New uses for an old drug

Latest research shows that aspirin may have value for the treatment or prevention of a wide range of cancers.

Felix Hoffman, a German chemist working for Bayer, formulated aspirin as it is currently understood in 1897 when he used salicylic acid to create acetylsalicylic.

The drug is a direct descendant of the willow bark and other salicylate-containing plants used for pain relief since the time of Galen and Hippocrates.

Now, it may possibly be used as a cancer treatment or chemopreventive agent.

Aspirin has shown the most promise in breast and colorectal cancers, but studies have also shown that the drug may treat or prevent prostate, lung, stomach and esophageal cancers.

Aspirin appears to reduce risk in some cancers by blocking expression of the cyclooxygenase-2 (COX-2) enzyme. A 2007 paper by Chan and colleagues showed aspirin reduced the risk for colorectal tumors that over-expressed COX-2 (RR=0.64; 95% CI, 0.52-0.78) but had no effect on tumors that did not express the enzyme or had weak expression (RR=0.96; 95% CI, 0.73-1.26).

Michelle D. Holmes, MD, DrPH, associate professor of medicine at Harvard Medical School and associate physician with Brigham and Women’s Hospital, said patients with breast cancer could realize huge benefits from an inexpensive drug such as aspirin. Photo courtesy of Michelle D. Homes

“One of the exciting and fascinating things that has been a constant issue in the whole story is that inhibition of COX does not seem to explain the chemopreventive effect of NSAIDs, at least not entirely,” said John A. Baron, MD, professor of medicine at the University of North Carolina School of Medicine. “So what is actually happening may not be as clear as it appears at first glance.”

Proving aspirin’s efficacy, especially as a prevative, could be extremely challenging, experts told HemOnc Today.

It is not clear exactly who might benefit from daily aspirin. Moreover, not all experts are convinced that aspirin provides a substantial overall benefit for patients.

In a 2010 interview with Cancer Research UK, Janusz Jankowski, MD, PhD, researcher for the Aspirin Esomeprazole Chemoprevention Trial (AspECT) exploring the efficacy of aspirin in esophageal and colorectal cancers, said only 20% to 25% of the population was likely to benefit. He added that researchers have not determined the ideal aspirin dose, and long-term aspirin use carries an increased risk for gastrointestinal bleeding, a risk that may be too great for physicians to safely recommend aspirin to healthy people as a cancer prevative.

If, however, researchers can show aspirin can treat or prevent cancer, the implications for oncology could be enormous.

Promise for colorectal cancer

Baron and colleagues conducted a randomized controlled trial showing that aspirin may be able to prevent colorectal adenomas. In that study, published in The New England Journal of Medicine in 2003, patients with a recent history of histologically documented adenomas were randomly assigned to placebo (n=372), 81 mg daily aspirin (n=377) or 325 mg daily aspirin (n=372).

At 12 months, 1,084 patients had follow-up colonoscopy. Incidence of one or more adenomas was 47% in the placebo group, 38% in the 81-mg group (RR=0.81; 95% CI, 0.69-0.96) and 45% in the 325-mg group (RR=0.96; 95% CI, 0.81-1.13).

For adenomas measuring at least 1 cm in diameter or with tubulovillous or villous features, severe dysplasia or invasive cancer, the RR was 0.59 (95% CI, 0.38-0.92) in the 81-mg group and 0.83 (95% CI, 0.55-1.23) in the 325-mg group.

Baron was part of a team of investigators that published results of a meta-analysis in 2009 of four randomized, double blind, placebo-controlled trials that evaluated aspirin for the prevention of colorectal adenomas. Each trial evaluated aspirin for the secondary prevention of colorectal adenomas. Daily doses tested ranged from 81 mg to 325 mg, and the average age of participants at baseline was 58 years.

At a median follow-up of 33 months, 2,698 participants had a follow-up colonoscopy. Researchers found adenomas in 37% of those assigned to placebo (n=1,156) vs. 33% for those assigned to any dose of aspirin (n=1,542). Twelve percent of participants in the placebo group had advanced lesions compared with 9% of patients assigned to any dose of aspirin.

