0.70–0.87) and a 21% reduction in CRC mortality (RR, 0.79; 95% CI, 0.65–0.95). Outcome data were also reported separately by gender, indicating an effect in men but little or no effect in women. In women, the CRC incidence hazard ratio (HR) was 0.92 (95% CI, 0.79–1.07), and the CRC mortality ratio was 1.01 (95% CI, 0.77–1.33). In men, the CRC incidence HR was 0.66 (95% CI, 0.57–0.78), while the CRC mortality ratio was 0.63 (95% CI, 0.47–0.83).[45]

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. Three RCTs (NCT01239082, NCT00883792, and NCT00906997) of colonoscopy have been initiated.
The Nordic-European Initiative on Colorectal Cancer (NordICC) is a population-based randomized trial to investigate the effectiveness of colonoscopy screening on CRC incidence and mortality in several European countries (Norway, Poland, Sweden, and the Netherlands). NordICC comprises 94,959 men and women aged 55 to 64 years who were randomly selected from population registers and randomly assigned in a 1:2 ratio to one time colonoscopy screening or no screening. Control participants were not contacted. The primary endpoint is a comparison of the 15-year CRC mortality rates. Participation rates, participant experience, lesion yield, and complications of colonoscopy screening in the participating countries have been reported.[46]
Among 31,420 eligible participants randomly assigned to colonoscopy, 12,574 (40.0%) underwent screening. Participation rates were 60.7% in Norway (5354 of 8,816), 39.8% in Sweden (486 of 1,222), 33.0% in Poland (6,004 of 18,188), and 22.9% in the Netherlands (730 of 3,194). The cecum intubation rate of 97.2% was very similar across countries, with 9,726 participants (77.4%) not receiving sedation—10.8% in Norway rising to 90% in the Netherlands. Among the 12,574 screenees, there was one perforation (0.01%), two postpolypectomy serosal burns (0.02%), and 18 cases of bleeding caused by polypectomy (0.14%). Sixty-two individuals (0.5%) were diagnosed with CRC (50 distal and 14 proximal) and 3,861 (30.7%) had adenomas. There were 725 (5.8%) distal versus 562 (4.5%) high-risk adenomas, and 2,439 (19.4%) distal versus 1,078 (8.6%) proximal serrated polyps. Performance differed significantly among endoscopists; recommended benchmarks for cecal intubation (95%) were not met by 17.1% of endoscopists and benchmarks for adenoma detection (25%) were not met by 28.6% of endoscopists. Moderate or severe abdominal pain after colonoscopy was reported by 16.7% of participants examined with standard air insufflation versus 4.2% examined with carbon dioxide (CO2) insufflation.[46]

Prevalence of lesions in asymptomatic populations

In a colonoscopy 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.[47] 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 (OR, 3.4; 90% CI, 1.8–6.5) than were patients with no distal adenomas (OR, 2.6; 90% CI, 1.7–4.1). One-half of those with advanced proximal neoplasia had no distal adenomas. In a study of 1,994 adults (aged 50 years or older) who underwent colonoscopy screening (as part of a program sponsored by an employer), 5.6% had advanced neoplasms.[48] Forty-six percent of those with advanced proximal neoplasms had no distal polyps (hyperplastic or adenomatous). If colonoscopy 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. Of the 1,463 women, cancer was found in 1 woman and advanced colonic neoplasia was found in 72 women (4.9%), which is about 50% of the prevalence in 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.[49]
Analysis of data from a colonoscopy-based screening program in Warsaw, Poland demonstrated higher rates of advanced neoplasia in men than in women. Of the 43,042 participants aged 50 to 66 years, advanced neoplasia was detected in 5.9% (5.7% in women with a family history of CRC, 4.3% in women without a family history of CRC, 12.2% in men with a family history of CRC, and 8.0% in 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. The authors also reported that collection of 30-day complications data was not systematic; therefore, the data may not be reliable.[50]

Detection of right-sided versus left-sided lesions

Flat or difficult-to-detect lesions include serrated polyps, which may be more common in the right colon than in the left. The term serrated polyp is currently used to include hyperplastic polyps, sessile serrated adenomas, traditional serrated adenomas, and mixed serrated polyps.[51,52] The clinical significance of these lesions is uncertain because the natural history of any polypoid lesion is difficult to learn. However, the histologic and molecular characteristics of some serrated lesions suggest possibly important malignant potential (e.g., mutations in the BRAF gene may be an early step toward carcinogenesis in serrated polyps).[53] 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 colon.
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 and observed a wide variation in detection rates 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.[51] The overall proportion of polyps that are serrated is unknown, in part because these lesions have been unappreciated and/or difficult to identify.

