Aspirin dec colorectal cancer, if less healthy lifestyle

 A recent large prospective epidemiologic assessment found that taking aspirin decreased the incidence of colorectal cancer in people with less healthy lifestyles (see aspirin dec colorectal cancer JAMAonc2024 in dropbox, or doi:10.1001/jamaoncol.2024.2503)

 

Details:

-- 63,957 women from the Nurses’ Health Study (female nurses aged 30-55, from 1980-2018) and 43,698 men from the Health Professionals Follow-up Study (males aged 40-75, from 1986-2018), a total of 107,655 study participants, were assessed with data analyzed from 2021-2023

    -- participants completed biennial questionnaires that included validated assessments of diet, lifestyle factors, medication use, and disease outcomes (including colorectal cancer: CRC), and had a 90% available person-time follow-up. The dietary intake was from a self-reported semiquantitative food frequency questionnaire every four years (dietary quality was defined as adherence to the six recommendations by the World Cancer Research Fund and the American Institute for Cancer Research Third Expert Report for intake of red meat, processed meat, dietary fiber, dairy products, whole-grain, and calcium supplements)

    -- a healthy lifestyle score was based on BMI of 18.5-25, never smoking or past smoking of less than five pack-years, no-to-moderate alcohol intake (allowing up to one drink for women and two drinks for men per day), moderate-to-vigorous physical activity of at least 30 minutes per day, and meeting at least three of six dietary recommendations per the above society guidelines

    -- this healthy lifestyle score was calculated based on BMI, alcohol intake, physical activity, diet, and smoking (scores ranged from 0-5, with one point for a healthy lifestyle for each of the 6 items)

-- mean baseline age 49 years (overall for the study had average of 63 years), 96% white, 85% of women were postmenopausal

-- family history of CRC in 16%, recent endoscopy 40%

-- BMI 26, current smoking 10%, past smoking 50%, cigarette pack-years 20, alcohol intake 10 g per day, physical activity 30 minutes per day

--dietary: red meat five times per week, processed meat two times per week, dietary fiber 20 g per day, dairy products nine servings per week, whole grains 20 g per day, calcium supplement 45%

    -- these last two lines are averages: many of these numbers varied dramatically over the 6 lifestyle score cohorts

-- regular aspirin use was defined as at least two 325 mg aspirin tablets per week, or at least six 81-mg tablets per week

-- multivariable models were adjusted for individual components of the lifestyle score, history of CRC in first-degree relatives, and endoscopic screening in the past two years

-- main outcomes: multivariable adjusted 10-year cumulative incidence of colorectal cancer, the absolute risk reduction (ARR) for CRC, and the number-needed-to-treat (NNT) of patients to avoid CRC in those taking regular aspirin stratified by lifestyle score, and the multivariable-adjusted hazard ratios for incident CRC across lifestyles

  

Results:

-- in the 3,038,215 person-years of follow-up:

    -- 41% were regular aspirin users

    -- 2544 incident cases of CRC were documented

-- 10-year cumulative CRC incidence:

    -- aspirin users: 1.98% (1.44%-2.51%)

    -- nonaspirin users: 2.95% (2.31%-3.58%)

        -- ARR: 0.97%

-- 10-year ARR assessment based on lifestyle scores:

    -- lifestyle score of 0-1 (least healthy): 1.28%

    -- lifestyle score of 4-5 (healthiest): 0.11%

        -- gradient of benefit increased in those with the least healthy lifestyle scores, p<0.001

 

-- 10-year NNT with aspirin:

    -- lifestyle score of 0-1 (least healthy): 78 participants

    -- lifestyle score of 2: 164 participants

    -- lifestyle score of 3: 154 participants

    -- lifestyle score of 4-5 (healthiest): 909 participants

 

 

-- Assessment of the 20-year outcomes:

    -- multivariable-adjusted cumulative incidence of CRC had similar findings to the 10-year findings:

        -- aspirin users: 4.05% (3.13%-4.95%)

        -- nonaspirin uses: 5.56% (4.54%-6.55%)

    -- ARR:

        -- statistically significant gradient with increasing unhealthy lifestyle measures:

            -- lifestyle score 0-1: NNT 72

            -- lifestyle score 4-5: NNT 2500

 

-- Subgroup analysis by lifestyle score:

  

  -- most profound risk reduction was found for those with normal BMI and no smoking 

 

Commentary:

-- there were many studies in the 1970s and 1980s finding that aspirin, as well as a variety of NSAIDs, were associated with decreased colorectal neoplasia, ranging from colorectal polyps to cancer, typically finding a 20 to 30% CRC risk reduction (as was found in the current study)

-- the USPSTF included the benefits of aspirin for prevention of CRC in adults aged 50-59 in their 2016 recommendations for aspirin use to decrease atherosclerotic events

