Colon cancer screening

ACRONYMS AND DEFINITIONS

ACP - American College of Physicians

ACR - American College of Radiology

ACG - American College of Gastroenterology

ACS - American Cancer Society

AGA - American Gastroenterological Association

ASGE - American Society for Gastrointestinal Endoscopy

BMJ - British Medical Journal

CTFPHC - Canadian Task Force on Preventive Health Care

FIT - Fecal immunochemical test

gFOBT - Guaiac-based fecal occult blood test

USMSTF - U.S. Multi-Society Task Force on Colorectal Cancer which represents the ACG, AGA, and ASGE

NCI - National Cancer Institute

USPSTF - United States Preventive Service Task Force

EPIDEMIOLOGY

Worldwide, colorectal cancer is the third most common type of cancer and the fourth most common cause of cancer death. Approximately 1.2 million people are diagnosed with colorectal cancer each year, and 600,000 people die from it annually. The incidence of colorectal cancer is highest in Europe and North America and lowest in Asia and Africa.
In the U.S., approximately 5% of the population will be diagnosed with colorectal cancer during their lifetime making it the third most common cancer and third leading cause of cancer death. The median age of colon cancer diagnosis is 69 in men and 73 in women, and the median age of rectal cancer diagnosis is 63 in men and 65 in women. Men are affected more than women, and blacks are affected more than other races.
The prognosis for patients with colorectal cancer has improved over time with an estimated 5-year survival for patients in the U.S. of 90% for localized disease, 70% for regional disease, and 13% for distant metastasis [1,2,3]

EFFICACY OF COLON CANCER SCREENING

Overview

There is limited data on the efficacy of colon cancer screening. Only colonoscopy, flexible sigmoidoscopy, and Hemoccult II have been studied in long-term randomized controlled trials. Results from those studies are presented below.

Colonoscopy - one large randomized controlled trial evaluated the effects of colonoscopy on colon cancer outcomes. The NordiCC Study published in 2022 randomized 84,585 patients in a 1:2 ratio to an invitation to screening colonoscopy (invited group) or no invitation (control group). The trial took place in Poland, Norway, Sweden, and the Netherlands - countries where screening colonoscopy is not widely performed or recommended. The primary outcome was risk of colorectal cancer or death from colorectal cancer after a median follow-up of 10 - 15 years. Of the 28,220 participants in the invited group, only 11,843 (42%) actually had a colonoscopy. In the intention-to-screen analysis, the risk of colorectal cancer at 10 years was 0.98% in the invited group, and 1.20% in the control group (RR 0.82; 95%CI [0.70 to 0.93]), and the risk of colorectal cancer death was 0.28% and 0.31%, respectively (RR 0.90; 95%CI [0.64 to 1.16]). There was no significant difference in overall mortality (11.03% vs 11.04%). [PMID 36214590] Given that 58% of subjects in the invited group did not undergo colonoscopy, it's difficult to draw conclusions about the true effects of screening. Per-protocol analyses showed a greater benefit, but these analyses are often biased.

Flexible sigmoidoscopy - combined results of 4 randomized controlled trials (N=458,002) where flexible sigmoidoscopy was performed every 3 - 5 years for 1 - 2 rounds of screening found that it reduced the incidence of colorectal cancer (IRR 0.78, 95%CI [0.74 to 0.83]) and colorectal cancer mortality (IRR 0.74, 95%CI [0.68 to 0.80]) over 11 - 17 years of follow-up. [19]

Hemoccult II - combined results of 5 randomized controlled trials (N=419,966) where Hemoccult was performed every 2 years for 2 - 9 rounds of testing found that it significantly reduced colorectal cancer mortality (relative risk range, 0.78 95%CI, [0.65-0.93] to 0.91 95%CI [0.84-0.98]) over 11 to 30 years of follow-up. It did not have a significant effect on colorectal cancer incidence. [19]

NATIONAL CANCER INSTITUTE RISK PREDICTION TOOL

The National Cancer Institute (NCI) has an online tool that can be used to estimate a person's risk of colorectal cancer
Based on a variety of personal information that the user provides, the tool estimates the 5-year, 10-year, and lifetime risk of colorectal cancer
In one study, the tool showed a modest ability to predict advanced neoplasia in patients undergoing screening colonoscopy (area under ROC curve - 0.61) [PMID 27219715]
The tool is available at the link below

