Colorectal Cancer Screening

IntroductionTop

Colorectal cancer (CRC) is the third most common malignancy and the fourth most common cause of cancer-related death worldwide. It is predicted that there will be a ≥25% increase in CRC-related death per year by 2035. More than 90% of CRC cases are thought to arise, over periods ≥10 years, from preexisting adenomas, as part of an adenoma-carcinoma development sequence; however, the prevalence of adenomas in individuals aged 50 to 75 years ranges from 22% to 58% and most adenomas do not progress to CRC. CRC survival rates at 5 years fall from 90% in those with localized disease to 70% in those who have local lymph node involvement and 12% in those who have distant metastases.

Risk factors for CRC include a family history of CRC, advanced colon polyps, a genetic syndrome, personal history of inflammatory bowel disease (IBD), and lifestyle factors (eg, alcohol consumption, smoking, red meat consumption). It is estimated that lifestyle factors such as smoking and red meat consumption are independently associated with a 20% increase in the relative risk of developing CRC, whereas alcohol consumption may be associated with a relative risk increase as high as 40%. About 3% to 10% of adults report having ≥1 first-degree relative (FDR) with colon cancer and ~0.3% report having ≥2 FDRs with CRC. However, at least three-quarters of CRC cases are sporadic, occurring in individuals who have no family history and are considered to be at an average risk of developing CRC. The incidence of CRC in average-risk individuals aged <50 years is low but rises >10-fold over the next 4 decades of life. More recently the prevalence of CRC in individuals aged <50 years has been also increasing.

The high prevalence and natural history of CRC have led to recommendations for screening strategies appropriate for individuals at average and high risk. In many countries, including the United States, CRC screening is “opportunistic,” arising directly from an interaction between the patient and the health-care provider. Conversely, in several European countries, Australia, and Canada, CRC screening is “programmatic” or “organized,” such that it is offered to all eligible patients in a population or health-care system. In general, programmatic screening is offered to average-risk individuals, while intensified personalized screening should be considered in high-risk individuals. The advantages of programmatic screening include facilitated access for all eligible individuals, quality assurance, follow-up of abnormal screening test results, and minimization of overscreening.

Most guidelines recommend that CRC screening be started at the age of 50 years for average-risk individuals; to date, there has been no widespread support for proposals that screening be started at the age of 45 years, either for African Americans or for all average-risk individuals. Most programmatic screening is discontinued for average-risk individuals once they reach the age of 75 years, in recognition of the fact that the risks of screening and treatment increase in older populations and may outweigh the potential benefits.

GoalsTop

To diminish the incidence and mortality of CRC, screening should detect early-stage, potentially curable CRCs as well as high-risk premalignant adenomatous polyps and other conditions, such as IBD, which may predispose to CRC.

The specific management strategies adopted in an individual with a positive CRC screening test result depend on the individual’s history and risk factors as well as on the screening test that has been used.

TestsTop

Screening can employ noninvasive tests for fecal or blood-based markers or structural examinations, which may be invasive (flexible sigmoidoscopy [FS], colonoscopy) or noninvasive (computed tomography [CT] colonography, video capsule endoscopy, digital rectal examination).

1. Noninvasive screening: Fecal occult blood test (FOBT) screening has been largely supplanted by fecal immunochemical testing (FIT), especially for programmatic screening. The guaiac FOBT (gFOBT) detects the heme component of hemoglobin in stool when heme catalyzes the oxidization of alpha-guaiaconic acid to generate a blue color on the guaiac test paper after the addition of hydrogen peroxide. FIT detects the globin component of hemoglobin in stool using specific antibodies; it has greater sensitivity (ie, fewer false negatives; fewer missed cases of cancer) for the detection of CRC and specificity similar to gFOBT. FIT does not involve any dietary or medication restrictions and generally requires only 1 stool sample rather than the 3 samples required for gFOBT. FIT is also very cost-effective, with an associated cost of ~20 Canadian dollars per test. Fecal DNA screening testing (FIT-DNA) detects biomarkers associated with CRC and advanced adenomas but has more false-positive results than FIT and a significantly greater associated cost.

A positive stool test result should be followed by full colonoscopy to determine whether the patient has CRC, which should be localized and confirmed histologically if present; an adenoma or adenomas, which should be removed, if possible, during colonoscopy; or other lesions (eg, IBD, vascular lesions) that require treatment or further investigation.