Adenoma detection rate (ADR)

Detection rates in colonoscopy screening vary with the rate at which the endoscopist examines the colon while withdrawing the scope. In one study, there were differences among gastroenterologists in the rates of detection of adenomas (range of the 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 of withdrawal of the scope (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).[54]
In the first 10 years of the German CRC screening program, detection of nonadvanced adenomas increased in men from 13.3% to 22.3% and in women from 8.4% to 14.9%. The great majority of the nonadvanced adenomas, however, were small (<0.5 cm) and had uncertain clinical significance. The detection of advanced adenomas and CRC increased by a much smaller amount.[55]
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 these flat or nonpolypoid lesions were about 9.8 times as likely as polypoid lesions to contain cancer (in situ neoplasia or invasive cancer).[39] 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. The existence of very flat or depressed lesions—depressed lesions are very uncommon but are highly likely to contain cancer—requires that endoscopists pay increasing attention to this problem.[56] Flat lesions may play a role in the phenomenon of missed cancers.[57]
The impact of ADRs was assessed by a health maintenance organization in follow-up after 314,872 colonoscopies done from 1998 to 2010 by 136 gastroenterologists, each of whom had done at least 300 colonoscopies during that period. The goal was to determine rates of interval CRC, interval advanced CRC, and CRC death, and to relate those rates to a gastroenterologist’s ADR. There were 712 interval cancers (155 advanced) and 147 CRC deaths. The risk of interval cancer from lowest-to-highest quintile of ADR was 9.8, 8.6, 8.0, 7.0, and 4.8 per 10,000 person-years of follow-up. The adjusted HR, for physicians in the highest quintile compared with the lowest, was 0.52 for any interval CRC, 0.43 for advanced CRC, and 0.38 for fatal CRC. Each 1.0% increase in ADR was associated with a 3% decrease in risk of cancer, although the CI for each quintile was broad. Limitations of the study include the inability to determine which specific feature of ADR led to reduced interval cancer; for example, it is unclear whether it was due to the following:
  • Removal of small adenomas that may grow rapidly to become CRC.
  • ADR being a surrogate outcome for an endoscopist’s ability to more completely remove adenomas.
  • ADR being a surrogate outcome for an endoscopist’s ability to better detect large, flat, serrated lesions.
  • Higher ADR leading to recommendations for more frequent postpolypectomy surveillance colonoscopy.
Another limitation is that the harms of a colonoscopy associated with ADR could not be measured.[58]

Nonrandomized controlled trial evidence about colorectal cancer incidence or 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. A 2009 case-control study of colonoscopy raised questions about whether the impact of colonoscopy on right-sided lesions might be different than the impact on left-sided lesions.[59] Using a province-wide administrative database in Ontario, Canada, 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. However, this study had limited data about whether examinations were complete to the cecum and about bowel prep. Further, many endoscopists were nongastroenterologists.
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.[60] 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 did not assess CRC mortality, the results suggested that the magnitude of the right-side versus the left-side difference may be smaller than previously found.[59] It would be extremely useful to assess right side-versus left side differences in a RCT.
Other case-control data suggest a reduction of CRC incidence on the right-side of about 64% compared with about 74% on the left-side.[61]
Because there is no RCT evidence and case-control evidence is limited, it is important to consider the degree of mortality reduction from colonoscopy. While a figure of 90% is sometimes cited as the degree of mortality reduction,[62] the question will not be properly answered until the European RCT that has a control group of “routine care” that involves minimal screening of any kind is completed.[63] Until there are more reliable results from colonoscopy RCTs, studies of FS may provide the best estimate of CRC mortality incidence reduction, of at most 50% on the left-colon, by extending efficacy on the left-colon to the right-colon.

