Case
A 56-year-old man with no significant medical history was seen in clinic by his primary care physician (PCP). The patient had not followed his PCP’s recommendation at prior clinic visits to undergo colonoscopy for colorectal cancer (CRC) screening, and during this visit, he declined colonoscopy without first undergoing a less invasive screening test for CRC. The patient had no history of hematochezia or abnormal bowel movements but reported that his father had died from CRC at age 80. His hemoglobin was 13.7 g/dL (reference,13.5 – 17.0 g/dL).
What Would You Do Next?
Fecal immunochemical test (FIT)
Fecal immunochemical test - multi-target stool DNA test (s-DNA-FIT)
High-sensitivity guaiac fecal occult blood test (gFOBT)
Recommend A, B or C
Answer
D. Recommend A, B or C
Test Characteristics
High-sensitivity guaiac fecal occult blood test (gFOBT), fecal immunochemical test (FIT) and multi-target stool DNA-FIT (s-DNA-FIT) are stool-based tests recommended by the US Preventive Services Task Force (USPSTF) for colorectal cancer screening in asymptomatic persons at average-risk of CRC beginning at age 45 years.1 Colonoscopy, instead of stool-based testing, is recommended for screening of individuals with a personal or family history of polyps or CRC, inflammatory bowel disease or those with inherited cancer syndromes.2 Importantly, in order for stool-based screening tests to provide benefit, a positive result must be followed up with a colonoscopy, which generates the tissue diagnosis of CRC.
High-sensitivity gFOBT uses a chemical to detect heme in a stool sample.3 FIT uses antibodies to measure the presence and concentration of human hemoglobin in stool and is reported as positive if >20 μg hemoglobin/g feces is detected.4 s-DNA-FIT includes FIT and detection of DNA biomarkers for cancer in cells that are shed into the stool from the lining of the colon and rectum, such as mutant KRAS, aberrant methylation of BMP3, and NDGR4.5 s-DNA-FIT is reported as positive if either the FIT or DNA biomarker component is abnormal.5
Stool-based tests screening tests for CRC do not require fasting or bowel preparation and can be performed at home. For high-sensitivity gFOBT, a portion of 3 consecutive stool samples is smeared onto a slide or test card, and the kit is mailed to a lab or returned to a PCP’s office. Prior to undergoing high-sensitivity gFOBT, invididuals may be recommended to avoid use of anticoagulants, non-steroidal anti-inflammatory drugs (NSAIDs), red meat (such as rare beef or lamb), vitamin C and iron. FIT can be obtained from a clinic, pharmacy or via mail, and requires collection of a small stool sample in a container that should be mailed within 24 hours of collection to prevent degradation of hemoglobin. s-FIT-DNA requires a prescription, and the kit is mailed to the patient. For s-DNA-FIT, a full stool sample needs to be collected in a bucket that contains a buffer for DNA stability, and a small stool sample is provided for the FIT component of the test.
The sensitivity and specificity of stool-based screening tests for CRC, and the USPSTF recommendations about frequency of screening are shown in the Table. Meta-analysis has shown that 13.5% of s-DNA-FIT tests are positive compared to 6.4% of FIT,6 and 45% of patients with a positive s-DNA-FIT have no significant findings on colonoscopy.5 According to the 2022 Medicare fee schedule, reimbursement for high-sensitivity gFOBT was $4.38, and reimbursement was $18.05 for FIT and $509 for s-DNA-FIT.7
Table:
Stool-based screening tests for detection of colorectal cancer
| High-sensitivity gFOBT | FIT | s-DNA-FIT | |
|---|---|---|---|
| Sensitivity | 0.50–0.75 (95%CI, 0.09–1.0) |
0.74 (95%CI, 0.64–0.83) |
0.93 (95%CI, 0.87–1.0) |
| Specificity | 0.96–0.98 (95%CI, 0.95–0.99) |
0.94 (95%CI, 0.93–0.96) |
0.84 (95%CI, 0.84–0.86) |
| USPSTF screening recommendation | Every year | Every year | Every 1 to 3 years |
Application of the Test Result to This Patient
The patient underwent stool-based testing with s-DNA-FIT, which was reported as positive (reference, negative). After receiving this positive test result, the patient agreed to undergo colonoscopy.
What Are Alternative Diagnostic Testing Approaches?
The most appropriate test for this patient would have been an initial screening colonoscopy because he had a first-degree relative with CRC.1,2,8 For asymptomatic patients at average risk of CRC, other CRC screening tests recommended by the USPSTF include colonoscopy every 10 years, CT colonography every 5 years, flexible sigmoidoscopy every 10 years along with FIT yearly, or flexible sigmoidoscopy every 5 years.1
Patient Outcome
Five weeks after the patient’s positive s-DNA-FIT result, he underwent colonoscopy, which revealed 3 sessile cecal polyps (2–3 mm in diameter), one 3-mm polyp in the transverse colon, 2 sessile sigmoid polyps (2–6 mm in diameter) and a 5-cm rectal mass. On histological examination, 5 of the polyps were adenomas, 1 was benign mucosal polyp, and the rectal mass was invasive well-differentiated microsatellite stable adenocarcinoma, staged by CT imaging as T3N0 rectal adenocarcinoma. His serum CEA was <1 ng/mL (reference <3.0 ng/mL). The patient underwent 8 cycles of neoadjuvant chemotherapy with FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) for 4 months, followed by 28 treatments of radiation therapy over 5.5 weeks. Two months later, he underwent low anterior resection of the rectum. Due to his age, family history, and presence of multiple adenomas, a genetic evaluation was performed with a 58-gene custom cancer panel, which did not reveal any germline mutations. The patient was last seen in January 2023 with plans for follow-up CT imaging and serum CEA a year after surgery.
Clinical Bottom Line.
Stool-based tests are recommended for individuals at average-risk of colorectal cancer (CRC) beginning at age 45.
High-sensitivity guaiac fecal occult blood test (gFOBT) uses a chemical to detect heme in a stool sample; fecal immunochemical test (FIT) uses antibodies to measure hemoglobin in stool; s-DNA-FIT includes FIT and detection of DNA biomarkers for cancer in stool.
A positive stool-based test must be followed up with a colonoscopy in order to make the diagnosis of CRC.
Acknowledgements.
Dr. Carethers work is supported by the United States Public Health Service (R01 CA258519). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Disclosure of potential conflicts of interest.
Dr. Carethers reports grants from the National Cancer Institute and funds from the University of Michigan during the conduct of the study. Dr. Carethers reports personal fees from Avantor, Inc., provided consultancy to Geneoscopy, Inc., and being a Board member for the American Gastroenterology Association and on the Advisory Board for the National Institute for Diabetes and Digestive and Kidney Diseases outside of the submitted work.
References
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