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Update on the Role of Low-Dose Aspirin in Colorectal Cancer Prevention


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Updating its 2016 recommendation on the use of aspirin to prevent cardiovascular disease and colorectal cancer, the U.S. Preventive Services Task Force (USPSTF) issued a draft recommendation statement. It noted the potential harms of daily aspirin, with the most serious being bleeding in the stomach, intestines, and brain; advised against starting aspirin use after age 60; and included other changes in the use of aspirin to prevent cardiovascular disease.

Unlike the 2016 final statement, the new draft statement does not, however, include a recommendation on the use of aspirin to prevent colorectal cancer. Following a review of new trial evidence and additional analyses of previous data, the USPSTF “concluded that the evidence is inadequate that low-dose aspirin use reduces colorectal cancer incidence or mortality.”1


“Because the risks of bleeding are much lower in younger patients, there may be an optimal window in which aspirin could make sense and be an appropriate complement to screening.”
— Andrew T. Chan, MD, MPH

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That assessment was disputed by Andrew T. Chan, MD, MPH, a gastroenterologist, Director of Epidemiology at Massachusetts General Cancer Center, and Professor of Medicine at Harvard Medical School. “The data are quite compelling supporting the use of aspirin,” Dr. Chan said in an interview with The ASCO Post. “Looking back, the recommendation statement of 2016 was a milestone for cancer prevention—recognition of the compelling data supporting the use of aspirin to reduce colorectal cancer risk. At the time, the task force incorporated very convincing evidence of benefit found in clinical trials of individuals with colon polyps, which are common and a risk factor for colon cancer, and individuals with hereditary colon cancer. Unfortunately, the 2021 draft guidelines from the USPSTF disregarded those studies; I think that was a mistake because they do provide very compelling evidence of cancer preventive effects.”

Younger Populations

Although the 2016 USPSTF recommendation in favor of aspirin use referred primarily to those aged 50 and older, Dr. Chan said, “it is possible that aspirin might be more beneficial in a younger population. We know people younger than 50 are already starting to develop colon polyps, which predispose them to developing a future cancer.”

Because “the risks of bleeding are much lower in younger patients, there may be an optimal window in which aspirin could make sense and be an appropriate complement to screening. This could have an impact that would be important for a lot of individuals and their families,” he added.

Dr. Chan continued: “We are seeing this alarming increase in early-onset colorectal cancer. Although we have started to nudge the screening age down to address this, we clearly can’t screen everybody. We simply don’t have the resources, and not everybody at a young age wants to be screened. We need other tools for cancer prevention, particularly in younger populations, to address some of these alarming epidemiologic trends.”

Dr. Chan considers the USPSTF’s statement about the inadequacy of the data to support the use of aspirin to prevent colorectal cancer “misleading and potentially damaging to progress in identifying appropriate candidates for using a drug like aspirin.” He pointed out there have been a multitude of studies “with vitamins and nutritional agents, and other drugs to prevent cancer, and none of those drugs have had the track record of studies supporting its effect” aspirin has. Aspirin “also has a long-standing body of literature regarding its safety profile and benefits from the familiarity that patients and clinicians have with its use. Instead of completely disregarding its potential as a cancer preventive, we need to refocus our efforts on making sure that aspirin remains an option for the right patients,” Dr. Chan stated.

Different Results Among the Elderly

In 2018, the primary analysis of the ASPREE trial found that after 5 years, the risk of death from any cause in elderly participants was higher among those randomly assigned to receive low-dose (100 mg) aspirin daily than those randomly assigned to receive placebo. “Cancer was the major contributor to the higher mortality in the aspirin group,” the authors reported.2 The authors also noted that previous studies “have shown a protective effect of aspirin on cancer-related death,” although those studies include small numbers of people aged 70 and older. In addition, the ASPREE study follow-up “may have ended before the possible emergence of a preventive effect on cancer.”