The pooled RR for any adenoma for any dose of aspirin vs. placebo was 0.83 (95% CI, 0.72-0.96), corresponding to an absolute risk reduction of 6.7% (95% CI, 3.2-10.2). The pooled RR for any advanced lesion was 0.72 (95% CI, 0.57-0.90).

A 2007 article published in The Lancet by University of Oxford researchers Enrico Flossmann, MRCP, and Peter M. Rothwell, MD, PhD, included results of a meta-analysis showing that 300 mg aspirin per day for about 5 years was “effective in the primary prevention of colorectal cancer” with a latency of about 10 years. There was no similar effect at lower doses.

In 2010, Rothwell led a team that evaluated eight randomized controlled trials that included 25,570 patients. They found that daily aspirin was associated with a reduced risk for cancer death (OR=0.79; 95% CI, 0.68-0.92).

The benefits only appeared after 5 years of daily doses. The HR was 0.66 (95% CI, 0.50-0.87) for all cancers and 0.46 for gastrointestinal cancers (95% CI, 0.27-0.77).

John A. Baron

The 20-year risk for cancer death was lower in all aspirin groups compared with all control groups for solid cancers (HR=0.80; 95% CI, 0.72-0.88) and gastrointestinal cancers (HR=0.65; 0.54-0.78). The benefit increased along with scheduled duration of trial treatment.

The latent period before an effect on deaths was about 5 years for esophageal, pancreatic, brain and lung cancers but appeared later for stomach, colorectal and prostate cancers. For lung and esophageal cancer, the benefit was confined to adenocarcinomas (HR=0.66; 95% CI, 0.56-0.77).

There was no dose effect observed, and benefit was not associated with gender or smoking. The benefit associated with aspirin increased with age, with absolute reduction in 20-year risk for cancer death reaching 7.08% for those aged at least 65 years. The number needed to treat to prevent one cancer death was calculated to be less than 20 in this population. Those results only translate into a survival difference of 0.5% to 0.7% and a 0.5% difference in cancer rates.

Amanda I. Phipps, PhD, a postdoctoral research associate in the Public Health Sciences Division of Fred Hutchinson Cancer Research Center, was part of a research team that presented results at the 2011 AACR International Conference on Frontiers in Cancer Prevention Research.

An analysis of aspirin and nonaspirin NSAID use and colorectal cancer mortality among 160,143 women in the Women’s Health Initiative showed that women who reported aspirin use at baseline and again at 3 years had a reduced risk for disease-specific death compared with women who did not report aspirin use at both time points (HR=0.72; 95% CI, 0.54-0.95).

“Overall, there isn’t any difference in colorectal cancer mortality for women who do use these drugs vs. women who don’t,” Phipps said. “But when we look at that relationship a little bit more closely, when we consider the duration of use and the dosage of use, we find that women who are consistently using these drugs over prolonged periods of time do have a reduced risk for death. In women who used NSAIDs for at least 10 years, we find about a 36% lower risk of dying from colorectal cancer.”

There was no such effect observed with ibuprofen or prescription NSAIDs, she said.

Breast cancer evidence less clear

The evidence supporting the use of aspirin in breast cancer, for either treatment or prevention, is less strong.

However, some study results have suggested that aspirin could extend survival for women diagnosed with the disease.

Amanda I. Phipps

Michelle D. Holmes, MD, DrPH, associate professor of medicine at Harvard Medical School and associate physician with Brigham and Women’s Hospital, said the drug deserves a randomized trial to fully explore its potential.

“It could have huge implications for the developing world where women won’t be able to get drugs like Herceptin (trastuzumab, Genentech) any time soon because of the expense,” she said. “If it is true that something like aspirin or NSAIDs could decrease the risk for death in women with breast cancer, that would be of immense benefit to the whole world.”

In a 2008 study published in the British Journal of Cancer, Zhang and colleagues recruited 39,876 women with no history of cancer or cardiovascular disease from 1992 to 1996. Participants were randomly assigned to 100mg aspirin and 600 IU vitamin E every other day and vitamin E for the prevention of cancer and CVD.