FIT offers higher detection rates than gFOBT for both CRC and advanced adenomas; a systematic review showed FIT was associated with higher participation rates (ie, higher proportions of patients who were invited proceeded to participation) related to the ease of completing the test. There are no randomized clinical trial (RCT) data demonstrating reduced CRC-related mortality with FIT; however, studies have demonstrated a similar efficacy of colonoscopy screening every 10 years. To date, there have been no RCTs to show that FIT-DNA reduces the mortality of CRC or the incidence of late-stage CRC as compared with other screening modalities (eg, gFOBT, sigmoidoscopy, colonoscopy).

2. Invasive screening: Flexible sigmoidoscopy (FS) allows for inspection and biopsy of the rectum and left colon. It can generally be performed with limited patient preparation and no sedation and is associated with lower complication rates than colonoscopy. FS permits the direct diagnosis of CRC, polyps, or other mucosal lesions in the left colon as well as complete removal of small (<10 mm) polyps in most cases. A full colonoscopy is recommended if CRC or polyps are found, as FS cannot generally visualize the right colon, proximal to the splenic flexure.

Similarly to gFOBT, FS has been shown to reduce CRC-related mortality and the incidence of late-stage CRC in RCTs.

Colonoscopy allows for inspection of the entire colon, as far as the terminal ileum, provided that the procedure is completed satisfactorily. It permits the direct diagnosis of CRC, polyps, or other lesions and, in most cases, removal of significant polyps and biopsy of any areas of abnormal mucosa. Colonoscopy has the highest sensitivity and specificity for the diagnosis of CRC, adenomas, and other lesions. However, it is also associated with a higher adverse event rate than FS and requires more extensive and less well-tolerated bowel preparation, sedation and, often, greater loss of time from work. The major complications associated with screening colonoscopy are perforation, clinically significant bleeding, and death. A systematic review and meta-analysis of studies performed up to December 2015 reported overall colonoscopy-related adverse event rates of 1/2000 procedures for perforation, 1/500 procedures for bleeding, and estimated 1/35,000 procedures for death.Evidence 1Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Reumkens A, Rondagh EJ, Bakker CM, Winkens B, Masclee AA, Sanduleanu S. Post-Colonoscopy Complications: A Systematic Review, Time Trends, and Meta-Analysis of Population-Based Studies. Am J Gastroenterol. 2016 Aug;111(8):1092-101. doi: 10.1038/ajg.2016.234. Epub 2016 Jun 14. PMID: 27296945. Tomaszewski M, Sanders D, Enns R, et al. Risks associated with colonoscopy in a population-based colon screening program: an observational cohort study. CMAJ Open. 2021;9(4):E940-E947. PMID: 34642256; PMCID: PMC8513602.

To date, there only has been one RCT evaluating the impact of screening colonoscopy on CRC-related mortality and CRC incidence. It suggested that the CRC incidence at 10 years was lowered, in relative terms, by 18% when patients were invited to participate in screening colonoscopy as compared with usual care, but the CRC-related mortality remained unchanged. That trial was limited by its pragmatic nature as only 42% of patients in the screening group underwent screening colonoscopy. Observational studies and data modelling suggest that overall outcomes for colonoscopy in terms of CRC-related mortality and late-stage CRC incidence are improved as compared with other screening modalities. Overall it is likely that colonoscopy significantly decreases CRC-related mortality and CRC incidence, with absolute reductions as high as 3055 and 8140 patients per year, respectively, in Canada only.Evidence 2Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias. Lin JS, Piper MA, Perdue LA, et al. Screening for Colorectal Cancer: A Systematic Review for the U.S. Preventive Services Task Force [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2016 Jun. PMID: 27441328. US Preventive Services Task Force, Bibbins-Domingo K, Grossman DC, Curry SJ, et al. Screening for Colorectal Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2016 Jun 21;315(23):2564-2575. doi: 10.1001/jama.2016.5989. Erratum in: JAMA. 2016 Aug 2;316(5):545. Erratum in: JAMA. 2017 Jun 6;317(21):2239. PMID: 27304597. Shaukat A, Kahi CJ, Burke CA, et al. ACG Clinical Guidelines: Colorectal Cancer Screening 2021. Am J Gastroenterol. March 2021;116(3):458-479. PMID: 33657038. Bretthauer M, Loberg M, Wieszczy P. Effect of Colonoscopy Screening on Risks of Colorectal Cancer and Related Death. N Engl J Med. Oct 27, 2022;387:1547-1556. PMID: 36214590.

