Colorectal Cancer Screening (PDQ®)–Health Professional Version
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.
References
- 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
- 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.
- American Cancer Society: Cancer Facts and Figures 2019. Atlanta, Ga: American Cancer Society, 2019. Available online. Last accessed January 23, 2019.
- 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.
- 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.
- 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.
- 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]
- 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]
- 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]
- Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 61 (5): 759-67, 1990. [PUBMED Abstract]
- 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.
- Muto T, Bussey HJ, Morson BC: The evolution of cancer of the colon and rectum. Cancer 36 (6): 2251-70, 1975. [PUBMED Abstract]
- 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]
- 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]
- 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]
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.
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]
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