Is FIT an Acceptable Screening Test for Colorectal Cancer?

As a card-carrying gastroenterologist, I enjoy performing screening colonoscopy just like most of my society brethren. However, I feel strongly that the fecal immunochemical test (FIT) is a fully acceptable alternative for colorectal cancer (CRC) screening. Perhaps the easiest defense for those of us who are enthusiastic about stool-based screening is the quality of evidence supporting it. There are at least three high-quality, large-scale randomized controlled trials that unequivocally demonstrate the effectiveness of programmatic fecal occult blood tests (FOBT) in reducing death from CRC.1 Moreover, those results were obtained with conventional guaiac-FOBT that relies on indirect evidence for blood in the stool. A major advantage of FIT relative to such testing is that it directly assesses the presence of human hemoglobin in stool. That mechanistic difference translates into a host of benefits that result in FIT being a better test than conventional FOBT (table). I recently led an effort by the U.S. Multi- Society Task Force (USMSTF) on Colorectal Cancer that provided guidance on FIT use. One of the important recommendations from that paper includes a clear preference for FIT over conventional FOBT.2 So FIT, by extension of the FOBT trial results, is supported by the highest levels of evidence and is certainly acceptable as a CRC screening test on that basis.

Beyond this defense is the simple fact that FIT is a very good test to detect CRC. In the large, often-cited meta-analysis by Lee and colleagues,3 one-time sensitivity of FIT for cancer was 79 percent. Of course, that means that FIT will not detect cancer in the remaining cases on the initial screening. However, stool-based screening is designed to be applied annually, and so cancers not detected on the first round could be detected subsequently and while still in a treatable stage. While a test like colonoscopy has a modestly better one-time cancer-detection sensitivity, important lesions are occasionally missed.4 Further, follow-up testing, when negative, is at a much longer interval, up to 10 years. From a programmatic standpoint, while FIT may miss a lesion in the first year, it can detect it on the following cycle. Initial misses by colonoscopy are less common, but when they occur, subsequent opportunities for early detection are often lost. In fact, approximately 7 percent of cancers are diagnosed in persons who had a negative colonoscopy in the prior three years.5

The criticism most often used when arguing against the acceptability of FIT for screening is that the test is only a cancer detection test. In fact, this is not an entirely fair critique. In the USMSTF paper, we summarized studies examining FIT detection for advanced neoplastic lesions. Results from studies where FIT was applied regularly in a population over a number of annual cycles suggest its sensitivity for advanced neoplasia remains at about 30 percent across each repeated cycle. So over repeated rounds of testing, FIT will detect some of those with advanced neoplasia and provide true cancer prevention.

But the relative deficiency of FIT to colonoscopy in detecting adenomas is really at the heart of the argument that FIT is not acceptable. Colonoscopy enthusiasts will point out that only structural exams can routinely find adenomas and remove them and thus prevent cancer at high rates. The question is this: at what cost? To be clear, I am not just talking about the actual societal cost, which is higher with primary colonoscopy screening relative to FIT. There is also a physical cost to the patient. The vast majority of the population is never destined to develop CRC. The U.S. lifetime risk of cancer is approximately 5 percent. So the other 95 percent can never benefit from screening colonoscopy (or any screening test for that matter). They can only be harmed. Is this an argument not to screen for CRC? Of course not! As just discussed, randomized controlled trials suggest unequivocal benefit from screening and the U.S. Preventive Services Task Force (USPSTF) gives screening a grade-A recommendation.6 However, should we start with the most invasive and risky test first? Even small amounts of harm in the 95 percent (i.e., those never destined to get CRC) can counterbalance benefits in the few detected with or prevented from cancer. In this context, finding adenomas and removing them through repeated examinations becomes somewhat less attractive. Given that adenoma detection rates in average-risk screening populations are likely greater than 50 percent, it calls into question the importance of finding and removing this surrogate marker. Put another way, a real advantage of noninvasive testing may be that it finds fewer adenomas and subjects fewer individuals to invasive testing. When you think of the frequency with which an individual may undergo surveillance colonoscopy for adenomas (e.g., from age 50 to 80), this may be a real benefit.

Moving beyond the complicated calculus of balancing risk and benefits with screening is the simple fact that FIT is a test that is attractive to many patients and is likely to get done. At the end of the day, successful screening is largely about adherence. Modeling clearly shows that when adherence to a FIT-based program is high, outcomes rival or even exceed that which could be obtained with colonoscopy.7

While I am convinced that FIT is an acceptable screening test, could evidence be developed to convince me otherwise? The type of evidence would need to come from high-quality comparative-effectiveness studies. Worldwide, there are three trials underway that directly compare a strategy of up-front screening colonoscopy to FIT. I serve as national co-chair for the U.S.-based effort called the CONFIRM trial (NCT01239082), which aims to enroll 50,000 average-risk veterans to either initial screening colonoscopy or annual stool testing with FIT. To date, CONFIRM has randomized over 42,000 participants and will likely complete enrollment this year. Unfortunately, assessment of the primary outcome (CRC mortality) will take another decade or so. But the results of a head-to-head study like CONFIRM may one day determine the best test for screening.

In the interim, providers should have no hesitation recommending FIT to their patients as a primary screen for CRC. The test is simple and safe, and RCT-level evidence supports its use. Given what we know, those advising patients about screening should follow the guidance of the USPSTF, offer options and encourage their patients to choose the test they are most likely to complete. When given options, I suspect many will be attracted to a safe and effective test like FIT. Until large-scale trials convince us otherwise, we should all feel good about that decision.

Dr. Robertson serves on the advisory board of Medtronics.

The contents of this work do not represent the views of the Department of Veterans Affairs or the U.S. Government.

References

1. Hewitson, P., Glasziou, P., Irwig, L., Towler, B., Watson, E. Screening for colorectal cancer using the faecal occult blood test, Hemoccult. Cochrane Database Syst Rev. 2007 Jan 24; (1): CD001216.

2. Robertson, D.J., Lee, J.K., Boland, C.R., 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. Am J Gastroenterol. 2017 Jan; 112(1): 37-53.

3. Lee, J.K., Liles, E.G., Bent, S., Levin, T.R., Corley, D.A. Accuracy of fecal immunochemical tests for colorectal cancer: systematic review and metaanalysis. Ann Intern Med. 2014; 160: 171.

4. Adler, J., Robertson, D.J. Interval colorectal cancer after colonoscopy: exploring explanations and solutions. Am J Gastroenterol. 2015; 110: 1657-64.

5. Cooper, G.S., Xu, F., Barnholtz Sloan, J.S., Schluchter, M.D., Koroukian, S.M. Prevalence and predictors of interval colorectal cancers in Medicare beneficiaries. Cancer. 2012; 118: 3044-52.

6. US Preventive Services Task Force. Screening for colorectal cancer: US preventive services task force recommendation statement. JAMA. 2016; 315: 2564-75.

7. Sharaf, R.N., Ladabaum, U. Comparative effectiveness and cost-effectiveness of screening colonoscopy vs. sigmoidoscopy and alternative strategies. Am J Gastroenterol. 2013; 108: 120-32. 

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