Saturday, July 02, 2022

Of all the drugs in the pharmacopoeia of medicine, I don’t think there is any that is as remarkable as aspirin, the simple cheap drug we all keep in our medicine cabinets. Its forebears, salicylates, are found in the leaves and bark of willow trees and have been utilized in that form by ancient physicians going back millennia, and certainly to Hippocrates and the Greeks. The form we are familiar with, acetylsalicylic acid, was synthesized in the middle of the 19th century and really hit it big when the Bayer company named it aspirin and marketed it.

What makes aspirin so useful is that it has several pharmacologic effects:

1. The most important is that it inhibits the enzyme cyclooxygenase 2 (COX-2). It is this effect for which we mostly utilize it. COX-2 inhibition leads to an anti-inflammatory effect as well as pain reduction and an antipyretic effect (fever reduction). These effects are why we keep it in the medicine cabinet. Thus, aspirin is highly useful for our daily aches and pains, as well as long-term pain, as in arthritis. Thus, it shares the category of nonsteroidal anti-inflammatory drugs (NSAIDs) along with Advil, motrin, naprosyn, etc.

2. Aspirin also inhibits cyclooxygenase-1 (COX-1), which protects the gastric mucosa. Because of this effect, its use leads to irritation of the stomach lining, can cause ulcers and gastrointestinal bleeding. This side effect can be quite injurious and dangerous to health.

3. Through its inhibition of COX-1, aspirin also indirectly inhibits platelet clumping and thus inhibits clot formation. It is this function that makes it useful in prophylaxis against coronary artery disease as well as cerebrovascular disease and stroke. Loss of platelet function can also be a risk, though: If one is involved in a traumatic event, like a motor vehicle accident, then enhanced bleeding can occur; and aspirin should be avoided before surgical procedures.

This is all fascinating, but what brings it to our attention in a column on cancer is that COX-2 acts, in effect, as an oncogene for many tumors, especially those in the GI tract. It is over-expressed in many of them, and apparently aspirin inhibits it. In the late 1970s, it was discovered that arthritis patients who regularly utilized aspirin for pain control had a reduced incidence of colorectal cancer. This was repeated in multiple studies and in many ways, but always came out the same. Basically, it appears that the use of aspirin on a regular basis, even a baby aspirin, reduces one’s risk of colorectal cancer by 50% or more. It prevents other GI tract cancers as well, though not nearly as much, and also breast cancer. These observations are quite definitive.

So does the U.S. Preventive Services Task Force recommend that we all take aspirin for cancer prevention? The answer is no, because of the significant side-effect profile from this drug. As a back-of-the-envelope calculation, let us assume that the incidence of colorectal cancer is 1/1,000/year. We would need to treat 2,000 people to prevent one colorectal cancer (since 25% die, that would require treating 8,000 to prevent one death). If 2,000 people are treated with a daily aspirin, 20-30 would have significant adverse effects, including significant GI bleeding and other problems, which would outweigh the benefits of the aspirin in cancer prevention.

Some years ago, there appeared even more exciting data suggesting that aspirin could be utilized even in the therapeutic setting. Since many tumors over-express COX-2, notably colorectal cancers and breast cancers, then it appeared that patients who used daily aspirin after resection of their tumors, in addition to normative adjuvant chemotherapy, had superior outcomes to those who did not. Indeed, the beneficial effects of aspirin were quite powerful, so much so that it led to the conduct of a randomized trial. Celecoxib is a selective COX-2 inhibitor (inhibits COX-2 without affecting COX-1).

In the randomized trial, there were 2,526 stage III colon cancer patients who received standard adjuvant chemotherapy for their disease who were then randomized to receive three years of daily celecoxib or placebo. With six years of follow-up, the disease-free survival was 76.3% for the celecoxib group versus 73.4% for the placebo group, not statistically different. A similar study was conducted among breast cancer patients which compared two years of celecoxib to placebo and, after six years of follow-up, disease-free survival was similar in the two groups.

This raises the question, always present in human studies, of why the results of observational studies, which show dramatic benefits for COX-2 inhibitors, differ from the randomized trials. Obviously it is very disappointing, and clinicians as a whole will follow the trials. I believe there are other trials still in progress so there may be more data in future. And perhaps aspirin differs from celecoxib—perhaps the anti-platelet effect also contributes to its efficacy. But at least for now, we will have to resist the use of aspirin and other NSAIDs as adjuncts to cancer therapy.

Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York.

This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.

By Alfred I. Neugut


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