About half of U.S. citizens aged 45–75 years recently surveyed are taking aspirin daily or every other day, hoping to prevent stroke or a heart attack (Am. J. Prev. Med. 2015;48:501–7). But they may also be lowering their risk of gastrointestinal cancers, such as those of the colon, stomach, and esophagus.
Data presented at the American Association of Cancer Research annual meeting in April showed that long-term, regular use of aspirin reduced overall cancer rates by 5%, including a 25% reduction in colorectal cancer and a 14% decrease in esophageal cancers. Researchers collected data over 32 years from 82,600 women in the Nurses’ Health Study and 47,651 men in the Health Professionals Follow-up Study. Participants benefiting from the drug took two or more tablets (325mg each) per week for at least 16 years. Risk continued to decrease 4 years after stopping use.
Senior study author Andrew Chan, M.D., M.P.H., associate professor in the department of medicine at Harvard Medical School and a gastroenterologist at Massachusetts General Hospital Boston, is one of several researchers examining the aspirin–cancer link. Studies over the past two decades have yielded “overwhelming evidence for a reduction in colorectal cancer incidence and mortality from regular aspirin use,” according to Jack Cuzick, Ph.D. Cuzick is from the center for Cancer Prevention at Queen Mary University of London. He is the principal author of a meta-analysis in January’s Annals of Oncology on the benefits and harms of aspirin use. This is the latest of several recent reviews of aspirin use and cancer risks.
Combining data from about 60 observational studies, Cuzick found a 27% overall reduction in colorectal cancer (CRC) incidence. Similarly, two randomized trials with high-dose aspirin (300–1,500mg/day) reported a 37% reduction in CRC incidence after 10 years and three other randomized trials reported a 25% reduction in CRC incidence with 20-year follow-up and low-dose aspirin (75–300mg/day). The five randomized trials saw a 52% reduction in CRC mortality with at least 5 years of treatment.
Esophagus and stomach are two other sites where aspirin appears to offer protection. Cuzick cites data from randomized trials, which show a 58% reduction in mortality for esophageal cancer and a 44% mortality reduction in cohort studies. Observational studies report a statistically significant reduction in incidence of esophageal cancers. Although not as extensive as CRC, the results are consistent.
Likewise, statistically significant reductions in mortality and incidence of stomach cancer were seen in both randomized and cohort studies with aspirin use. Two observational trials reported a 41% lowering of mortality, whereas two others found a 39% and 25% reduction in stomach cancer incidence. Again, according to Cuzick, the data are neither as extensive nor as consistent as those for CRC.
Chan said he agrees that both randomized trials and observational studies show that aspirin use is associated with lower incidence of overall cancer and particularly colorectal cancer. “The difference,” he said, “is the impact on other types of cancer. Some of the randomized trials have seen an association of aspirin in reducing risk of other cancer types that are not in the [gastrointestinal] tract, such as breast cancer. The associations for these nongastrointestinal cancers have not been as strong in observational studies.” The other issue is dose, Chan said. “Most observational studies suggest that higher doses are more strongly associated with lowering rates of cancer, whereas in randomized trials it looks like even low doses are as effective.”
One example of this is the Woman’s Health Study, which reported a 43% lower colon cancer risk in women taking 100mg of aspirin every other day for 10 years (Ann. Intern. Med. 2013;159:77–85).
The U.S. Preventive Services Task Force is sifting through all these data to decide whether to recommend routine use of aspirin to prevent cancer in the general population. In 2007, the task force recommended against regular aspirin use to prevent colon cancer, saying that the harms outweighed the benefits. An updated recommendation is expected this year.
The harms are fairly well documented: Aspirin increases incidence of gastrointestinal bleeding, as well as of hemorrhagic stroke and peptic ulcer. The most serious side effect, hemorrhagic stroke, is potentially fatal but also rare. Bleeding is the most common side effect. And according to the task force, age and sex are the most important risk factors for bleeding: Bleeding increases particularly after age 70 years, and men are twice as likely to experience gastrointestinal bleeding as women.