    -- however, the USPSTF rescinding the general recommendation for aspirin use for CRC prevention because of excess adverse effects, limiting their aspirin recommendations to aspirin for those at very high atherosclerosis risk (see https://jamanetwork.com/journals/jama/fullarticle/2791401)

 

-- it has clear for a long time that many lifestyle issues are associated with colorectal cancer, and observational studies have found benefit of a healthy diet and BMI, physical activity, avoiding cigarettes, and limiting alcohol in decreasing the incidence of CRC, though the specifics did vary some from one study to another

-- reported mechanisms for aspirin benefit include: inhibition of inflammatory signals that promote cellular proliferation and angiogenesis, and modulation of antitumor response (for more info, see https://doi.org/10.1016/j.bpg.2011.10.016)

 

-- this study found that regular aspirin users had in 18% relative risk reduction in the incidence of CRC compared to nonregular aspirin users, with similar relative risk reductions over the lifestyle scores (though the absolute risks was significantly lower in those with healthier lifestyles)

-- this study is particularly poignant given a few issues:

    -- CRC is not only a common cause of morbidity and mortality, but seems to be increasingly an issue for younger people: see https://gmodestmedblogs.blogspot.com/2024/04/colon-cancers-earlier-onset.html and https://gmodestmedblogs.blogspot.com/2024/08/earlier-age-of-onset-in-17-cancers.html

    -- as noted above, the USPSTF initially included CRC risk reduction attributable to aspirin use as part of their aspirin/ASCVD recommendations, but then rescinded the CRC indication after further assessment of the risks and benefits of aspirin in the general average-risk population

    -- this study confirms prior studies suggesting that there was a differential benefit of aspirin use by dietary factors, adiposity, and smoking

    -- so, it is not surprising that there would be an aspirin benefit that tracked with lifestyle issues

    -- it was notable in this study that the two most impressive determinants of aspirin benefit were in patients who had higher BMIs and history of smoking 

-- the strongpoints of this study include the fact that the observational studies included had more than 30 years of lots of granular data, and they were prospective and included continually updated risk factor assessments. In addition, the current study assessed absolute risk reduction for healthier lifestyles as defined above, and absolute risk reduction is our primary target in clinical care

 

Limitations:

-- these cohorts were from very narrowly-defined groups with pretty non-diverse populations that included people with a higher educational level and socioeconomic class and lower risks of many adverse health factors (relatively low levels of alcohol, smoking, consumption of processed meats) and in an overwhelmingly white population. this does limit the generalizability of their conclusions

-- there was no information on comorbidities/meds that might have played a role (diabetes, inflammatory bowel disease, personal history of breast/ovarian/uterine cancer, exposure to ionizing radiation, etc)

-- based on the clinical perspectives at the times of these studies, they did include some smoking and alcohol consumption as still being in the healthy lifestyle cohort

    -- this study did not provide information on the specifics of when patients actually stopped smoking or the tracking of alcohol intake over the time course of the study

    -- at this point we consider smoking cessation of at least 20-30 years to decrease atherosclerotic risk in smokers (https://gmodestmedblogs.blogspot.com/2024/01/smoking-cessation-20-30yrs-to-normalize.html), and zero alcohol intake to be the target  (https://gmodestmedblogs.blogspot.com/2023/11/alcohol-use-disorder-meds.html)

-- another issue is whether increasing use of statins might supplant the benefit of aspirin in those with unhealthy lifestyles. these individuals are at much higher risk of cardiovascular disease, and perhaps aggressive statin therapy (which, as with aspirin, is anti-inflammatory), targeting a much lower LDL level, might provide great benefit with low risk of adverse effects: https://gmodestmedblogs.blogspot.com/2018/08/very-low-ldl-levels-benefit-without-harm.html and https://gmodestmedblogs.blogspot.com/2021/12/ldl-less-than-40-in-high-risk-patients.html (the latter reviews the well-conducted Fourier study)

-- so, a few general comments:

    -- it is not surprising that by targeting the strong associations between lifestyle factors and colorectal cancer, there would be a pretty dramatic gradation of CRC risk in the general population

    -- this study suggests that the increased aspirin benefit in those with the less-healthy lifestyles may well overcome the well-described potential harms of long-term aspirin therapy

        -- but there does need to be clear-cut statistical evaluations to firmly assess this relative risk-benefit analysis

    -- one clear teaching point here regarding healthy lifestyles is that there does seem to be a gradation of risk, especially evident for smoking and BMI, which not only should reinforced the importance of smoking cessation and weight reduction, but also perhaps lower our threshold for aspirin prescription

        -- a side note here is that GLP-1 receptor agonists may well have positive effects in both decreasing weight as well as alcohol dependence and likely other addictions such as smoking: https://gmodestmedblogs.blogspot.com/2023/09/glp-1-receptor-agonists-for-alcohol.html and https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.15677

geoff

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