normal colonoscopy can wait >10yrs if low risk

 

A recent study found that low-risk people with negative colonoscopy screening may well be able to wait more than 10 years before a repeat colonoscopy, and those at higher risk perhaps should be rescreened sooner than 10 years (see colon ca screening inc colo interval if low risk JAMAOnc2024 in dropbox, or doi:10.1001/jamaoncol.2024.5227)

 

Details:

-- 3 prospective US population–based cohorts from the Nurses’ Health Study (121,000 registered female nurses aged 30-55), Nurses’ Health Study II (116,429 registered female nurses aged 25-42), and Health Professionals Follow-up Study (51,529 male health professionals aged 40-75) were followed up from 1988 and 1991 to 2020

    -- participants were mailed a biennial questionnaire that inquired about detailed medical and lifestyle information, including history of endoscopic examinations and diagnosis of CRC (colorectal cancer) and polyps

        -- participants were asked biennially whether they had undergone a colonoscopy in the past 2 years

        -- there were specific questions regarding the colonoscopy screening, if done, including whether it was conducted for routine screening or because of a family history of CRC, and if there was a finding of any polyp (including hyperplastic polyps) or CRC findings.

        -- a negative colonoscopy screening (NCS) was defined as no presence of CRC or polyps

    -- diet was assessed by a validated food frequency questionnaire, every fourth year

    -- individuals excluded from the analysis included those with a history of cancer (except nonmelanoma skin cancer), ulcerative colitis, had missing information on CRC risk factors, or a BMI <18.5

-- data from the National Health and Nutrition Examination Survey (NHANES) from the 2017-2019 cycle were used (the most recent cycle prior to covid) to compare the risk profile distribution with that of the general US population

   -- the high-risk CRC profile score is a composite of a history of first-degree relatives with CRC, cigarette smoking, BMI, tall stature, physical inactivity, alcohol consumption, no regular use of aspirin or nonsteroidal anti-inflammatory drugs, unhealthy diet, age, and sex.  Each one of these variables has a score of 1 if it makes their criterion cutpoint, or 0 if not, except for age which has a score ranging from 0-3 (reflecting the linear relationship between age and CRC risk).  Hence, the total score is from 0-12, with a higher score indicating higher CRC risk. some of these risk factors were continuous (eg tall stature, alcohol intake, BMI, physical activity) and some binary (smoking, use of aspirin/NSAIDS 2 tablets or more/week). more info on the cutpoints of these individual risk factors is in the comments under the graph below

-- all individuals with CRC diagnoses reported on the biennial CRC questionnaires had their medical records accessed to confirm the diagnosis; all deaths were identified through the National Death Index or reports from next-of-kin family members

 

-- a total of 195,453 participants were analyzed

    -- baseline median age 44; 81% female; 94% white

    -- BMI 25, ever-smokers 35% with mean of 14 pack-years, alcohol 2 g/d (ie average of 1 standard drink/week), physical activity 18 MET-h/wk, use of aspirin or NSAID at least 2x/week in 37%

    -- diet in servings/d: red meat 0.5, processed meat 0.1, dietary fiber 19g, dairy 1.8, whole grains 6

-- overall risk scores: 0-5 in 72% not having endoscopy/49% having; 6-7 in 23% not having/40% having; 8-12 in 5% not having and 11% having

 

-- main outcome: incidence and mortality from colorectal cancers (CRCs) 

-- followup data extended up to 32 years in these 3 large US cohort studies

-- overall follow-up achieved in >90% for all three cohorts

 

Results:

-- 81,151 individuals had NCS (negative colonoscopy screening) results and 114,302 did not have endoscopy (colonoscopy), after median followup of 12 years:

    -- incident CRC cases:

        -- NCS result: 394 cases

        -- No endoscopy: 2229 cases

            -- 49% decrease over the entire followup in those with NCS results vs no endoscopy, HR 0.51 (0.44-0.58), per adjusted model

                -- at 5 years: 41% decrease, HR 0.59 (0.36-0.95)

                -- at 20 years: 47% decrease, HR 0.53 (0.45-0.63)

    -- CRC deaths:

        -- NCS result: 167 deaths

        -- No endoscopy: 637 deaths

            -- 44% decrease over the entire follow-up in those with NCS results, HR 0.56 (0.46-0.70) per adjusted model

                -- at 5 years: 59% decrease, HR 0.41 (0.13-1.32)

                -- at 20 years: 42% decrease, HR 0.58 (0.43-0.78)

    -- of note, those individuals with NCS results had a higher prevalence of family history of CRC, were more physically active, and consumed more alcohol, fiber, and whole grains

 

-- CRC incidence by site of cancer, over entire follow-up:

    -- proximal colon cancer: 175 vs 744 cases, 32% decrease, HR 0.68 (0.56-0.84)

    -- distal colon cancer: 64 vs 639 cases, 66% decrease, HR 0.34 (0.35-0.46)