NCI Colorectal Cancer Risk Assessment Tool

SCREENING RECOMMENDATIONS BY GROUP

American College of Gastroenterology 2021
Whom to screen Age 45 - 49 years: suggest screening average-risk individuals (conditional recommendation, low evidence) Age 50 - 75 years: recommend screening average-risk individuals (strong recommendation, moderate evidence) Age > 75 years: decision to continue screening should be individualized (conditional recommendation, low evidence) Screening methods Colonoscopy every 10 years or annual FIT are preferred For patients unwilling to undergo colonoscopy or annual FIT, consider the following: Flexible sigmoidoscopy every 5 - 10 years Fecal DNA test every 3 years CT colonography every 5 years Colon capsule every 5 years mSEPT9 DNA testing (Epi proColon®) is not recommended [18]
U.S. Preventive Services Task Force 2020
Whom to screen Age 45 - 49 years: screen everyone (Grade B: high certainty that net benefit is moderate) Age 50 - 75 years: screen everyone (Grade A: high certainty that net benefit is substantial) Age 76 - 85 years: screening should be individualized and based on overall health and prior screening results Age > 85 years: screening not recommended Screening methods (no single method is preferred over another) Colonoscopy every 10 years CT colonography every 5 years Fecal DNA-FIT testing every 3 years or every year FIT every year Flexible sigmoidoscopy every 5 years Flexible sigmoidoscopy every 10 years + FIT every year High-sensitivity guaiac-based fecal occult blood test every year (Hemoccult SENSA)
American College of Physicians 2019
Whom to screen Screen everyone aged 50 - 75. Do not screen before 50 or after 75. Do not screen those with a life expectancy of ≤ 10 years. Screening methods (no single method is preferred over another) Colonoscopy every 10 years FIT every 2 years High-sensitivity (gFOBT) every 2 years Flexible sigmoidoscopy every 10 years with FIT every 2 years [12]
British Medical Journal 2019
Whom to screen Recommendations are intended for the U.K. population Estimate the 15-year colorectal cancer risk using the QCancer® 15-year colorectal risk calculator For individuals aged 50 - 79 years and estimated risk < 3%, do not screen For individuals aged 50 - 79 years and estimated risk ≥ 3%, screen with one of the methods below Do not screen those with a life expectancy of < 15 years Screening methods (no single method is preferred over another) FIT every 1 or 2 years A single colonoscopy A single sigmoidoscopy [17]
American Cancer Society 2018
Whom to screen Screen everyone beginning at age 45. The ACS makes no recommendation on an age to stop screening. Screening methods (no single method is preferred over another) Colonoscopy every 10 years CT colonography every 5 years Flexible sigmoidoscopy every 5 years Double contrast barium enema every 5 years Guaiac-based fecal occult blood test every year (use high-sensitivity test like Hemoccult SENSA) FIT test annually Fecal DNA-FIT every 3 years [16]
U.S. Multi-Society Task Force on Colorectal Cancer 2017
Whom to screen Start screening African Americans at age 45. Screen everyone else at age 50. Persons who are up to date with screening and have negative prior screening tests, particularly colonoscopy, consider stopping screening at age 75 or when life expectancy is less than 10 years Persons without prior screening should be considered for screening up to age 85, depending on consideration of their age and comorbidities. Screening methods Colonoscopy every 10 years (Tier 1, preferred) FIT every year (Tier 1, preferred) CT colonography every 5 years (Tier 2) Fecal DNA-FIT test every 3 years (Tier 2) Flexible sigmoidoscopy every 5 - 10 years (Tier 2) Capsule colonoscopy every 5 years (Tier 3) [15]
Canadian Task Force on Preventive Health Care 2016
Whom to screen Screen everyone aged 50 - 74. Do not screen before 50 or after 75. Screening methods: Flexible sigmoidoscopy every 10 years + FIT or gFOBT every two years [13]