Most of the participants in the ASPREE trial had not used aspirin regularly before joining the study. “It is not necessarily surprising that there was a different result seen in that population. Starting aspirin at that age may be too late to enjoy its benefits. And there are a lot of other health issues and confounding factors in those individuals that could counteract the benefits of aspirin,” Dr. Chan noted.

A more recent study led by Dr. Chan aimed to address the question of whether taking aspirin after the age of 70 is not a good idea and does it matter when you first start taking it? A pooled analysis of two cohort studies, with a total of 94,540 patients and data on their aspirin use over some 35 years, came to the following conclusion: “Those who used aspirin before age 70 and continued into their 70s or later had a reduced risk of colorectal cancer,” but “initiating aspirin at an older age was not associated with a lower risk of colorectal cancer.”3

Tuning Into Nuances

“There is nuance there,” Dr. Chan told The ASCO Post. “It may be that when you start taking aspirin earlier, there may still be benefit long term. That is the kind of nuance that the USPSTF was not able to address by focusing on making recommendations for very broad populations yet basing those guidelines on the results of very narrowly defined populations treated in a very specific way through clinical trials.”

“What the USPSTF is challenged to do is to try to provide broad-based recommendations,” Dr. Chan said. Although the task force works “to tailor its recommendations on factors such as age,” he acknowledged, “even these categories are still relatively blunt instruments to risk-stratify” and “may not optimally predict who is going to benefit from an agent for cancer prevention.”

Ongoing Research

“The doses of aspirin that have been shown to be associated with lower colorectal cancer risk have been as low as 81 mg of aspirin a day,” Dr. Chan noted. “There is the possibility that standard doses of aspirin, for example a 325-mg tablet, may be more effective. That is an open question. The data suggesting there is a major difference in bleeding rates between the two doses, particularly in younger people, are not compelling. Since the bleeding rates may not be significantly higher, the greater benefits of higher doses may offset,” Dr. Chan said, but additional clinical trials are needed to further study the risks and benefits of standard-dose aspirin.

A new clinical trial launched by Dr. Chan’s group is looking at aspirin use on cancer-related biomarkers in patients aged 65 and older with a history of polyps. The goal, he noted, is “to see whether there are differences in some biomarkers related to cancer risk.” Funded by the National Cancer Institute, the ASPIRED-XT trial is expected to open in early 2022.

“We are also doing additional experimental laboratory work to understand whether there are mechanistic differences in the effect of aspirin in preclinical models,” Dr. Chan explained. The clinical and laboratory work “will hopefully help us better understand the mechanisms by which aspirin may prevent cancer. Understanding the mechanism, and whether that mechanism differs in younger adults vs older adults, will be important in terms of helping us stratify people for use of the drug, potentially through biomarkers,” Dr. Chan commented.

“There is plenty of optimism going forward for the field of cancer prevention,” Dr. Chan remarked, “and we want to be able to deliver the message to the general population that we shouldn’t throw out a potentially effective agent simply because we are not able to make a sweeping recommendation. That shouldn’t nullify its potential for continued investigation into its appropriate use.” 

DISCLOSURE: Dr. Chan has served as a consultant to Pfizer, Bayer AG, and Boehringer Ingelheim.

REFERENCES

1. U.S. Preventive Services Task Force: Aspirin use to prevent cardiovascular disease: Preventive medication. Available at www.uspreventiveservicestaskforce.org/uspstf/draft-recommendation/aspirin-use-to-prevent-cardiovascular-disease-preventive-medication#bootstrap-panel--6. Accessed November 9, 2021.

2. McNeil JJ, Nelson MR, Woods RL, et al: Effect of aspirin on all-cause mortality in the healthy elderly. N Engl J Med 379:1519-1528, 2018.

3. Guo CG, Ma W, Drew DA, et al: Aspirin use and risk of colorectal cancer among older adults. JAMA Oncol 7:428-435, 2021.


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