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Aspirin and cancer: Will a tablet a day keep tumors at bay?

OCT 2011

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It has been on the market for over a century, and its major chemical ingredient has been in medical use for more than 3,500 years, yet it's still the subject of intense scientific study and controversy. About 40,000 tons are produced every year worldwide, and over 50 million Americans take it regularly, but many who should use it don't do so. It costs only a few pennies a day, but it's often overlooked in favor of much more expensive drugs that have similar benefits but more side effects. It earned its good name from its ability to relieve pain, soothe arthritis, and reduce fever, but its most important benefit is the ability to prevent heart attacks and strokes in people at high risk. It's found in nearly every medicine cabinet in America, but it doesn't get the respect it deserves. It's aspirin — and research suggests this old friend may soon find a new role in fighting cancer.

Aspirin, up close and personal

Aspirin is known to chemists as acetylsalicylic acid. It is the first, and in many ways the best, representative of a large group of medications today known as the NSAIDs, or nonsteroidal anti-inflammatory drugs. The best known NSAIDs include ibuprofen (Motrin, Advil, generic) and naproxen (Aleve, Naprosyn, generic). A closely related drug, celecoxib (Celebrex), shares some properties with true NSAIDs.

The target: COX enzymes

The cyclooxygenase (COX) enzymes are widely distributed in the human body. Two forms exist, COX-1 and COX-2. COX-1 is responsible for generating chemicals that help control blood pressure, regulate blood flow to the kidneys, and protect the stomach lining — all good things. COX-1 also activates platelets, initiating the clotting process. That's good if you're bleeding from a wound, bad if you're having a heart attack. In contrast, COX-2 triggers the production of chemicals that cause fever, create inflammation in joints and other tissues, and aggravate pain — all bad things.

Like the other NSAIDs, aspirin inhibits both COX-1 and COX-2. By inhibiting COX-2, these medications fight inflammation, pain, and fever. But because they also inhibit COX-1, all NSAIDs increase the risk of ulcers and gastric bleeding, and all can occasionally raise the blood pressure and interfere with kidney function. But when it comes to the heart, aspirin has an important advantage over other NSAIDs. Aspirin sharply reduces the risk of heart attack and stroke in patients who have survived a first attack, and it may also reduce the risk of a first heart attack in men at high risk. In contrast, the other NSAIDs all increase the risk of heart attack and stroke, though to a modest degree. Because celecoxib inhibits COX-2 but not COX-1, it is safer for the stomach; unfortunately, though, it's much riskier for the heart and head, increasing the likelihood of heart attack and stroke.

Why cancer?

At first glance, cancer seems to have nothing in common with an inflamed knee or a raging fever. But research suggests that the same COX-2 enzymes that provoke pain, inflammation, and fever may have a role in certain malignancies. Here is some of the evidence to date. COX-2 appears to promote angiogenesis, the process that generates new blood vessels to support the rapid growth of tumors. COX-2 may also interact with various growth factors to stimulate the multiplication of malignant cells, and it appears to inhibit apoptosis, a natural defense mechanism that helps prevent runaway tumor growth by triggering cell death by suicide.

COX-2 is far from the only thing that contributes to the unrestrained growth of cancer cells, but experiments in test tubes and animals suggest that inhibiting COX-2 can prevent various chemicals from turning normal cells malignant. Similar research also suggests that tamping down COX-2 can slow the growth and the spread of existing cancers. The information about COX-2 inhibitors and human cancer is less complete, but scientists have already discovered that many of the most aggressive colon cancers have unusually high levels of COX-2, as do many prostate cancers. In addition, randomized clinical trials have demonstrated that COX-2 inhibitors help prevent people at high risk of colon cancer from producing colorectal adenomas, the benign polyps that give rise to nearly all colon cancers. In fact, the FDA has already approved celecoxib for patients with familial adenomatous polyposis, an uncommon genetic disorder that carries an extremely high risk of colon cancer.

Preventing cancer

Low-dose daily aspirin may help reduce your risk of colon cancer and other malignancies. But even if future research doesn't confirm this hope, there are other ways you can protect yourself and your family. Here are 10 tips:

1. Avoid tobacco in all its forms, including exposure to secondhand smoke.

2. Eat properly. Reduce your consumption of saturated fat, processed meat, and red meat, which appear to increase the risk of colon and prostate cancers. Limit your intake of charbroiled foods (especially meat), and avoid deep-fried foods. Increase your consumption of fruits, vegetables, and whole grains; although other reports are mixed, two large 2003 studies found that high-fiber diets may reduce the risk of colon cancer. And don't forget to eat fish two to three times a week; you'll get protection from heart disease, and you may reduce your risk of prostate cancer.

3. Exercise regularly. Physical activity has been linked to a reduced risk of colon cancer, and it may even help prevent prostate cancer. Exercise also appears to reduce a woman's risk of breast cancer and possibly reproductive cancers.

4. Stay lean. Obesity increases the risk of many forms of cancer. Calories count; if you need to slim down, take in fewer calories and burn more with exercise.