They found low-dose aspirin treatment had no significant effect on risk for total cancer (HR=0.98; 95% CI, 0.88-1.08), invasive cancer (HR=0.98, 95% CI, 0.87-1.09) or in situ cancers (HR=0.96; 95% CI, 0.78-1.20); nor did they observe significant effects of low-dose aspirin on risk for invasive breast cancer according to tumor size, histology or histologic grading and differentiation. Those findings echoed results of a study by Cook and colleagues published by the Journal of the American Medical Association in 2005.

Similarly, results of a 2009 study published in the Archives of Internal Medicine showed there was no protective effect for women who used aspirin at least twice per week (RR=1.07; 95% CI, 0.89-1.29). Eliassen and colleagues said use of either nonaspirin NSAIDs or acetaminophen also was not consistently associated with breast cancer risk. Results did not differ by frequency of use, dose, duration of use, or ER or PR status of the tumor.

But, in 2007, results of a meta-analysis and meta-regression of 10 epidemiological cohort-studies and case-control studies conducted from 2001 to 2005 published in Pharmacoepidemiology and Drug Safety showed that aspirin may reduce breast cancer risk, and there appeared to be an associated dose response.

Estimated combined RR was 0.75 (95% CI, 0.64-0.88) using the random effects model in that study. Researchers said each additional pill-year reduced risk by about 2%.

The Western New York Exposures and Breast Cancer Study, a population-based case-control study published in Cancer Causes & Control in 2010, showed that recent aspirin use was associated with a reduced risk for breast cancer (OR=0.80; 95% CI, 0.68-0.94). Women who took two or more pills daily had the greatest effect (OR=0.74; 95% CI, 0.61-0.90). Women with an adult lifetime use of more than 10 times per month also enjoyed a protective effect (OR=0.68; 95% CI, 0.46-1.00). Researchers did not observe a similar effect with ibuprofen or acetaminophen.

Results from a 2010 study published in the Journal of Clinical Oncology by Holmes and colleagues found that among women who lived at least 1 year after a breast cancer diagnosis, aspirin use was associated with a decreased risk for distant recurrence and breast cancer death.

Holmes and colleagues conducted a prospective, observational study based on responses from 4,164 female registered nurses in the Nurses’ Health Study. The women were diagnosed with stage I to III breast cancer from 1976 to 2002 and observed until death or June 2006, whichever came first. There were 341 breast cancer deaths.

Adjusted RRs for breast cancer was 0.29 (95% CI, 0.16-0.52) for 1 to 5 days of aspirin use per week and 0.36 (95% CI, 0.24-0.54) for 6 to 7 days of aspirin use per week compared with nonusers. Disease stage, menopausal status, BMI and ER status had no effect on the association. Results were similar for distant recurrence.

These results, if verified, could have significant implications for the treatment of breast cancer, Holmes said. The bleeding risks associated with aspirin may be too great to justify use in millions of healthy people, but patients with cancer could realize huge benefits from an inexpensive drug such as aspirin.

Jack Cuzick

“It’s one thing to talk about healthy people taking a drug. It’s altogether different to talk about people who have cancer taking a drug that is over-the-counter and has well-known side effects,” she said. “Yes, there is increased risk for bleeding, but look at some of the side effects caused by chemotherapy.”

New evidence in the new year

In early 2012, Jack Cuzick, PhD, head of cancer research at the Centre for Epidemiology, Mathematics and Statistics at the Wolfson Institute in London, expects to issue a new international consensus statement on the use of aspirin and other NSAIDs in cancer. Long-term follow-up results from several studies show aspirin’s potential, he said.

“What we said in our original consensus paper was that the most important thing to do was to continue the long-term follow-up on the available trials because it did appear that the effects of aspirin didn’t show up for some years,” Cuzick said. “Long-term follow-up results have been published, particularly in the Rothwell paper. [Professor Sir] John Burn’s paper in The Lancet is interesting because they’re giving aspirin to the Lynch type II patients who had a high risk for colorectal cancer. The early report didn’t show any reduction of colorectal cancer, but with longer follow-up, that’s also become positive. A number of studies are actually showing effects, but they don’t show up for 5 years. Initial results are often negative, but with longer follow-up, it’s becoming clear this is an attractive proposition.”