SCREENING METHODS

^✝Advanced adenoma defined as adenoma with any of the following: ≥ 10 mm in size, tubulovillous or villous histology, high-grade dysplasia
Colonoscopy
Description Procedure where an endoscope is inserted through the anus and advanced all the way to the terminal ileum Endoscope allows visualization of the entire colon and a portion of the terminal ileum Advantages: allows visualization of the entire colon; considered the "gold standard" for colon cancer screening/detection; allows for biopsy of lesions and removal of polyps; if normal, screening interval is 10 years Disadvantages: invasive procedure that requires sedation; bowel prep is required that may be uncomfortable; serious adverse events (e.g. bleeding, perforation) occur in about 0.28% of procedures [4] Accuracy Colonoscopy is considered the reference standard It is estimated that the colorectal cancer miss rate for colonoscopy is as high as 6%. The miss rate for adenomas > 1 cm is 12 - 17%. [4] Recommendations ACP - screen everyone every 10 years starting at age 50 ACS - screen everyone every 10 years starting at age 45 BMJ - screen individuals 50 - 79 years old with 15-year estimated risk ≥ 3% one time USMSTF - start screening African Americans at age 45. Screen everyone else at age 50. Screen every 10 years. USPSTF - screen everyone every 10 years starting at age 50 Cost $911 - $6946, depending on insurer and location Cost is higher if biopsies are performed
Flexible sigmoidoscopy (flex sig)
Description Procedure where an endoscope is inserted through the anus and advanced into the sigmoid colon. The standard sigmoidoscope is 60 cm long. Approximately two-thirds of colorectal cancers and adenomas are located in the rectum and sigmoid colon [7] Advantages: performed in office without sedation; prep only requires 2 fleet enemas although oral prep may be better; allows for biopsy and polypectomy Disadvantages: only allows visualization of the sigmoid and descending colon; patient discomfort; perforation and bleeding are rare but may occur [6] Accuracy No well-done studies have compared flexible sigmoidoscopy to colonoscopy in average-risk populations Recommendations ACP Flex sig + FIT - starting at age 50, perform flex sig every 10 years and FIT every 2 years ACS - starting at age 45, screen every 5 years BMJ - screen individuals 50 - 79 years old with 15-year estimated risk ≥ 3% one time CTFPHC - starting at age 50, perform flex sig every 10 years and FIT or gFOBT every 2 years USMSTF - start screening African Americans at age 45. Screen everyone else at age 50. Screen every 5 - 10 years. (Tier 2) USPSTF Flex sig alone - starting at age 50, screen every 5 years Flex sig + FIT - starting at age 50, perform flex sig every 10 years and FIT annually Cost $500 - $3000 depending on insurer and location Cost is higher if biopsies are performed
CT colonography
Description Specialized CT scan of the abdomen that creates 2D and 3D images of the colon for polyp and neoplasm detection Patient must undergo bowel prep beforehand. A small amount of contrast may be mixed with the prep so that residual fluid and stool is "tagged." This helps distinguish the residua from soft tissue masses. During the scan, a rectal tube is inserted so that the colon can be insufflated with CO₂ or room air Patients with polyps ≥ 6 mm are referred for colonoscopy [6] Advantages: no sedation is required; procedure takes about 10 minutes with no recovery time; colon perforation is rare; in studies, significant extracolonic findings are found in 4.5% of patients Disadvantages: bowel prep is recommended; colonoscopy may be necessary depending on findings; patient receives small amount of radiation; extracolonic findings may lead to unnecessary testing [6] Accuracy Sensitivity (colorectal cancer): 96% Sensitivity (adenomas ≥ 10 mm): 85 - 93% Specificity (adenomas ≥ 10 mm): 97% Sensitivity (adenomas 6 - 9 mm): 70 - 86% Specificity (adenomas 6 - 9 mm): 86 - 93% [6] Recommendations ACS - starting at age 45, screen everyone every 5 years USMSTF - start screening African Americans at age 45. Screen everyone else at age 50. Screen every 5 years. (Tier 2) USPSTF - starting at age 50, screen everyone every 5 years Cost $300 - $1500 depending on the insurer and location Reimbursement for screening varies
Fecal immunochemical test (FIT)
Description Like gFOBT, FIT is performed on a stool sample collected by the patient FIT testing detects human globin, a component of human hemoglobin. FIT differs from gFOBT in that it directly detects blood in the stool where gFOBT relies on the peroxidase activity of hemoglobin. FIT testing is also more specific for lower GI bleeding because globulin is degraded by digestive enzymes in the upper GI tract Diet, medications, and supplements are not supposed to interfere with FIT testing, although some studies have found that FIT testing has a lower positive predictive value (PPV) in patients taking aspirin or anticoagulants [PMID 30689972]. Another study found that taking an aspirin 2 days before FIT testing did not increase the sensitivity of the test. [PMID 31063574] Examples of currently available FIT tests include Hemoccult ICT, OC-Light, Hemosure, QuickVue iFOB, and Clearview. Some tests use cards and some tests use bottles. The optimal number of samples to test has not been determined but varies from one to three. The US Multi-Society Task Force on colorectal cancer recommends testing one sample. Most tests give only qualitative result (positive or negative) while a few tests give qualitative and quantitative results (i-Chroma iFOBT, OC-Micro, OC-Sensor) [5,6,14] Advantages: performed at home; no procedure; inexpensive; no diet or medication restrictions Disadvantages: positive result requires colonoscopy; more frequent testing; does not detect polyps Accuracy Hemoccult ICT Sensitivity (colorectal cancer): 82% Specificity (colorectal cancer): 97% Sensitivity (advanced