FIT testing dec colorectal mortality

 a recent Taiwanese study found that biennial fecal immunochemical test (FIT testing) led to large reductions in both advanced colorectal cancer (CRC) and deaths from CRC (see colon ca screening FIT dec mortality gut2021 in dropbox, or doi. org/ 10. 1136/gutjnl- 2020- 322545).

Details:

--nationwide prospective study of 5,417,699 people aged 50-69 invited for screening from 2004-9, with follow-up until 2014

--3,067,853 had at least one FIT screen and 2,349,846 did not receive any

    --1,065,200 had at least 2 rounds of FIT tests

--overall screening rate was 57%

--those with positive FITs were referred for colonoscopy within 3 months

    --70% of FIT-positive subjects had diagnostic screening, 90% of which was colonoscopy

--advanced stage CRC was defined as stage II+

--a total of 6756 CRCs were diagnosed on the first screen and 3118 on subsequent rounds (ie, detection rate of about 2/1000 FITs)

Results:

--FIT testing, comparing those screened to the rest of the population, was associated with:

    --incidence of advanced stage CRC: 34% reduction, aRR 0.66 (0.63-0.70), absolute rate 48.4 vs 75.7/100,000

    --CRC mortality: 40% reduction, aRR 0.60 (0.57-0.64), absolute rate 20.3 vs 41.3/100,000

--effect on distal CRC:

    --incidence of advanced stage CRC: 39% reduction, aRR 0.61 (0.58-0.64), absolute rate 32.3 vs 55.6/100,000
    --CRC mortality: 44% reduction, aRR 0.56 (0.53-0.69), absolute rate 13.7 vs 30.4/100,000

--effect on proximal CRC:

    --incidence of advanced stage CRC: 16% reduction, aRR 0.84 (0.77-0.92), absolute rate 15.7 vs 19.6/100,000
    --CRC mortality: 28% reduction, aRR 0.72 (0.66-0.80), absolute rate 6.5 vs 10.6/100,000

Commentary:

--this large prospective national study found impressive decreases in advanced CRC and CRC mortality by FIT testing every 2 years. The confidence intervals were quite narrow, typical in such a large study but further affirming the actual benefit of the intervention

    --they did attempt to control for several biases, including a self-selection bias (were those volunteering to be screened different from the ones who did not?) and the quality of the colonoscopy (eg the cecal intubation rate). And the study was based on a huge population of people with 10 years of follow-up. all adding to its validity

--CRC mortality is the 3rd leading cause of death worldwide, 1,096,000 new cases of colon cancer and 704,000 of rectal cancer in 2018, combined being 11% of all cancers (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791134/ )

    --there is large variation by countries, highest in Australia/New Zealand at 41.7/100K, decreasing some in Europe to about 35/100K, then down to about 7-8/100K in Africa, perhaps related to many of the "modifiable" risk factors of obesity/physical inactivity, diet (esp red and processed meats), smoking, alcohol, and microbiome changes (antibiotics can be associated with gut microbiome changes leading to colonic adenomas: see http://gmodestmedblogs.blogspot.com/2017/04/antibiotics-microbiome-changes-and.html )

    -- overall, there is a uniform increase in CRC cases that tracks with economic development

--there does seem to be important differences between right- and left-sided colonic cancers: several studies have found that excision of colonoscopy-discovered right colonic lesions (i.e. beyond the reach of the sigmoidoscope) do not affect mortality (eg see colonoscopy right sided lesions not helped AIM2009 in dropbox, or Baxter NN. Ann Intern Med 2009; 150:1).

    --some suggest that the left-sided ones may not bleed as easily as right-sided ones (and do so mostly when they are bigger and more advanced) and therefore would not be picked up patients/clinicians at an earlier and potentially treatment stage.

    --or perhaps the level of colonoscopy completeness is different, more likely to be less complete the higher up they go. but this study did control for the quality of the colonoscopy by assessing cecal intubation rate (and this study did find better FIT effectiveness when taking cecal intubation rate into account)

    --or maybe there are fundamental differences in tumor biology: perhaps proximal tumors actually grow faster and there needs to be more frequent FIT testing to pick them up early enough. this could be simply figuring out how to get people back for subsequent screens, since only 1/3 of the screened group in the above study had more than one screen

    --some studies have found that proximal lesions are more likely to be sessile serrated adenomas/polyps; these are more frequently missed by both FIT and colonoscopy (which again might suggest that more frequent FIT testing might be advantageous)

    --or perhaps there is more blood degradation as it moves the longer distance from the proximal colon to the rectum, esp since adenomas bleed less than cancers. so FIT testing might be more likely to miss proximal adenomas.

    --though a surprising finding above was that the apparent protection from CRC mortality was almost twice the benefit of advanced CRCs. not sure how to explain that one.

Limitations

--this was not an RCT, and there might have been fundamental differences between the cohort being screened and those not. 

    --most importantly, this study did not give any information about the distribution of CRC risk factors (including the modifiable ones noted above), and there might have been a difference in the two groups in terms of diet, exercise, smoking, etc

--there was a significant fall-off from the number of people in the initial screen group to those getting subsequent screens by about 2/3. so, hard to know if actually doing screening every 2 years would have been optimal to pick up adenomas or early CRCs

--this was a 10-year study, which is great, but given the anticipated progression of early adenoma to CRC is in the 10-15 year range, it is likely that the benefit would be more significant in a longer study

    --some studies have suggested it takes an average of 17 years from adenoma to carcinoma, though it does seem that this is not always a linear progression, and some "interval cancers" may occur more rapidly, perhaps related to epigenetic changes that may add to the genetic alterations in the tumors and accelerate malignant transformation: see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859121/ 

so, another affirmation that FIT testing is an appropriate and effective screening test with a 2-year interval for screenings (see blogs below: this 2-yr interval is the most recent recommendation by the American College of Physicians, with input from many different national and international organizations)

--but we really do need to figure out ways to make sure people are screened regularly. and perhaps this is better done not by clinicians, who are typically swamped with addressing the patients' often many difficult medical and/or psychosocial issues, but by public health people or others working with clinicians in population management

--and, patients should understand that healthy eating, exercise, not smoking, not drinking, and maintaining appropriate BMI are important for preventing colon cancer (as well as a myriad of cardiorespiratory diseases (eg see http://gmodestmedblogs.blogspot.com/2017/01/leisure-time-activity-and-lower-cancer.html )

    --i am always a bit concerned that the focus on screening for cancer may undercut the bigger message about how important it is to help patients develop a healthier lifestyle (and, it is easier/less time-consuming to just order a test than to engage in motivational interviewing to help patients change their lifestyle.....)

other relevant blogs:

http://gmodestmedblogs.blogspot.com/2019/11/colon-ca-screening-per-acp.html a review of the Am College of Radiology, the Canadian Task Force on Preventive Health Care, USPSTF, Am Cancer Society, Scottish Intercollegiate Guidelines Network, and the US Multi-Society Task Force on Colorectal Cancer, with some upgraded recommendations, such as FIT testing every 2 years (had been yearly), and a hint that the lower age for screening should be <50yo (which is quite reasonable per the shifting incidence to younger people), but these recommendations do not commit to that.

http://gmodestmedblogs.blogspot.com/2016/02/colorectal-screening-canada.html with the Canadian recommendation for FIT every 2 years and not to use colonoscopy for screening

http://gmodestmedblogs.blogspot.com/2017/12/fit-testing-long-term-study.html , a long-term huge Italian study on FIT testing every 2 years with apparently pretty equivalent CRC/advanced adenoma pickup as with primary colonoscopy

geoff

 

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