3. Other screening tests: These include CT colonography, capsule endoscopy, blood-based markers, and digital rectal examination, but there is no high quality evidence to show that any of these reduces CRC incidence or mortality. Other than CT colonography, none of these are recommended for screening by any of the major guidelines. While CT colonography is associated with fewer adverse events than colonoscopy, it still requires bowel preparation, is less sensitive for small polyps (<1 cm) or flat lesions, and may identify clinically irrelevant incidental findings that require further follow-up.

Risk AssessmenTTop

Risk factors for CRC include a first-degree family history of CRC (eg, recognized familial genetic syndromes and nonsyndromic familial CRC), family history of documented advanced adenomas, and personal history of IBD, adenomas, or CRC. A first-degree family history is associated with a 2- to 6-fold increase in the risk of CRC.

Risk assessment for CRC requires information on the individual’s family history of CRC and adenomas, including the number of affected family members, their degree of relatedness, and age at diagnosis in addition to information regarding familial genetic syndromes and personal medical history of CRC, adenomas, and IBD (duration, extent, and location). An initial risk assessment in individuals aged <40 years identifies those who require screening before the age of 50 years and those who may require genetic testing.

ApproachTop

Average-Risk Individuals (General Population)

The major guidelines are broadly in agreement that CRC screening should be offered to all individuals aged 50 to 75 years, the exception being the United States Preventive Services Task Force (USPSTF), which recommends that screening begin at the age of 45 years, although there are some differences between guidelines with respect to the recommended first-line test.

For average-risk individuals aged 50 to 74 years, the Canadian Task Force on Preventive Health Care (CTFPHC) recommends:

1) FOBT (gFOBT or FIT) every 2 years; or

2) FS every 10 years.

This is supported by moderate-quality evidence, the recommendation being strong for individuals aged 60 to 74 years and weak for individuals aged 50 to 59 years. The weak recommendation for younger individuals is based on the lower incidence of CRC and, hence, a lower expected absolute benefit in those aged 50 to 59 years.

The CTFPHC suggests against CRC screening in individuals aged >75 years and against the use of colonoscopy for CRC screening (both weak recommendations with low-quality evidence).

Current United States recommendations for average-risk individuals endorse the use of stool-based tests and structural examinations without prioritizing either class of tests. For stool-based tests, the American Cancer Society (ACS) endorses FIT or high-sensitivity gFOBT every year or a multitarget stool DNA test every 1 to 3 years, while, for structural examinations, they endorse colonoscopy every 10 years, CT colonography every 5 years, or FS every 5 years as acceptable options, depending on patient preference and test availability. Recently the ACS has also recommended that average-risk screening begin at the age of 45 for African American patients given their increased risk of young-onset CRC. The USPSTF updated its recommendations in 2021 to recommend screening in all average-risk patients aged 45 years.

Full colonoscopy should be performed in all individuals who have a positive FOBT result or ≥1 adenoma on FS within 8 weeks. Upper endoscopy is not recommended routinely in otherwise asymptomatic individuals who have had a positive screening FOBT result and no explanatory findings on colonoscopy.

High-Risk Individuals

1. Family history: For individuals who have 1 FDR with CRC, the Canadian Association of Gastroenterology (CAG) guideline on screening in individuals with a family history recommends high-risk screening colonoscopy, with FIT as a second-line option, starting at the age of 40 to 50 years or 10 years younger than the age of CRC diagnosis for the FDR, whichever is earlier. Recommended screening intervals after a negative test result are 5 to 10 years for colonoscopy and 1 to 2 years for FIT. For those who have ≥2 FDRs with CRC, the CAG family history guideline recommends screening colonoscopy starting at the age of 40 years or 10 years younger than the age of the earliest FDR’s diagnosis and a subsequent screening interval of 5 years. Recent Cancer Care Ontario (CCO) guidelines have further stratified family history risk based on the age at diagnosis of the FDR. If the FDR was older than 60 years at the time of diagnosis, a screening interval of 10 years is sufficient, whereas if the FDR was aged <60 years at the time of diagnosis, a screening interval of 5 years is recommended. Individuals who have second-degree relatives with CRC should follow average-risk screening guidelines.