adenoma^✝): 30% Specificity (advanced adenoma^✝): 97% [9] NOTE: In this study (n=5356), the reference standard was flex sig or colonoscopy, and three stool samples were tested OC FIT-CHEK Sensitivity (colorectal cancer): 74% Sensitivity (advanced adenoma^✝): 24% Specificity (negative colonoscopy): 96% [10] NOTE: In this study (n=9989), only one stool sample was tested Recommendations ACP FIT alone - screen every 2 years starting at age 50 Flex sig + FIT - starting at age 50, perform flex sig every 10 years and FIT every 2 years ACS FIT alone - screen annually starting at age 45 Fecal DNA-FIT - screen every 3 years starting at age 45 BMJ - screen individuals 50 - 79 years old with 15-year estimated risk ≥ 3% every 1 or 2 years CTFPHC - starting at age 50, perform flex sig every 10 years and FIT or gFOBT every 2 years USMSTF FIT alone - start screening African Americans at age 45. Screen everyone else at age 50. Screen annually. (Tier 1, preferred) Fecal DNA-FIT - screen every 3 years starting at age 50 (Tier 2) USPSTF FIT alone - screen annually starting at age 50 FIT + Flex Sig - starting at age 50, perform flex sig every 10 years and FIT annually Fecal DNA-FIT - screen every 3 years starting at age 50 Cost $10 - $20
Guaiac-based fecal occult blood test (gFOBT)
Description Guaiac-based fecal occult blood tests detect blood in the stool through the pseudoperoxidase activity of hemoglobin Patients typically collect 1 stool sample on 3 different days at home. The samples are developed in a doctor's office or lab. NSAIDs should be avoided for 7 days before and during the collection period Vitamin C in excess of 250 mg/day should be avoided for 3 days before and during the collection period (may cause false-negative) Red meats should be avoided for 3 days before and during the collection period Specimens should be developed within 14 days of collection Hemoccult SENSA is more sensitive than Hemoccult II [5,6] Advantages: performed at home; no procedure; inexpensive Disadvantages: diet and drug restrictions; positive result requires colonoscopy; more frequent testing; does not detect polyps; low sensitivity Accuracy Hemoccult II Sensitivity (colorectal cancer): 13% Sensitivity (advanced adenoma^✝): 11% Specificity (combined): 95% [8] Hemoccult SENSA Sensitivity (colorectal cancer): 64% Specificity (colorectal cancer): 90% Sensitivity (advanced adenoma^✝): 41% Specificity (advanced adenoma^✝): 91% [9] NOTE: In this study (n=5799), the reference standard was flex sig or colonoscopy Recommendations ACP - screen every 2 years starting at age 50 (use high-sensitivity test like Hemoccult SENSA)>/li> ACS - screen annually starting at age 45 (use high-sensitivity test like Hemoccult SENSA) CTFPHC - starting at age 50, perform flex sig every 10 years and FIT or gFOBT every 2 years USPSTF - screen annually starting at age 50 (use high-sensitivity test like Hemoccult SENSA) Cost $6 - $20
Fecal DNA test (Cologuard®)
Description Fecal DNA tests are performed on a single sample of stool that is collected by the patient at home. A FIT test is also performed with the fecal DNA test. If the FIT test is positive and the DNA test is negative, the results come back as positive. Colorectal cancers and adenomas continually shed cells into the stool. These cells contain certain types of genetic mutations that are common in many cancerous and precancerous tumors. Fecal DNA tests are able to detect these mutations in cells present in the stool sample. The test is not 100% sensitive in that not all cancers or precancerous lesions carry the genetic mutations that are detected. [5,6,10] Advantages: performed at home; no procedure; no diet or medication restrictions Disadvantages: positive result requires colonoscopy; expensive; does not detect all cancers; manufacturer does not report FIT results and DNA results separately; optimal screening interval has not been determined; unclear how to handle a positive test that is followed by a negative colonoscopy Accuracy Cologuard without FIT Sensitivity (colorectal cancer): 92% Sensitivity (advanced adenoma^✝): 42% Specificity (negative colonoscopy): 90% [10] Recommendations ACS - screen every 3 years starting at age 45 USMSTF - start screening African Americans at age 45. Screen everyone else at age 50. Perform test every 3 years. (Tier 2) USPSTF - screen every 3 years starting at age 50 Cost $500 - $600
Double-contrast barium enema (air-contrast barium enema)
Description Procedure where a tube is inserted into the rectum and barium is infused. The patient's position is adjusted under fluoroscopy so that the barium coats the entire lining of the colon. After removing some barium, the colon is then insufflated with air. Air and barium serve as the "double-contrast," and radiographic images are obtained. Colon prep before the procedure is required. The procedure typically lasts 20 - 40 minutes. [6] Advantages: no sedation is required; no recovery time Disadvantages: bowel prep is required; colonoscopy may be necessary depending on findings; exam can be uncomfortable; test accuracy highly dependent on examiner's experience Accuracy Sensitivity (colorectal cancer): 85 - 97% Sensitivity (adenomas > 7 mm): 73% (based on 1 study, n=56) [6] Recommendations ACS - screen everyone every 5 years starting at age 45 Cost $350 - $1000 depending on insurance and location
mSEPT9 DNA testing (Epi proColon®)
Description mSEPT9 DNA testing is performed on a blood sample The test detects methylated SEPT9 DNA, which in high quantities, is a marker for colorectal cancer The test is marketed under the name Epi proColon® [11] Advantages: blood test; no procedure Disadvantages: low sensitivity; positive result requires colonoscopy; does not detect polyps Accuracy Sensitivity (colorectal cancer): 48% Sensitivity (advanced adenoma^✝): 11% Specificity (colorectal cancer): 92% [11] Recommendations No organization currently recommends this test Cost ∼ $91

