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.

References

1. Quintero E, Castells A, Bujanda L, et al.: Colonoscopy versus fecal immunochemical testing in colorectal-cancer screening. N Engl J Med 366 (8): 697-706, 2012. [PubMed: 22356323]
2. Dominitz JA, Robertson DJ, Ahnen DJ, et al.: Colonoscopy vs. Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM): Rationale for Study Design. Am J Gastroenterol 112 (11): 1736-1746, 2017. [PubMed: 29016565]
3. Church TR, Ederer F, Mandel JS: Fecal occult blood screening in the Minnesota study: sensitivity of the screening test. J Natl Cancer Inst 89 (19): 1440-8, 1997. [PubMed: 9326913]
4. Mandel JS, Church TR, Bond JH, et al.: The effect of fecal occult-blood screening on the incidence of colorectal cancer. N Engl J Med 343 (22): 1603-7, 2000. [PubMed: 11096167]
5. Mandel JS, Bond JH, Church TR, et al.: Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med 328 (19): 1365-71, 1993. [PubMed: 8474513]
6. 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: 18479499]

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 October 18, 2019.
2. American Cancer Society: Cancer Facts and Figures 2019. Atlanta, Ga: American Cancer Society, 2019. Available online. Last accessed December 12, 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 February 20, 2020.
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 13, 2020.
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 February 13, 2020.
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: 12050337]
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. [PMC free article: PMC3999205] [PubMed: 24343171]
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: 22763141]
9. Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 61 (5): 759-67, 1990. [PubMed: 2188735]
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: 1203876]
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: 8247072]
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: 15239144]
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: 26482858]

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]

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. Fecal immunochemical tests may vary with regard to numbers of stools tested and cutoff values for a positive result.[26]

A systematic review of FIT studies in 2019 found 31 studies, with 120,255 participants and 18 types of FIT tests, that used screening colonoscopy as the reference standard, thus allowing calculation of test sensitivity and specificity.[27] Performance depended on the threshold for a positive result, so that a threshold of 10 µg/g (micrograms of hemoglobin per gram of feces) resulted in a CRC sensitivity of 0.91 (95% CI, 0.84–0.95) and a specificity of 0.90 (95% CI, 0.86–0.93), while a threshold greater than 20 µg/g resulted in a sensitivity of 0.71 (95% CI, 0.56–0.83) with specificity of 0.95 (95% CI, 0.94–0.96). For advanced adenomas, at a threshold of 10 µg/g, sensitivity was 0.40 (95% CI, 0.33–0.47) with a specificity of 0.90 (95% CI, 0.87–0.93). Comparison of three FITS at three thresholds was inconclusive because CI's overlapped and the comparisons were across rather than within studies. Overall, FIT appears to provide a substantially improved sensitivity compared with gFOBT, although with some compromise in specificity.

The diagnostic sensitivity of FIT testing may vary depending on lesion location in the colon. Right-sided lesions may be harder to detect for several reasons, including that they may arise from serrated lesions that are flat and, because they are less vascular than traditional adenomas, tend to bleed less frequently. In a population-based screening program of every-other-year FIT (set to detect 100 ng of hemoglobin per mL of buffer) testing, individuals who had six FITs over time were assessed to learn the frequency with which proximal and distal lesions were discovered.[28] Over 12 years (2002–2014), 123,000 participants had 441,000 FITs. The detection rate for proximal colon cancer declined only from the first to the second screening round (0.63–0.36 per 1,000 screened participants), while the rate for both distal colon and rectal cancer decreased across all six rounds (distal cancer, 1.65 in the first round to 0.17 in the sixth round). (Similar trends occurred for advanced adenomas.) The proportional interval cancer rate—the number of cancers observed versus expected—was higher in the proximal colon than in the distal (25.2% vs. 6.0%), suggesting that many proximal cancers (or their immediate precursors) may have been missed by FIT. These results suggest that FIT is less sensitive for right-sided CRC and certainly for advanced adenomas, although it is possible that the miss rate may have been inflated if colonoscopy done in response to a positive FIT had missed a precursor lesion. Overall, these results raise questions about the degree of efficacy of FIT in preventing right-sided CRC mortality.

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-back method 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.[29]

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.[30]

Sigmoidoscopy

The flexible fiberoptic sigmoidoscope was introduced in 1969. The 60 cm flexible sigmoidoscope became available in 1976.[31] 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.[32,33] 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.[34] Most of these adenomas are polypoid, flat, and depressed lesions, which may be somewhat more prevalent than previously recognized.[35]

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 Flexible Sigmoidoscopy Screening Trial (UKFSST); the Screening for COlon REctum (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).[36] A meta-analysis showed a statistically significant, although clinically small, effect on all-cause mortality (RR, 0.97; 95% CI, 0.96–0.99).[37]

Three of the above four trials published long-term follow-up analyses of trial results. For UKFSST, median follow-up was 17.1 years. The RRs for CRC incidence and mortality were similar to those originally reported: an RR of 0.70 (95% CI, 0.62–0.79) for CRC mortality and an RR of 0.74 (95% CI, 0.70–0.80) for CRC incidence. For the PLCO trial, median follow-up was 15.8 years for incidence and 16.8 years for mortality; RRs were 0.75 (95% CI, 0.66–0.85) for CRC mortality and 0.82 (95% CI, 0.76–0.88) for CRC incidence. Median follow-up in the NORCCAP trial was approximately 15 years; HRs were 0.79 (95% CI, 0.65–0.96) for CRC mortality and 0.78 (95% CI, 0.70–0.87) for CRC incidence.[38,39]

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 from studies of sigmoidoscopy to determine the optimal frequency of screening tests in programs of screening.

Combination of FOBT and Flexible Sigmoidoscopy: Impact on Neoplasm Detection

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.[40] 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.[41]

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.[42]

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 screened participants, 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.[42]

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.[60]

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:[61]

• 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.[62] 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.[63] The particular tagging material used in this study caused about 10% of patients to become nauseated; however, other materials are being assessed.

Another study [64] 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.[65] 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.[66]

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);[67] 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 [68] found that 8.6% of patients had an extracolonic finding of at least moderate importance, while 24% of patients in the smaller study [69] 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.[70]

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.[71]

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.[72] Advanced techniques have been developed to detect several of these gene mutations that have been shed into the stool.[73-76] 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.[77,78]

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 cutoff 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.[79]

Overall, the multitargeted test was more sensitive than FIT for both CRC and advanced precancerous lesions, but the test was less specific.[79] 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%.[80]

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.[81]

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.[82]

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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.

Evidence Summary

References

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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).

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Levels of Evidence

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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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