For individuals who have ≥1 FDR with a documented advanced adenoma, the family history guideline recommends colonoscopy or FIT, starting at the age of 40 to 50 years or 10 years younger than the age of the earliest FDR’s diagnosis, whichever is earlier. Recommended screening intervals after a negative test result are 5 to 10 years for colonoscopy and 1 to 2 years for FIT.

Screening and genetic testing strategies for individuals who have a personal or family history of high-risk genetic syndromes, such as familial adenomatous polyposis (FAP), attenuated FAP (AFAP), Lynch syndrome (hereditary nonpolyposis colon cancer [HNPCC]), juvenile polyposis syndrome (JPS), Cowden syndrome, Peutz-Jeghers syndrome, MUTYH-associated polyposis (MAP), and Li-Fraumeni syndrome, should be guided by the appropriate, relevant guidelines. In general, endoscopic screening is recommended every 1 to 2 years, starting earlier than the age of diagnosis of the youngest affected relative. Moreover, many of these syndromes are associated with other types of malignancies that require screening starting at a young age (eg, patients with FAP require screening for duodenal adenomas via side-viewing upper endoscopy starting at the time when their first colonic polyp is identified; patients with HNPCC require annual transvaginal ultrasonography to screen for endometrial cancer starting between the ages of 20 and 25 years).

2. Personal history factors: Surveillance colonoscopy recommendations following oncologic resection with curative intent for CRC are highly variable. The American Society for Colon and Rectum Surgeons (ASCRS) recommends surveillance colonoscopy 1 year after surgery followed, in the absence of recurrent malignancy or polyps, by repeat colonoscopy after 3 years and then every 5 years thereafter for high-risk stage I, stage II, stage III, and stage IV disease. If a complete colonoscopy was not performed before surgery, completion colonoscopy within 6 months is recommended. Similarly, the European Society for Medical Oncology (ESMO) recommends completion colonoscopy within 3 to 6 months, in the absence of a full preoperative colonoscopy, to exclude synchronous lesions. The ESMO recommendations otherwise differ slightly from those provided by the ASCRS, with a colonoscopy recommended 1 year postoperatively and then at 3- to 5-year intervals thereafter depending on colonoscopic findings. Other societies present slight variations in the suggested follow-up interval and thus practitioners should familiarize themselves with these and aim to follow the guidelines most applicable to their patient population. There are currently no data suggesting one routine is superior to another.

Recommended surveillance intervals after a complete colonoscopy in patients who have had colon polyps removed completely are also heterogeneous across societies. Recommendations from the US Multi-Society Task Force: see Table 1. In general, high-risk polyps (ie, >10 mm, ≥3 adenomas, villous histology, high-grade dysplasia) require short-term interval follow-up (ie, <5 years), whereas patients with polyps without high-risk features should have repeat colonoscopies within 5 to 10 years (ie, a standard colonoscopy interval). More recently the CCO recommended that patients without high-risk features can return to FIT testing 5 years after their colonoscopy.

Patients with IBD and left-sided or extensive ulcerative colitis or with Crohn disease involving more than one-third of the colon should be offered screening colonoscopy after ~8 years of disease duration. The subsequent surveillance intervals of 1 to 3 years are determined by the presence of risk factors for malignancy, such as active inflammation, stricturing, multiple pseudopolyps, history of dysplasia, concomitant primary sclerosing cholangitis, or a family history (FDR) of CRC (see Ulcerative Colitis).

Differences Between Approaches

Despite the ongoing vigorous debate on the advantages of a particular approach, it appears that performing a screening procedure holds greater significance than the specific method chosen as the basis of the screening program. For example, the model included in the 2016 guidelines of the USPSTF estimates that the number of life-years gained per 1000 individuals screened is 221 years for a program using flexible sigmoidoscopy every 5 years as its primary screening modality, 244 years for FIT testing every year as its primary screening modality, and 270 years for colonoscopy every 10 years as its primary screening modality. The number of colorectal cancer–related deaths averted per 1000 individuals undergoing screening was 20, 22, and 24, respectively. Importantly the number of screening-associated moderate-to-major gastrointestinal and cardiovascular complications ranged from 10 (sigmoidoscopy every 5 years and FIT every year) to 15 (colonoscopy every 10 years) per 1000 screened individuals.

TablesTop