In the previous statement, published by The Lancet in 2009 after the Fifth International Conference on Cancer Prevention in St. Gallen, Switzerland, Cuzick and colleagues determined that aspirin was associated with a 40% reduced incidence of colorectal cancer in those who regularly use aspirin. Proper dose and duration of necessary treatment was undefined, although the evidence in favor of aspirin is fairly consistent.

Aspirin was associated with an increased risk for serious gastrointestinal bleeds during 10 years compared with nonusers (2%-3% vs. 1%). Risk increased with age and dose. Incidence of gastric or duodenal ulcers as a result of NSAID use increased linearly, from about 10% in those younger than 45 years to 25% in those older than 75 years.

However, proton pump inhibitors can prevent upper gastrointestinal bleeding, so researchers are awaiting results from the AspECT trial, due sometime in 2012. AspECT is a phase 3, multicenter chemoprevention trial involving more than 2,500 patients in the United Kingdom exploring the role of combination therapy with aspirin and the proton pump inhibitor esomeprazole in patients with Barrett’s metaplasia.

Prevention difficult to prove

There are two challenges to widespread use of aspirin as a prevative for cancer.

First, a certain percentage of people will not benefit, and the drug can be fatal to the small percentage of those who are allergic. That could mean exposing perhaps millions of people to serious risk for minimal benefit, and although the risks are rare, the absolute numbers of those who experience such adverse effects could be huge.

“Any time that we have this kind of potential with a medication that is inexpensive and readily available, it is exciting and potentially of great public health benefit,” Phipps said. “But, again, we have to weigh the harms and the benefits.”

Second, a trial to prove a preventive effect will require a huge study population. Because aspirin is so widely used, it will be even more difficult to find a control population.

That trial likely would take years — if not decades — before results are available, and because aspirin is so inexpensive, there is little financial incentive for a pharmaceutical company to conduct such a costly study. Such a trial could take as long as 20 years, Baron said.

“There are limits to what medical research can do,” Baron said. “It does appear that for aspirin to prevent cancer in basically healthy people, we’re looking at 8 to 10 years before the prevention even begins. Then you’ll need some years afterward to see the prevention.

“In practical terms, it’s almost impossible to organize a trial with a drug as widely used as aspirin, a drug with so many good effects as aspirin. You just can’t do it,” he added.

Government agencies, which would realize the greatest benefit from reduced health care spending, should step in and fund trials in the place of pharmaceutical companies, Cuzick said.

“The evidence is pointing to the fact that the effect of aspirin will not be apparent for about 5 years,” he said. “Any kind of study has to be set up to work in the long term. It’s not a short-term project.” – by Jason Harris

Disclosure: Dr. Baron reports serving as a consultant with Bayer HealthCare Pharmaceuticals. Drs. Cuzick, Holmes and Phipps report no relevant financial disclosures.

For more information:

• Bardia A. Breast Cancer Res Treat. 2011;126:149-155.
• Baron JA. N Engl J Med. 2003;348:891-899.
• Brasky TM. Cancer Causes Control. 2010;21:1503-1512.
• Burn J. Lancet. 2011;378:2081-2087.
• Chan AT. N Engl J Med. 2007;356:2131-2142.
• Coghill AE. #A69. Presented at: 10th AACR International Conference on Frontiers in Cancer Prevention Research; Oct. 22-25, 2011; Boston.
• Cole BF. J Natl Cancer Inst. 2009;101:256-266.
• Cuzick J. Lancet. 2009;10:501-507.
• Eliassen AE. Arch Intern Med. 2009;169:115-121.
• Flossmann E. Lancet. 2007;369:1603-1613.
• Holmes MD. J Clin Oncol. 2010;25:1467-1472.
• Mangiapane S. Pharmacoepidemiol Drug Saf. 2008;17:115-124.
• Marshall SF. J Natl Cancer Inst. 2005;97:805-812.
• Moayyedi P. BMJ. 2010;341:c7326.
• Rothwell P. Lancet. 2011;377:31-41.
• Walter RB. J Clin Oncol. 2011;29:2424-2431.
• Van Dyke AL. Cancer Epidemiol Biomarkers Prev. 2008;17:148-157.
• Yong E. Aspirin cuts risk of dying from several types of cancer. Cancer Research UK.
• Available at: http://scienceblog.cancerresearchuk.org/2010/12/07/aspirin-cuts-risk-of-dying-from-several-types-of-cancer. Accessed Dec. 5, 2011.
• Yong. E. Expert opinion: aspirin and cancer – the unanswered questions. Cancer Research UK.
• Available at: http://scienceblog.cancerresearchuk.org/2010/12/07/expert-opinion-aspirin-and-cancer-the-unanswered-questions. Accessed Dec. 5, 2011.