Chan is cautious about how likely it is that the task force will make a broad recommendation about routine aspirin use, since large randomized clinical trials of aspirin and cancer with long enough follow-up have not occurred. Such trials are typically the evidence that the task force requires to make widespread public health recommendations. Most of the data are either from observational trials, which cannot reliably prove cause and effect, or from randomized trials that study cardiovascular disease, not cancer.
Unfortunately, at least in the U.S. he worries that doing such a randomized prevention trial is almost impossible now, not only because of cost and time but also because many people already take aspirin. Thus, ethically randomizing people to aspirin therapy is hard. “I think we need to think about making recommendations within the context of imperfect evidence.”
Asad Umar, D.V.M., Ph.D., chief of the gastrointestinal and other cancers research group at the National Cancer Institute’s division of cancer prevention, said he sees the need to clarify which doses have the best risk–benefit profile and how these profiles change with age.
Despite these shortcomings, both he and Nancy Cook, Sc.D., of Brigham and Women’s Hospital and professor of medicine at Harvard Medical School in Boston, think that that the Preventive Task Force might recommend routine aspirin use. Cook said it might recommend aspirin for certain high-risk people—those with a family history of colorectal cancer or a history of polyps.
“There’s a lot of controversy about whether aspirin should be used,” Cook said. “There are benefits for cardiovascular disease in those at high risk, but the incidence of CRC is not very high and there are also harms of bleeding, peptic ulcer, or GI hemorrhage. However, hemorrhagic stroke or serious GI hemorrhaging that requires hospitalization are rare and are probably outweighed by the benefits. And peptic ulcer or other bleeding is not necessarily life-threatening. It’s not clear how to weigh these various factors.”
One option that Peter Rothwell, M.D., Ph.D., F.R.C.P., of England’s University of Oxford, suggested in his recent review (Curr. Opin. Oncol. 2014;26:441–7) is to recommend aspirin use between the ages of 50 and 70 years, when the risk of bleeding is lower. He added that trials show that the incidence and mortality due to cancer would be reduced for at least another 10 years after stopping.
Richard Wender, M.D.
Rothwell also pointed out that aspirin improves the outcome and reduces metastases in patients who develop cancer while taking aspirin. Researchers have seen this effect for several tumor types, indicating that aspirin may be useful as a treatment option.
So while the risk and dosage issues are being sorted out, researchers are proceeding with trials to test aspirin in various treatment settings. The ASCOUT trial, for example, is enrolling patients recently treated for colon cancer to see whether 200mg of aspirin every day for 3 years will improve survival. The Add-Aspirin program is recruiting breast, colorectal, esophageal, and prostate cancer patients to test whether either 300 or 600mg of daily aspirin will improve survival. Another trial, AspECT, is enrolling 2,500 people with Barrett esophagus to see whether aspirin added to an acid reflux drug used to treat this condition will reduce risk of esophageal cancer. (Clinicaltrials.gov lists more than 100 trials for aspirin and cancer.)
While treatment trials progress, Chan said he believes that researchers now need to better understand individual factors that help predict which patients are more likely to benefit from aspirin use as well as which patients are more likely to experience complications such as bleeding.
To get closer to that answer, Chan led a team looking for clues in DNA that could predict whether someone may respond to aspirin for chemoprevention. When they compared the genetic composition of about 8,600 people with colon cancer to that of the same number without the disease, nearly all individuals using aspirin had a 30% reduction in CRC risk. But a small percentage of people with specific gene mutations on chromosomes 12 and 15 (5%–9%) were either not protected from developing CRC or had an increased risk of developing the disease. These mutations, single-nucleotide polymorphisms, were near two genes, MGST1 and IL16. Both genes may be involved in mediating inflammatory responses, one mechanism by which aspirin is thought to act. The participants were from 10 large cohorts in United States, Canada, Australia, and Germany (JAMA 2015;313:1133–42).
Validating these findings with a larger follow-up study could have a tremendous influence on which subset of the population would benefit from aspirin use and which would be harmed. “This study puts us a step closer to being able to deliver preventive interventions to people more likely to benefit while withholding interventions from individuals with little likelihood of benefit or even risk of harm,” wrote Richard Wender, M.D., of Thomas Jefferson University in Philadelphia, in an accompanying editorial.