BIBLIOGRAPHY

1 - PMID 24225001 Lancet review
2 - USPSTF website
3 - Colorectal cancer facts and figures 2014 - 2016
4 - PMID 21951473 Complications of colonoscopy
5 - PMID 19240699 - ACG screening recs
6 - PMID 18384785 - ACS screening recs
7 - PMID 20430429 - Flex Sig study
8 - PMID 15616205 - Hemoccult II vs DNA
9 - PMID 17895475 - Hemoccult SENSA vs FIT vs both
10 - PMID 24645800 - Cologuard vs FIT
11 - PMID 23408352 - SEPT9 DNA Test study
12 - PMID 31683290 - Screening for Colorectal Cancer in Asymptomatic Average-Risk Adults: A Guidance Statement From the American College of Physicians, Annals of Intern Med (2019)
13 - PMID 26903355 - CTFPHC screening recs
14 - PMID 27753435 - Recommendations on fecal immunochemical testing to screen for colorectal neoplasia: a consensus statement by the US Multi-Society Task Force on colorectal cancer, Gastrointestinal Endoscopy, 2017
15 - PMID 28600072 - Colorectal Cancer Screening: Recommendations for Physicians and Patients From the U.S. Multi-Society Task Force on Colorectal Cancer, Gastroenterology (2017)
16 - American Cancer Society website
17 - PMID 31578196 - Colorectal Cancer Screening With Faecal Immunochemical Testing, Sigmoidoscopy or Colonoscopy: A Clinical Practice Guideline, BMJ (2019)
18 - PMID 33657038 - ACG Clinical Guidelines: Colorectal Cancer Screening, Am J Gastroenterol (2021)
19 - PMID 34003220 - Screening for Colorectal Cancer Updated Evidence Report and Systematic Review for the US Preventive Services Task Force, JAMA (2021)

COLON CANCER SCREENING - AVERAGE RISK