5. If you choose to drink, limit yourself to one to two drinks a day. Excess alcohol increases the risk of cancers of the mouth, larynx (voice box), esophagus (food pipe), liver, and colon, especially in smokers; it also increases a woman's risk of breast cancer. Smoking further increases the risk of many alcohol-induced malignancies.

6. Avoid unnecessary exposure to radiation. Get medical imaging studies only when you need them, and ask your doctor to choose the test that will provide the information he needs with the lowest radiation dose. Check your home for residential radon, which increases the risk of lung cancer. Protect yourself from ultraviolet radiation in sunlight, which increases the risk of melanomas and other skin cancers.

7. Avoid exposure to industrial and environmental toxins such as asbestos fibers, benzene, aromatic amines, and polychlorinated biphenyls (PCBs).

8. Avoid infections that contribute to cancer, including hepatitis viruses, HIV, and the human papillomavirus.

9. Get enough vitamin D. Many experts now recommend 800 to 1,000 IU a day, a goal that's nearly impossible to attain without taking a supplement. Although protection is far from proven, evidence suggests that vitamin D may help reduce the risk of prostate cancer, colon cancer, and other malignancies. And even if these hopes don't pan out, vitamin D should help keep your bones strong and may also reduce your risk of falling.

10. Don't count on other supplements. Careful studies show that selenium, vitamins C and E, beta carotene, folic acid, and multivitamins are not protective, and that some may do more harm than good.

Early clinical evidence

In general, doctors rely on two types of research to decide if a medication or treatment is effective. In most cases, observational studies come first. In this type of research, epidemiologists evaluate large groups of people to see if the occurrence of a particular disease (in this case, cancer) is lower in individuals who take a particular drug (in this case, aspirin or other NSAIDs) than in people who don't use the medication.

Most observational studies of NSAIDs have linked long-term regular use with protection against colon adenomas and cancers; in many studies, the benefit appears substantial, with a 30% to 50% reduction in risk. The results for prostate cancer have been more variable and less positive, but a 2004 Canadian meta-analysis of 12 observational studies linked aspirin use with a 10% lower risk of all prostate cancers and, in the studies that evaluated the severity of the disease, a 30% reduction in the risk of advanced prostate cancers; a 2010 American observational study reported similar results. Other reports suggest possible protection against a wide range of malignancies, including Hodgkin's disease and cancers of the throat, lung, esophagus, pancreas, stomach, bladder, breast, and ovaries. It's a long list, but the results are inconsistent, the evidence is preliminary, and the possible protection incomplete.

When observational studies generate hopeful but conflicting results, the next step is to conduct randomized clinical trials. In this type of research, volunteers agree to take either the study drug or a look-alike placebo. Scientists randomly assign the subjects to one of the groups and then evaluate the outcome without knowing who is getting the real thing and who has been taking the dummy pill.

Randomized clinical trials are more difficult and expensive than observational studies, but they are the gold standard for clinical research, so the negative results reported by two high-quality trials seemed to deliver a body blow to the theory that aspirin could reduce the risk of cancer. The results were particularly disappointing since both trials focused on colon cancer, the malignancy that seemed most likely to benefit from a COX-2 inhibitor.

Harvard's U.S. Physicians' Health Study randomly assigned 22,071 healthy male physicians to take either 325 milligrams (mg) of aspirin or a placebo every other day. The aspirin study was terminated early, after five years, because aspirin use produced a 44% reduction in the risk of a first heart attack, so continuing to deny aspirin to the members of the placebo group was considered unethical. Both during the active trial and during an additional seven years of follow-up, the men who took aspirin did not experience a lower risk of colon cancer than the men who did not use aspirin on a regular basis.

Results from the Women's Health Study were equally disconcerting. In this case, the 39,876 volunteers were randomly assigned to take 100 mg of aspirin or a placebo every other day for an average of 10 years. When the results were tallied, aspirin failed to provide protection against colon cancer and other malignancies.

End of story? Not quite.

A second look

Despite these discouraging reports, scientists continued to perform randomized clinical trials of aspirin. These efforts did not focus primarily on cancer, but on cardiovascular disease. Still, these investigations gave researchers in the U.K. an opportunity to take a second look at aspirin and cancer.

The British scientists analyzed fully completed, high-quality, randomized trials of aspirin. They excluded the Physicians' Health Study and the Women's Health Study because both trials administered aspirin on an every-other-day basis. Alternate-day aspirin succeeds in reducing the risk of heart attacks and certain strokes because a single, small dose permanently blocks COX-1 in all of the body's platelets, thus inhibiting the blood clots that trigger most heart attacks and strokes. But aspirin's effect on COX-2 in other tissues is much less durable, suggesting that daily dosing might be necessary for benefit. Because cancer evolves slowly, the research included only studies that administered aspirin for at least four years. Finally, the analysis was restricted to cancer deaths, rather than the incidence of nonfatal malignancies, which are harder to track in large studies that focus primarily on cardiovascular disease.

Eight trials that covered a total of 25,570 individuals met the researchers' inclusion criteria. When analyzed together, these trials reported that daily aspirin reduced the risk of dying from cancer by 21%.