Virtual Colonoscopy (Computed Tomographic Colonography [CTC])

Virtual colonoscopy (also known as CTC 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.[64]
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 ≥10 mm, 4%; mean age about 58 years) screened with both CTC and optical colonoscopy (OC). The gold standard was the OC, including repeat OC exams for people with lesions found by CTC but not by OC. Of 109 people with at least one adenoma or cancer 10 mm or larger, 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:[65]
  • 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.[66] In this study, the sensitivity of OC could not be determined because it was done in an unblinded manner. This study suggested that virtual colonoscopy might be an acceptable screening or surveillance test for persons with a high risk of CRC, but this cross-sectional study did 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.[67] The particular tagging material used in this study caused about 10% of patients to become nauseated; however, other materials are being assessed.
Another study [68] 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 of at least 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.[69] 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.[70]
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);[71] 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 [72] found that 8.6% of patients had an extracolonic finding of at least moderate importance, while 24% of patients in the smaller study [73] 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.[74]

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.[75]

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.[76] Advanced techniques have been developed to detect several of these gene mutations that have been shed into the stool.[77-80] 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.[81,82]
A next-generation multitargeted stool test 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.[83]
Overall, the multitargeted test was more sensitive than FIT for both CRC and advanced precancerous lesions, but the test was less specific.[83] The U.S. Food and Drug Administration approved this multitargeted test for colorectal screening in 2014.

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%.[84]