Is there enough evidence to recommend aspirin as a prophylactic for cancer?

Yes, but we still need to determine which patients are most likely to benefit.

Andrew T. Chan

There are substantial data that has accumulated supporting the concept that there is an anticancer benefit for aspirin. Many now believe that the evidence is compelling enough to warrant regular use of aspirin for cancer prevention. However, the question remains: For what patients should we make such a recommendation?

We know that aspirin has side effects as well as benefits. Thus, balancing risks and benefits according to an individual patient’s profile is important.

For colorectal cancer, the use of molecular markers as a means of personalizing prevention as well as treatment is a promising strategy. For example, an important anti-cancer mechanism of aspirin is the inhibition of the cyclooxygenase-2 (COX-2) enzyme, which promotes tumorigenesis. Based on our previous studies, we have shown that aspirin use appears to improve colorectal cancer-specific survival, particularly among individuals with overexpression of the COX-2 enzyme. Thus, at least for patients with established colorectal cancer, there may be molecular or pathologic features from tumor tissue that can be used for risk stratification for aspirin treatment.

The question is more complicated among individuals without prior cancer for which there are no tumor markers available to guide recommendations. There is a clear need for us to find ways to identify if an individual is at risk for developing a COX-2 overexpressing cancer that may be more likely to benefit from aspirin treatment. This has led to interest in determining whether there are other biomarkers, including plasma analytes or genetic markers, that we can use to predict not only who is at high risk for cancer but also individual responsiveness to aspirin.

Andrew T. Chan, MD, MPH, is associate professor of medicine at Harvard Medical School and a gastroenterologist at Massachusetts General Hospital. Disclosure: Dr. Chan serves as a consultant for Bayer HealthCare.

No, not until we can know which patients are at enough risk to make prevention worthwhile.

Douglas Yee

Within colorectal cancer, there has been good evidence in high-risk familial syndromes that aspirin chemoprevention is a good strategy, but just because something works in high-risk familial syndromes does not necessarily mean it’s a good overall intervention for the population. These randomized trials can’t be used to generalize benefit to the overall population.

One of the issues about prevention, and particularly about chemoprevention, is that nothing — including the drugs that have been approved — have been powered to demonstrate reduction in mortality. When we talk about colonoscopy or mammography or Pap smear, the reason we do these interventions is to reduce death from that disease. In chemopreventive agents, this type of benefit has not been shown. Even tamoxifen, which has been FDA-approved to reduce risk of developing breast cancer compared with placebo in high-risk women, hasn’t been proven to prolong life when taken by healthy subjects. We haven’t done randomized trials large enough to produce proof that statements about reduction of mortality are true.

Aspirin is a reasonably benign drug, but not completely benign. Some people just don’t tolerate aspirin all that well. The idea that it can increase bleeding risk, particularly gastric bleeding risk, is a real issue. This is why this is a drug that shouldn’t be necessarily recommended to the general population.

Maybe people who have had colon polyps might benefit from risk reduction with a drug like aspirin (just as women with a previous benign breast biopsy benefit from tamoxifen), but it’s never been proven in a randomized way. Even if there were benefit in these high-risk subgroups, it would still be a relatively small subset of people.

The biggest question in chemoprevention is whether we can do a randomized trial with appropriate risk stratification and biomarker modulation to prove a drug intervention is effective.

The other major challenge is that all cancers are not the same. If a drug only reduces a specific molecular subtype of cancer, we do not have the tools to determine in advance whether the person who is at risk is going to develop that particular kind of cancer.

Douglas Yee, MD, is director of the Masonic Cancer Center at the University of Minnesota and breast cancer section editor for HemOnc Today. Disclosure: Dr. Yee reports no relevant financial disclosures.