Aspirin and ibuprofen may significantly reduce the risk of esophageal cancer among people with Barrett's esophagus

Aspirin and other nonsteroidal anti- inflammatory drugs, such as ibuprofen, may significantly reduce the risk of esophageal cancer among people with Barrett's esophagus, a precancerous condition associated with chronic heartburn that affects an estimated 1 million to 2 million Americans.

These findings, by Thomas L. Vaughan, M.D., M.P.H., and colleagues at Fred Hutchinson Cancer Research Center, appear in the online edition of The Lancet Oncology. Researchers at Virginia Mason Medical Center in Seattle and The Brigham and Women's Hospital and Harvard Medical School in Boston also collaborated on the study, which was funded by the National Institutes of Health.

In the largest and longest observational study of its kind, lead author Vaughan and colleagues studied the impact of nonsteroidal anti-inflammatory drugs, or NSAIDs, on changes in the lining of the esophagus that signal the advancement toward cancer.

"We found that people with Barrett's esophagus who regularly took NSAIDs like aspirin or ibuprofen did not go on to get cancer as frequently or as soon as people who did not take these medications regularly," said Vaughan, head of the Epidemiology Program and member of the Hutchinson Center's Public Health Sciences Division. "Current users of NSAIDs had one-third the risk of getting esophageal adenocarcinoma as compared to never users," he said.

Five years after joining the study, the incidence of esophageal cancer was 14.4 percent among never users, 9.7 percent among former users (those who had used NSAIDs regularly for a year or more prior to joining the study) and 6.6 percent among current users (those who took NSAIDs at least once a week).

Because this was a long-term observational study and not a clinical trial, the investigators cannot recommend NSAIDs for people with Barrett's esophagus and they advise anyone who considers taking these medications for this condition should do so under the direction of a physician.

"If I had Barrett's I'd be looking for anything that would help, and this is something that might help," said Vaughan, also a professor of epidemiology at the University of Washington School of Public Health and Community Medicine. "But since these drugs can have serious side effects, such as gastrointestinal bleeding, this is a decision that Barrett's patients should make with their doctor."

Although the researchers' results suggest that regular, current use of NSAIDs may inhibit the progression of Barrett's esophagus, they also found that the protective effect wears off pretty quickly. "The protective association appears to be limited to current users," Vaughan said. "Once you quit taking aspirin or other NSAIDs the effect rapidly disappears." After three years of discontinuing use of NSAIDs, a person's risk of developing esophageal cancer reverts back to that of a never user, he said.

Previous randomized clinical trials in humans have shown that aspirin and other NSAIDs significantly reduce the risk and mortality for cardiovascular disease and colorectal cancer. Preliminary studies also suggest these drugs may be protective against breast and lung cancers.

It is hypothesized that NSAIDs may fight cancer by reducing chronic inflammation, which is a driving force behind the development of many cancers and other diseases. Specifically, NSAIDs have been shown to inhibit the production of the cyclooxygenase-2 (COX-2) enzyme. Disruption of this pathway slows the growth of abnormal cells and facilitates the normal process of programmed cell death, or apoptosis, both of which can thwart cancer development.

While the risk of developing esophageal cancer in a person with Barrett's is only about 1 percent per year, the outlook is grim if the disease is not diagnosed early. The majority of patients with invasive esophageal cancer die within a year of diagnosis.

"Most Barrett's patients will never get esophageal cancer, but since it is such a rapidly fatal cancer once you get it, it's very important to identify ways to prevent it," Vaughan said. "This research gives us hope that there may be an inexpensive, accessible and relatively safe way to lower Barrett's- related cancer risk."

Currently there is no proven medical or surgical therapy for lowering esophageal-cancer risk in people with this condition; care is limited to treating symptoms of reflux, or heartburn, and frequent endoscopic surveillance, which involves inserting a tube-like instrument down the throat to examine the esophageal lining and to take tissue samples that are examined for signs of cancer or precancerous changes.

For the study, Vaughan and colleagues collected data between 1995 and 2003 from 350 people with Barrett's esophagus. Upon entering the study the participants were interviewed about their medical history, diet and medication use, and they gave a blood sample. The participants were then closely monitored for signs of disease progression through regular endoscopies. Frequency of endoscopic surveillance was determined by the stage of the condition.

The study participants were selected from a group of more than 450 Barrett's patients whose disease progression is being carefully monitored through the Seattle Barrett's Esophagus Program, a multidisciplinary research effort established in 1983 at the University of Washington. The goals of the program, now based at the Hutchinson Center and conducted in collaboration with researchers at UW, are to understand the biological mechanisms by which esophageal cancer develops, to identify lifestyle and other factors that promote or inhibit progression toward cancer, and to identify genetic markers of increased risk so the disease can be prevented or detected early, while it is still curable.

The Barrett's research team, led by Hutchinson Center researcher Brian J. Reid, M.D., Ph.D., and co-author of The Lancet Oncology paper, has shown that a systematic, multidisciplinary approach to early cancer detection can boost the five-year survival rate for esophageal cancer from about 10 percent to more than 80 percent.

Other promising research findings from the Seattle team -- all of which require additional research -- suggest that reducing overweight and quitting smoking also may prevent progression of Barrett's.

Esophageal cancer strikes more than 14,500 Americans a year, according to the American Cancer Society, and since the late 1990s the incidence of the most common form, esophageal adenocarcinoma (the type associated with Barrett's) has been rising faster than that of any other cancer in the United States, increasing fourfold to ninefold in different areas of the country since 1974. Esophageal adenocarcinoma, which accounts for about 60 percent of esophageal-cancer cases, is most prevalent among residents in western Washington for reasons not yet known, Vaughan said.

While the condition is eight times more common in men than women and five times more common in white males than black males, the rates are rising as well among women and African Americans.

"The incidence of esophageal adenocarcinoma is rising really fast in Westernized countries, and we're not really sure of the reason," Vaughan said. "However, it looks like obesity is a driving factor, partly because it promotes acid reflux, a key risk factor for both Barrett's and cancer. But it's pretty likely that there's something else going on, too, because obesity is just as high in women and African Americans. Hormonal factors also might be important, but at this point we just don't know."