Tailoring Screening to Risk

Benefit of screening might be improved by tailoring the recommended screening test to a person’s degree of CRC risk. For example, if a subgroup of young women were to have a substantially lower risk of proximal neoplasms, then recommending sigmoidoscopy instead of colonoscopy (both are recommended by the U.S. Preventive Services Task Force without preference, as part of a program of screening persons with average risk) might lead to higher compliance.
In a study to identify persons in an average-risk group who had a higher versus lower risk of advanced neoplasia (CRC and advanced adenomas) anywhere in the colon, 2,993 persons having a screening colonoscopy were stratified by age, gender, waist circumference, smoking, and family history (persons in high-risk family categories, e.g., Lynch syndrome or adenomatous polyposis coli, were excluded). In a classification system derived in a training set, the risks of advanced neoplasm in four groups were: 1.92%, 4.88%, 9.93%, and 24%. In the two lowest risk groups, sigmoidoscopy would have detected 51 (73%) of 70 advanced neoplasms. In the independent validation set, results were similar. Whether this system increases overall compliance has yet to be determined.[85]
A similar stratification system based on age, gender, smoking, and family history—and combined with FIT—was tested in Asia to determine whether use of the stratification system plus FIT could detect which persons need colonoscopy. If either the stratification system or FIT was positive, a person was recommended for colonoscopy. Using this strategy, 95% of persons with CRC were correctly told to have colonoscopy.[86]
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  34. Brenner H, Tao S, Haug U: Low-dose aspirin use and performance of immunochemical fecal occult blood tests. JAMA 304 (22): 2513-20, 2010. [PUBMED Abstract]
  35. Fath RB, Winawer SJ: Endoscopic screening by flexible fiberoptic sigmoidoscopy. Front Gastrointest Res 10: 102-111, 1986.
  36. Read TE, Read JD, Butterly LF: Importance of adenomas 5 mm or less in diameter that are detected by sigmoidoscopy. N Engl J Med 336 (1): 8-12, 1997. [PUBMED Abstract]
  37. Wallace MB, Kemp JA, Trnka YM, et al.: Is colonoscopy indicated for small adenomas found by screening flexible sigmoidoscopy? Ann Intern Med 129 (4): 273-8, 1998. [PUBMED Abstract]
  38. Levin TR, Palitz A, Grossman S, et al.: Predicting advanced proximal colonic neoplasia with screening sigmoidoscopy. JAMA 281 (17): 1611-7, 1999. [PUBMED Abstract]
  39. Soetikno RM, Kaltenbach T, Rouse RV, et al.: Prevalence of nonpolypoid (flat and depressed) colorectal neoplasms in asymptomatic and symptomatic adults. JAMA 299 (9): 1027-35, 2008. [PUBMED Abstract]
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  42. Lieberman DA, Weiss DG; Veterans Affairs Cooperative Study Group 380: One-time screening for colorectal cancer with combined fecal occult-blood testing and examination of the distal colon. N Engl J Med 345 (8): 555-60, 2001. [PUBMED Abstract]
  43. Kato J, Morikawa T, Kuriyama M, et al.: Combination of sigmoidoscopy and a fecal immunochemical test to detect proximal colon neoplasia. Clin Gastroenterol Hepatol 7 (12): 1341-6, 2009. [PUBMED Abstract]
  44. Holme Ø, Løberg M, Kalager M, et al.: Effect of flexible sigmoidoscopy screening on colorectal cancer incidence and mortality: a randomized clinical trial. JAMA 312 (6): 606-15, 2014. [PUBMED Abstract]
  45. Holme Ø, Løberg M, Kalager M, et al.: Long-Term Effectiveness of Sigmoidoscopy Screening on Colorectal Cancer Incidence and Mortality in Women and Men: A Randomized Trial. Ann Intern Med 168 (11): 775-782, 2018. [PUBMED Abstract]
  46. Bretthauer M, Kaminski MF, Løberg M, et al.: Population-Based Colonoscopy Screening for Colorectal Cancer: A Randomized Clinical Trial. JAMA Intern Med 176 (7): 894-902, 2016. [PUBMED Abstract]
  47. 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 Abstract]
  48. 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 Abstract]
  49. 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 Abstract]
  50. Regula J, Rupinski M, Kraszewska E, et al.: Colonoscopy in colorectal-cancer screening for detection of advanced neoplasia. N Engl J Med 355 (18): 1863-72, 2006. [PUBMED Abstract]
  51. Kahi CJ, Hewett DG, Norton DL, et al.: Prevalence and variable detection of proximal colon serrated polyps during screening colonoscopy. Clin Gastroenterol Hepatol 9 (1): 42-6, 2011. [PUBMED Abstract]
