Aspirin and Cancer

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.

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.