Clinical Validation of Fecal Immunochemical Test for Colorectal Cancer

From 2000 until 2012, colonoscopy was promoted in the US as the “gold standard” screening test for colorectal cancer (CRC); few other countries agreed. In 2008, the US Multi-Society Task Force on Colorectal Cancer (USMSTF) said that stool tests were inferior to structural exams and promoted the idea that there were two groups of screening tests—structural exams and fecal tests—and that fecal tests only detected CRC but not “precancerous, advanced” adenomas, a statement not supported by studies published before 2008.¹

It was known for decades before 2000 that the sensitivity of guaiac fecal occult blood tests (FOBT) for cancers and adenomas was poor, and attempts were made to improve that situation with a new FOBT called the sensitive guaiac FOBT—a guaiac test that detected peroxidase activity found in human and non-human blood and in vegetables. The test was more sensitive for cancers and advanced adenomas but less specific. In other countries (Japan, Australia, Israel, et al), studies were being done with the fecal immunochemical test (FIT) for human hemoglobin. In 1996, the first American study on FIT in a large average-risk population was published, showing that an FIT had superior performance characteristics for CRC and advanced adenomas compared with the guaiac FOBTs. ^2,3 

The problem for FIT since its introduction into the US has been persistent that it isn't a good enough screening test compared with colonoscopy. Recently, some progress has been made in countering these claims. Primary care practitioners and patients are learning that FIT, done properly, is as equally effective for CRC screening as colonoscopy, and its use can maintain screening participation when colonoscopy capacity is limited; for instance, during our continuing COVID pandemic. FITs have been proven to increase participation in CRC screening programs compared with colonoscopy because the test is noninvasive and offers the convenience of requiring no diet or medication modification. In the US, FIT is performed on an annual basis and has been demonstrated in cost-effectiveness analysis to yield similar life-years gained when compared with colonoscopy performed every 10 years.⁴ 

Critics point to the literature suggesting that rates of CRC and advanced precancerous lesion detection rates are higher with colonoscopy versus FIT and FIT is less effective at detecting advanced serrated polyps (ASP), one of the types of precancerous polyps, which may account for one-third of CRC. However, the sensitivity in most of these articles is application sensitivity—results from only one testing. The studies don't measure or report the programmatic sensitivity, which is vital in screening programs where testing is done annually or every 2 years. The multitarget stool DNA test detects hemoglobin with its own FIT, but also detects DNA markers. The advantage of a multitarget stool DNA test over FIT is its increased sensitivity for ASP, but with a lower specificity, much higher cost, increased number of false positives and, higher healthcare costs with unnecessary colonoscopies.⁵

The publication we are reviewing gives results from a team of researchers from the Netherlands, a country with many contributions to our better understanding that FITs are a valuable screening test for CRC. They report their work with the mtFIT—a test designed to detect hemoglobin, calprotectin, and SERPINF2 in stool—and demonstrated a greater sensitivity for advanced adenomas compared with FIT with equal specificity. When compared with FIT, the sensitivity of mtFIT for CRC was lower and its sensitivity for ASP was equally poor. The increase in sensitivity of the test was largely due to the detection of advanced adenomas, and most of these polyps have very slow progression to fatal cancer. It can be argued that the benefit of the mtFIT does not support it over a cost-effective annual FIT.⁴ In addition, mtFIT fails to increase sensitivity for ASP compared with FIT and has a notably lower sensitivity for ASP compared with the multitarget stool DNA test.¹ Although this study provides the framework for a protein-based test to improve the sensitivity of the current FIT tests, further investigation is needed.

An optimal CRC screening stool test would combine the superior sensitivity for ASPs of the multitarget stool DNA test, the increased sensitivity for advanced adenomas, and the increased specificity with mtFIT while remaining cost-effective to facilitate increased participation in CRC screening programs. At the present time, further education and awareness of the FIT's efficacy are crucial for primary care practitioners and patients, and more studies must be done to say with confidence that the mtFIT is a valuable addition to our CRC screening armamentarium.

References

1. Allison JE, Sakoda LC, Levin TR, et al. Screening for Colorectal Neoplasms with New Fecal Occult Blood Tests: Update on Performance Characteristics. J Natl Cancer Inst. 2007;99(19):1462-1470. https://academic.oup.com/jnci/article/99/19/1462/2544304
2. Allison JE, Tekawa IS, Ransom LJ, et al. A comparison of fecal occult-blood tests for colorectal-cancer screening. N Engl J Med. 1996;334(3):155-159. https://www.nejm.org/doi/full/10.1056/nejm199601183340304
3. Allison JE, Potter MB. New screening guidelines for colorectal cancer: a practical guide for the primary care physician. Prim Care. 2009;36(3):575-602. https://www.sciencedirect.com/science/article/abs/pii/S0095454309000360?via%3Dihub
4. Robertson DJ, Lee JK, Boland CR, et al. Recommendations on Fecal Immunochemical Testing to Screen for Colorectal Neoplasia: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2017;152(5):1217-1237.e3. https://www.nejm.org/doi/full/10.1056/nejm199601183340304
5. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;370(14):1287-1297. https://www.nejm.org/doi/full/10.1056/nejmoa1311194