  52. Snover DC, Batts KP: Serrated Colorectal Neoplasia. Surg Pathol Clin 3 (2): 207-40, 2010. [PUBMED Abstract]
  53. Snover DC, Jass JR, Fenoglio-Preiser C, et al.: Serrated polyps of the large intestine: a morphologic and molecular review of an evolving concept. Am J Clin Pathol 124 (3): 380-91, 2005. [PUBMED Abstract]
  54. Barclay RL, Vicari JJ, Doughty AS, et al.: Colonoscopic withdrawal times and adenoma detection during screening colonoscopy. N Engl J Med 355 (24): 2533-41, 2006. [PUBMED Abstract]
  55. Brenner H, Altenhofen L, Kretschmann J, et al.: Trends in Adenoma Detection Rates During the First 10 Years of the German Screening Colonoscopy Program. Gastroenterology 149 (2): 356-66.e1, 2015. [PUBMED Abstract]
  56. Lieberman D: Nonpolypoid colorectal neoplasia in the United States: the parachute is open. JAMA 299 (9): 1068-9, 2008. [PUBMED Abstract]
  57. Robertson DJ, Lieberman DA, Winawer SJ, et al.: Colorectal cancers soon after colonoscopy: a pooled multicohort analysis. Gut 63 (6): 949-56, 2014. [PUBMED Abstract]
  58. Corley DA, Jensen CD, Marks AR, et al.: Adenoma detection rate and risk of colorectal cancer and death. N Engl J Med 370 (14): 1298-306, 2014. [PUBMED Abstract]
  59. Baxter NN, Goldwasser MA, Paszat LF, et al.: Association of colonoscopy and death from colorectal cancer. Ann Intern Med 150 (1): 1-8, 2009. [PUBMED Abstract]
  60. Brenner H, Chang-Claude J, Seiler CM, et al.: Protection from colorectal cancer after colonoscopy: a population-based, case-control study. Ann Intern Med 154 (1): 22-30, 2011. [PUBMED Abstract]
  61. Doubeni CA, Weinmann S, Adams K, et al.: Screening colonoscopy and risk for incident late-stage colorectal cancer diagnosis in average-risk adults: a nested case-control study. Ann Intern Med 158 (5 Pt 1): 312-20, 2013. [PUBMED Abstract]
  62. Smith MJ: Colon cancer screening hitting its stride but obstacles impair reaching final goal. Gastroenterology and Endoscopy News 59 (3): 9, 2008. [Refer to "Screening: it’s not just a good idea, it’s the law … almost" within the article].
  63. Bretthauer M, Ekbom A, Malila N, et al.: [Politics and science in colorectal cancer screening] Tidsskr Nor Laegeforen 126 (13): 1766-7, 2006. [PUBMED Abstract]
  64. Ferrucci JT: Colon cancer screening with virtual colonoscopy: promise, polyps, politics. AJR Am J Roentgenol 177 (5): 975-88, 2001. [PUBMED Abstract]
  65. Johnson CD, Chen MH, Toledano AY, et al.: Accuracy of CT colonography for detection of large adenomas and cancers. N Engl J Med 359 (12): 1207-17, 2008. [PUBMED Abstract]
  66. Regge D, Laudi C, Galatola G, et al.: Diagnostic accuracy of computed tomographic colonography for the detection of advanced neoplasia in individuals at increased risk of colorectal cancer. JAMA 301 (23): 2453-61, 2009. [PUBMED Abstract]
  67. Iannaccone R, Laghi A, Catalano C, et al.: Computed tomographic colonography without cathartic preparation for the detection of colorectal polyps. Gastroenterology 127 (5): 1300-11, 2004. [PUBMED Abstract]
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  71. 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 Abstract]
  72. Pickhardt PJ, Hanson ME, Vanness DJ, et al.: Unsuspected extracolonic findings at screening CT colonography: clinical and economic impact. Radiology 249 (1): 151-9, 2008. [PUBMED Abstract]
  73. Kimberly JR, Phillips KC, Santago P, et al.: Extracolonic findings at virtual colonoscopy: an important consideration in asymptomatic colorectal cancer screening. J Gen Intern Med 24 (1): 69-73, 2009. [PUBMED Abstract]
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  75. Herrinton LJ, Selby JV, Friedman GD, et al.: Case-control study of digital-rectal screening in relation to mortality from cancer of the distal rectum. Am J Epidemiol 142 (9): 961-4, 1995. [PUBMED Abstract]
  76. Kinzler KW, Vogelstein B: Lessons from hereditary colorectal cancer. Cell 87 (2): 159-70, 1996. [PUBMED Abstract]
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  85. Imperiale TF, Monahan PO, Stump TE, et al.: Derivation and Validation of a Scoring System to Stratify Risk for Advanced Colorectal Neoplasia in Asymptomatic Adults: A Cross-sectional Study. Ann Intern Med 163 (5): 339-46, 2015. [PUBMED Abstract]
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Evidence of Harms