    -- rectal cancer: 58 vs 533 cases, 59% decrease, HR 0.41 (0.30-0.56)

        -- ie, those with distal and rectal cancers had the largest reduction in CRC incidence vs those with proximal cancers (see below)

-- CRC incidence, by CRC risk score: 

 

-- a few comments on this graph, per the 10-year CRC incidence (the currently recommended time for rescreening colonoscopy):

    -- those with the lowest risk after NCS required 1111 patients to be rescreened with colonoscopy to yield one new case

    -- those at intermediate risk after NCS required 169 patients to be rescreened with colonoscopy to yield one new case

    -- those with the highest risk after NCS required only 45 patients to be rescreened with colonoscopy to yield one new case

        -- this all translates to: those with NCS results at initial colonoscopy, if they had a low vs high risk score:

            -- CRC incidence: decreased 72%, HR 0.28 (0.21-0.37)

            -- CRC mortality: decreased 79%, HR 0.21 (0.13-0.32)

                -- and, no difference by site of tumors 

        -- and this translates to appropriate screening interval to repeat colonoscopy, by risk strata:

            -- those having low risk: 25 year hiatus on average

            -- those  having intermediate risk: 16 year hiatus on average

-- as a perspective here, the SEER data from 2013-2025 (Surveillance, Epidemiology, and End Results Program) basically confirmed these results: 

    -- neither the low- nor intermediate-risk groups reached the 10-year risk for CRC incidence expected by SEER

        -- the intermediate risk group required 16 years to reach the SEER CRC incidence expectation

        -- the low risk group required 20 years to reach the SEER CRC incidence expectation

        -- the high risk group: 7 year hiatus on average (and the graph above from this study does show much higher CRC risk beginning after about 5-7 years)

 

Commentary:

--Colorectal cancer is the third most commonly diagnosed cancer for both men and women, with substantial evidence that cancer screening reduces both the incidence and mortality of CRC

    -- Data from the American Cancer Society has found that the CRC incidence rates over the last decade have been stable for women but have an annual decline of 1.4% in cancer death rates; for men CRC incidence rates declined 2%/year and the cancer death rate declined 1.8%: https://acsjournals.onlinelibrary.wiley.com/doi/10.3322/caac.21551

-- There is pretty clear evidence in 4 randomized trials that sigmoidoscopy decreases CRC incidence and mortality significantly.  There have been no real randomized controlled studies to date comparing colonoscopy to no screening, however assuming that colonoscopy is providing the same benefit as sigmoidoscopy in the distal colon for CRC incidence and mortality, performing colonoscopy over sigmoidoscopy appears to yield only a marginal benefit compared to what was achieved by doing sigmoidoscopy versus no screening (see colon ca screening colo vs sigmoidosc JAMA2024 in dropbox, or https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2815644)

    -- one explanation regarding the marginal benefit of colonoscopy is that finding and treating right-sided colon cancer may be much less beneficial than finding and treating left-sided lesions, for a variety of potential reasons, both technical and biological:

https://gmodestmedblogs.blogspot.com/2022/11/colonoscopy-does-decrease-colon-cancer.html

    -- and this study also found a much lower colonoscopy benefit for right-sided lesions as well.

-- Current guidelines in both the US and Europe recommend rescreening colonoscopies at 10 years in those with negative initial exams and are at average colon cancer risk, based on our understanding of the natural history of the adenoma-carcinoma sequence

 

-- there have been several studies over the past decade or so that have found that those individuals with NCS (without risk stratifying) as a group have a quite low risk of developing colorectal neoplasia and CRC during an interval of up to 20 years

    -- However only 2 of these many studies had a followup of over 17 years

-- This study with its long follow-up of the large number of patients adds a lot to the argument of potentially extending follow-up in those with NCS:

    -- as noted above, there was a very dramatic difference in anticipated CRC cases in patients with a negative screening colonoscopy by risk stratifying them, with a projected need for rescreening in 16 years for the intermediate group and 25 years for the low risk group

    -- these findings were similar to those of the NHANES cohort of low risk individuals, and the SEER results, as noted above

 

-- These findings provide evidence for shared decision-making between patients and physicians to consider extending the rescreening intervals after an NCS result beyond the currently recommended 10 years, particularly for individuals with a low-risk profile. Specifically, these results showed, as a proof of concept, the importance of incorporating known CRC risk factors when making decisions for colonoscopy rescreening

-- one issue raised by these findings is that the new polyp follow-up guidelines recommend that those with 1-2 tubular adenomas <10mm have a repeat colonoscopy at 7-10 years (those with normal colonoscopy should have repeat in 10 years): https://gmodestmedblogs.blogspot.com/2020/11/colon-cancer-screening-updated.html . given that these recommendations are pretty similar here for NCS and a couple of small tubular adenomas, it would be very useful to have information on delaying repeat colonoscopy when stratified by risk score (though, i suspect there are not this type of granular data in the large retrospective studies.....)