Seven of the eight trials, which included a total of 23,535 people, provided enough information to permit analysis of individual patients and specific cancers. A reduced risk of death became evident after only five years of follow-up — but that benefit was an impressive 34% lower risk of dying from cancer. Aspirin was most effective against gastrointestinal cancers, reducing the risk of death by 54%; among these digestive tract tumors, pancreatic, colorectal, and esophageal cancers exhibited the largest benefit. Among other malignancies, aspirin use was linked to a trend toward fewer deaths from prostate and lung cancer, but these reductions did not meet the scientists' tough standards for statistical significance.

Closer inspection

After drilling down on these results, the U.K. investigators were able to offer additional observations. The benefit of aspirin was consistent in all the individual studies, even though the population groups varied considerably. The effects of aspirin were similar in men and women and in smokers and nonsmokers, but older individuals benefited more than younger people. Volunteers who took aspirin for the longest time enjoyed the greatest protection against cancer death. Risk reduction did not become evident until five years of follow-up, and the benefit was maintained for at least 20 years. Benefit was limited to certain types of cancer, especially adenocarcinomas, but these included colon cancer and other major killers. Finally, although a long duration of daily aspirin use was essential for benefit, a particular dose was not; various doses above 75 mg a day appeared equally effective.

Chemoprevention

A healthful lifestyle can sharply reduce your risk of getting cancer, but it takes thought and effort. Wouldn't it be nice if there were a pill for protection? The concept is called chemoprevention, and aspirin is a hopeful, but still unproven, example of a medication that may reduce cancer risk.

Another example applies to breast cancer. A randomized clinical trial of tamoxifen versus placebo in high-risk women showed that five years of treatment reduced the risk of breast cancer by about 50%. But there was a price to pay, including an increase in uterine cancer and blood clots. Based on this study, the FDA has approved tamoxifen for the prevention of breast cancer, but only in high-risk women.

Breast cancer is a hormonally responsive disease, and tamoxifen works because it's an anti-estrogen. Prostate cancer is also driven by sex hormones — and two drugs that block the conversion of the male hormone testosterone to dihydrotestosterone, the hormone that's active in the prostate, appear to reduce the risk of prostate cancer. But finasteride (Proscar, generic) and dutasteride (Avodart) also come with a price. Many men would gladly put up with uncommon, if troublesome, side effects such as sexual dysfunction, but while the drugs appear to reduce the risk of tame, low-grade prostate cancers, they also seem to increase the risk of high-grade, aggressive prostate cancers — which is why the FDA has approved them to treat benign prostatic hyperplasia but not to prevent prostate cancer.

Look again

The British analysis is a major contribution to the growing evidence that aspirin may have important anticancer activity, especially for colorectal, esophageal, and pancreatic cancers and possibly for lung and prostate cancers. Even so, the research has limitations. In particular, all eight studies included in the analysis were designed primarily to evaluate cardiovascular disease, making them less robust for an evaluation of cancer. Still, the U.K. team compensated for this limitation by collecting individual patient data and focusing on cancer deaths, which were well documented in the study population. More research is needed — and some is already available.

Aspirin after diagnosis?

Nearly all colorectal cancers arise from benign adenomas, or polyps. A 2003 trial asked if aspirin could reduce adenoma formation in 635 patients who were at high risk because of previously diagnosed colorectal cancer. Half the patients with treated cancer were randomly assigned to take 325 mg of aspirin a day, while the others took a placebo. Among the 517 patients who had follow-up colonoscopies, aspirin reduced new polyp formation by 35%.

A 2009 observational study from Harvard is even more impressive because it evaluated the thing that matters most, survival after a diagnosis of colon cancer. The subjects were 1,279 colorectal cancer patients who were followed for an average of 11.8 years after their initial diagnosis. Regular aspirin users enjoyed a 29% lower risk of dying from colorectal cancer as well as a 21% lower overall death rate when compared with their peers who did not take aspirin regularly. The apparent benefit was even greater in patients who started taking aspirin after their cancer diagnosis, and molecular analysis of the tumor specimens suggested that benefit depended on abnormally high levels of COX-2 in cancer cells.

Aspirin for cancer?

Not just yet, at least as a general recommendation. The United States Preventive Services Task Force recommends low-dose aspirin to prevent heart attacks only for high-risk men, citing peptic ulcer and bleeding as side effects that must be weighed against potential benefits. An international panel of experts on aspirin and cancer weighed the same side effects against aspirin's potential to prevent cancer and concluded that it was too early to recommend aspirin for general use. But both policy statements were published in 2009, two years before the British analysis appeared.

Although aspirin is inexpensive, plentiful, and widely available, it does have side effects. Even with the British analysis, it's premature to recommend routine aspirin use to prevent cancer. But people at high risk of cancer, particularly colon cancer patients, people with colonic adenomas, and individuals with a strong family history of colon cancer should discuss the issue with their doctors.

A doctor's advice to take two aspirin and call in the morning has become fodder for stand-up comics. But before too long, the advice to take a "baby" aspirin a day so you won't have to call your doctor about cancer may provide a much better reason to smile.