Potential harms are associated with the modalities used to screen for colorectal cancer (CRC), some of which have sufficient evidence and some that do not.

Overview

The tables for each screening test below show the magnitude of burden for several categories of harms encountered along the screening cascade. The magnitude of harms is a combination of the frequency and severity of harm, as perceived by the patient.
Harms are defined broadly as any negative effect on individuals or populations resulting from being involved in the screening process (cascade) compared with not screening. Potential harms are organized according to the type of harm (e.g., physical, psychological, and hassle/opportunity costs) and when they occur in the screening cascade (e.g., screening test/workup; screening test/workup results; surveillance and surveillance results; and early treatment and overtreatment). For example, potential harms of screening colonoscopy include harms of the screening test itself (e.g., perforation and bleeding), results of the screening test (e.g., anxiety from an abnormal result), surveillance (e.g. harms of more frequent colonoscopies), and treatment (e.g. earlier treatment or overtreatment). For other colorectal cancer screening tests, there are also harms associated with the workup (e.g. colonoscopy for positive fecal occult blood test [FOBT]). A recent study of three major hospitals found evidence that 71% of endoscopes tested positive for bacteria after cleaning and high-level disinfection of the scopes. This raises concern for endoscopy-associated pathogen transmission and patient safety, although no patients were involved in the study and the implications for patients are unknown.[1] For all aspects of participating in the screening cascade, there are time/effort and opportunity costs (nonfinancial harms) for the patient. We do not include here any financial harms to the patient/family, nor any psychological harm from anticipation of future financial costs related to screening.
Table 4. Colonoscopy
Stage of Screening Cascade
 PhysicalPsychologicalTime/Effort, Opportunity
CRC = colorectal cancer.
Screening Test/WorkupAverage 0.3% complications requiring hospitalization or resulting in death, higher with polypectomy and in older patients (fair evidence)Percentage of people who suffer psychological distress on consideration of having colonoscopy; severity and duration (insufficient evidence)About 38 hours (median) time required for preparation, procedure, sedation (one study, fair evidence) [2]
Discomfort of preparation and procedure. Adverse effects of preparation. (insufficient evidence to determine magnitude and frequency)
Complications from sedation during procedure (insufficient evidence to determine magnitude and frequency)
Screening Test/Workup ResultsIncreased risk of suicide and cardiovascular mortality soon after diagnosis (insufficient evidence)Percentage of people who suffer psychological distress after receiving positive screening and/or pathological results; severity and duration (insufficient evidence)Time and effort required to receive and understand screening test or workup results, including extra physician visits for positive tests (insufficient evidence)
Surveillance/ResultsMore frequent colonoscopyPercentage of people who suffer psychological distress after receiving positive screening and/or pathological results; severity and duration (insufficient evidence)Time and effort required to undergo colonoscopy (38 hours median, see above)
Time and effort required to receive and understand surveillance results (insufficient evidence)
Treatment (Early Treatment and Overtreatment)Overdiagnosis and overtreatment of precursor polyps or earlier treatment of CRC (may or may not receive benefit from earlier treatment) (insufficient evidence)Percentage of people who suffer psychological distress after undergoing overtreatment or earlier treatment without benefit; severity and duration. (insufficient evidence)Time and effort required to receive overtreatment or earlier treatment without benefit (insufficient evidence)
Table 5. FOBT/FIT, Other Stool-Based Tests (Including Fecal DNA)
Stage of Screening Cascade
 PhysicalPsychologicalTime/Effort, Opportunity
CRC = colorectal cancer; FIT= immunochemical fecal occult blood test; FOBT= fecal occult blood test; N/A = not applicable.
aWorkup test is colonoscopy. Descriptions of the associated harms can be found in the colonoscopy section (refer to the Colonoscopy section in the Evidence of Harms section of this summary for more information).
bTreatment harms will be the same for all screening tests.
Screening TestNone (no evidence)Percentage of people who suffer psychological distress on consideration of having CRC screening; severity and duration (insufficient evidence)Time and effort required to change diet (if required), collect samples, and return to appropriate facility: insufficient evidence
Screening Test ResultsN/APercentage of people who suffer psychological distress after receiving positive screening results; severity and duration (insufficient evidence)Time and effort required to receive and understand screening test results, including extra physician visits or communication for positive tests (insufficient evidence)
WorkupaSee colonoscopySee colonoscopySee colonoscopy
Workup ResultsN/ASee colonoscopySee colonoscopy
Surveillance/ResultsSee colonoscopySee colonoscopySee colonoscopy
Treatment (Early Treatment and Overtreatment)bSee colonoscopySee colonoscopySee colonoscopy
Table 6. Flexible Sigmoidoscopy
Stage of Screening Cascade
 PhysicalPsychologicalTime/Effort, Opportunity
N/A = not applicable.
aWorkup test is colonoscopy. Descriptions of the associated harms can be found in the colonoscopy section (refer to the Colonoscopy section in the Evidence of Harms section of this summary for more information).
bTreatment harms will be the same for all screening test.
Screening TestAverage serious complications for 0.03% of patients (fair evidence) [3]Percentage of people who suffer psychological distress on consideration of having colonoscopy; severity and duration (insufficient evidence)Time and effort required to perform preparation, travel to and attend screening, return to usual activities (insufficient evidence)
Screening Test ResultsN/ASee colonoscopySee colonoscopy
WorkupaSee colonoscopySee colonoscopySee colonoscopy
Surveillance/ResultsN/ASee colonoscopySee colonoscopy
Treatment (Early Treatment and Overtreatment)bSee colonoscopySee colonoscopySee colonoscopy
Table 7. Computed Tomography Colonography
Stage of Screening Cascade
 PhysicalPsychologicalTime/Effort, Opportunity
CRC = colorectal cancer.
Screening Test/WorkupDiscomfort of preparation and procedure; radiation exposure (insufficient evidence)Percentage of people who suffer psychological distress on consideration of screening; severity and duration (insufficient evidence)Time required for preparation, procedure (exact time and effort uncertain) (insufficient evidence)
Screening Test/Workup ResultsIncreased risk of suicide and cardiovascular mortality soon after diagnosis (insufficient evidence)Percentage of people who suffer psychological distress after receiving positive screening and/or pathological results; severity and duration. (insufficient evidence)Time and effort required to receive and understand screening test or workup results, including extra physician visits for positive tests (insufficient evidence)
Incidental extra-colonic findings [3]
Surveillance/ResultsMore frequent colonoscopyPercentage of people who suffer psychological distress after receiving positive screening and/or pathological results; severity and duration (insufficient evidence)Time and effort required to undergo colonoscopy (38 hours median, see above)
Time and effort required to receive and understand surveillance results (insufficient evidence)
Treatment (Early Treatment and Overtreatment)Overdiagnosis and overtreatment of precursor polyps or earlier treatment of CRC (may or may not receive benefit from earlier treatment) (insufficient evidence)Percentage of people who suffer psychological distress undergoing overtreatment or earlier treatment without benefit; severity and duration (insufficient evidence)Time and effort required to receive overtreatment or earlier treatment without benefit (insufficient evidence)