-- a Chinese study also found that a risk-based approach led to a higher rate of colonoscopy screening and a higher yield of neoplasm detection: https://gmodestmedblogs.blogspot.com/2022/09/colon-ca-screening-risk-stratified.html

 

Limitations:

--this was an impressive large study of 3 well-respected cohort studies (from which lots of important epidemiological information has resulted). But, the actual medically-trained participants in these cohorts are not really reflective of the overall general populations and the results are not necessarily generalizable to them

    -- in particular, especially in a study assessing risk factors, this study was 81% female, 94% white, had a higher level of education than the general population and eat a healthy diet with low alcohol use (and CRC is an alcohol-related cancer)

    -- and though there is a clear relationship between the inflammation associated with inflammatory bowel disease and CRC, there is also a change in gut permeability and local inflammation associated with stress (which increases systemic inflammation: https://www.tandfonline.com/doi/full/10.1080/19490976.2024.2327409 ) and may well be associated with the development of cancer (https://pmc.ncbi.nlm.nih.gov/articles/PMC5238416/ ), depression (https://www.mdpi.com/1424-8247/16/4/565 ) and likely the array of social conditions associated with chronic inflammation (housing density, racial discrimination, air pollution, microplastics.......).  And these epidemiologic studies in this current study did not assess these psychosocial factors, and these are likely very different in the general population.

--though these long-term cohort studies had frequent updates on demographics/risk factors, it is not clear how they would integrate changes over time into the overall risk model. for example, a person who smoked for part of the time, stopped, perhaps restarted at a lower cigarette consumption... how would that fit into their binary categorization?? or perhaps they ate lots of junk food when they first entered the study, then changed to a healthy diet... would that be considered a healthy diet or not?

-- the risk scores of those having vs not having endoscopy (colonoscopy) were pretty different between the groups (those with risk scores of 0-5, 72% did not having endoscopy, with risk scores of 6-7 in 23% did not and in those with risk scores of 8-12, 5% did not). there could therefore be significant bias in the results regarding this. and there were significant differences in specific risk factors: eg alcohol intake was 2.5 g/d in those having the colonoscopy vs 1.6 g/d in those not having one. also differences in diet and exercise. These differences could bias the results, even with statistical adjustments, given the wide overall scope of the differences

-- one issue as commented on in prior blogs: death certificates are pretty inaccurate. as a primary care physician, i typically am the person required to fill out the death certificate of my patients. overall, i typically have no idea. was it a PE? heart attack? stroke? the underlying cancer? electrolyte abnormalities from the underlying chronic kidney disease? a fall and bleed? a drug reaction? too much alcohol or other drugs, suicide??????.  and, i suspect that there is likely a bias: those with known cancer may well be likely to have that put on their death certificate, even if actually not related to the death. i just guess about the cause of death and most often state it was from a cardiopulmonary event. even hospital-based deaths are not so accurate unless there is an autopsy done (which is pretty unusual nowadays). BUT, many studies rely on death certificates, as in the one above, and actual studies of causes of death have found them to be remarkably inaccurate: eg https://pmc.ncbi.nlm.nih.gov/articles/PMC7153801/ 

 

so, this study would argue that we should tailor subsequent colonoscopy screenings depending on the individual risk of patients and not rely on a fixed time interval:

    -- low risk patients who have a normal colonoscopy screening may be able to have an extended interval prior to the next colonoscopy, with only 1 in 1111 chance of developing an incident cancer; high risk patients have a 1 in 45 chances in 10 years.  the overall SEER baseline for a 10-year risk was 0.61% for developing CRC in those aged 50, though this study found by risk assessment:

        -- low risk individuals should be screened every 20 years per the SEER data (this study suggested 25 years)

        -- high risk individuals should be screened every 7 years per the SEER data and confirmed by the graph above (ie, high risk individuals with a normal colonoscopy at baseline should perhaps have another 7 years later and not the accepted 10 years)

-- and, as when applying data from large databases to individual patients, there will always be a range of individual responses, depending on the individual’s values regarding the positives of waiting:

        -- not a pleasant test, and potentially associated with the concern about colonic perforation being 0.005% to 0.687% and mortality of about 0.007% to 0.07% (around 2.9/100K colonoscopies), all of these bad outcomes increasing in the elderly and in those with inflammatory bowel diseases: https://pmc.ncbi.nlm.nih.gov/articles/PMC6337013/

        -- versus the attendant negatives of still having a chance (albeit much lower) of developing CRC if one waits. Hence, the importance of shared decision-making

-- There may well be other options to be considered as well, including follow-up of a normal screening colonoscopy with annual FIT testing in the low-risk group. and ??? in the intermediate risk group as well??. We need further studies to assess this.

 

geoff

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