Evidence Summary

Colonoscopy

The potential physical harms of colonoscopy include adverse effects from the preparation and adverse effects from the procedure (colonic perforation and bleeding; effects of sedation).[4-6] A systematic review of 60 studies that assessed complications of colonoscopy screening in asymptomatic patients found infrequent serious morbidity, which comprised major bleeding (0.8/1,000 procedures; 95% confidence interval [CI], 0.18–1.63) and perforation (0.07/1,000 procedures; 95% CI, 0.006–0.17), and only minor and short-lasting psychological harms.[7] These complications can be serious, requiring hospitalization. Colonic perforation and serious bleeding occur more often with biopsy or polypectomy, with an overall average of three to five serious complications per 1,000 procedures. The physical harm of discomfort during the procedure has been reduced by sedation, although sedation has its own potential for physical harm (magnitude and severity uncertain due to insufficient evidence).
Physical harms are also associated with further steps in the screening cascade, including diagnosis of CRC (some large ecologic studies have shown an increase in suicide soon after diagnosis) and overdiagnosis/overtreatment due to treating lesions that would never have caused the patient important problems (evidence insufficient to determine magnitude and severity).
The potential psychological harms of colonoscopy include anticipation of the procedure and anxiety while awaiting the results of biopsy reports. For people with polyps, there may be increased distress in considering oneself at increased risk of CRC (evidence insufficient). For people newly diagnosed with CRC, many will experience increased anxiety and depression for at least 6 months, as prognosis and treatment are discussed (evidence insufficient).
The harm of time/effort and opportunity costs involved in moving through the demands of the screening cascade are present throughout the process (evidence insufficient to determine frequency and severity).

FOBT/immunochemical FOBT (FIT)

The potential physical harms of fecal-based testing include the same harms as for colonoscopy for people with a positive test who have been referred for diagnostic colonoscopy.
The potential psychological harms, as well as time/effort and opportunity costs are also similar to the description above for colonoscopy (refer to the Colonoscopy section in the Evidence of Harms section of this summary for more information).[8] These harms are associated with moving through the screening cascade, regardless of the initial screening test. Although it is highly likely that these psychological harms, plus time/effort and opportunity costs, do occur, the exact frequency and severity of these harms are uncertain due to insufficient evidence.

Sigmoidoscopy

The potential physical harms of sigmoidoscopy are considerably less than those of colonoscopy, with a less intensive preparation. Serious procedural complications occur in perhaps three in 10,000 sigmoidoscopies compared with in three in 1,000 colonoscopies.[3] There is usually no sedation with sigmoidoscopy, thus again lowering the potential for complications.
The potential psychological harms of sigmoidoscopy screening, as well as the time/effort and opportunity costs of screening, are the same as given above for other screening strategies.

Computed tomography colonography (CTC)

The potential physical harms due directly to the procedure of CTC are less than either colonoscopy or sigmoidoscopy, with rare procedural complications.[3] However, CTC does involve repeated radiation exposure, with uncertain associated harms, and it also detects a number of extra-colonic incidental findings.[9-13] Incidental findings have been detected in between 40% to 98% of CTCs, with a variable number of these considered significant enough to proceed with further diagnostic testing. As there is little evidence that early detection of any of these findings could improve health outcomes for patients, these findings may be considered as harms until proven otherwise.
The potential psychological harms or time/effort and opportunity costs for CTC are similar to the descriptions above for patients moving through the screening cascade (evidence insufficient to determine frequency and severity).
References
  1. Ofstead CL, Heymann OL, Quick MR, et al.: Residual moisture and waterborne pathogens inside flexible endoscopes: Evidence from a multisite study of endoscope drying effectiveness. Am J Infect Control 46 (6): 689-696, 2018. [PUBMED Abstract]
  2. Jonas DE, Russell LB, Sandler RS, et al.: Value of patient time invested in the colonoscopy screening process: time requirements for colonoscopy study. Med Decis Making 28 (1): 56-65, 2008 Jan-Feb. [PUBMED Abstract]
  3. Whitlock EP, Lin JS, Liles E, et al.: Screening for colorectal cancer: a targeted, updated systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 149 (9): 638-58, 2008. [PUBMED Abstract]
  4. Lin JS, Piper MA, Perdue LA, et al.: Screening for Colorectal Cancer: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA 315 (23): 2576-94, 2016. [PUBMED Abstract]
  5. Levin TR, Zhao W, Conell C, et al.: Complications of colonoscopy in an integrated health care delivery system. Ann Intern Med 145 (12): 880-6, 2006. [PUBMED Abstract]
  6. 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 Abstract]
  7. Vermeer NC, Snijders HS, Holman FA, et al.: Colorectal cancer screening: Systematic review of screen-related morbidity and mortality. Cancer Treat Rev 54: 87-98, 2017. [PUBMED Abstract]
  8. Bobridge A, Bampton P, Cole S, et al.: The psychological impact of participating in colorectal cancer screening by faecal immuno-chemical testing--the Australian experience. Br J Cancer 111 (5): 970-5, 2014. [PUBMED Abstract]
  9. Kimberly JR, Phillips KC, Santago P, et al.: Extracolonic findings at virtual colonoscopy: an important consideration in asymptomatic colorectal cancer screening. J Gen Intern Med 24 (1): 69-73, 2009. [PUBMED Abstract]
  10. Yee J, Kumar NN, Godara S, et al.: Extracolonic abnormalities discovered incidentally at CT colonography in a male population. Radiology 236 (2): 519-26, 2005. [PUBMED Abstract]
  11. Hara AK, Johnson CD, MacCarty RL, et al.: Incidental extracolonic findings at CT colonography. Radiology 215 (2): 353-7, 2000. [PUBMED Abstract]
  12. 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 Abstract]
  13. Xiong T, McEvoy K, Morton DG, et al.: Resources and costs associated with incidental extracolonic findings from CT colonogaphy: a study in a symptomatic population. Br J Radiol 79 (948): 948-61, 2006. [PUBMED Abstract]

Changes to This Summary (03/06/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Description of the Evidence
Updated statistics with estimated new cases and deaths for 2019 (cited American Cancer Society as reference 2). Also revised text to state that from 2006 to 2015, colorectal cancer (CRC) incidence declined by 3.7% per year among adults aged 55 years and older; however, from 2006 to 2015, in adults younger than 55 years, CRC incidence rates have been increasing by 1.8% per year. Also revised text to state that from 2007 to 2016, mortality rates from CRC declined by 2.7% per year among adults aged 55 years and older but increased by 1% per year among adults younger than 55 years.
This summary is written and maintained by the PDQ Screening and Prevention Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about colorectal cancer screening. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Screening and Prevention Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Screening and Prevention Editorial Board. PDQ Colorectal Cancer Screening. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/colorectal/hp/colorectal-screening-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389266]
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The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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  • Updated: March 6, 2019
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