NEWS

Barrett’s Esophagus: Major Issues Uncertain and Unsolved

Mike Miller

Although physicians reported large increases in gastroesophageal reflux disease (GERD) and Barrett’s esophagus in the 1990s, a series of recent workshops have concluded that there is insufficient information to make firm treatment, surveillance, or other recommendations about the diseases.

Most scientists in the field concur on how cancer evolves in the esophagus. The commonly accepted pathway for progression from normal squamous epithelium to cancer starts with reflux-associated esophageal damage (GERD), then advances to intestinal metaplasia (early Barrett’s esophagus), followed by low- and high-grade dysplasia (Barrett’s esophagus), and finally adenocarcinoma.

"We need to conduct studies to nail down the incidence and prevalence of Barrett’s [esophagus] and GERD, identify etiologies and risk factors for both diseases, and develop and validate biomarkers of progression for Barrett’s [esophagus] before we can rationally embark on large, randomized intervention trials to get at the root of what seems to be a growing problem," said Ernest Hawk, M.D., of the National Cancer Institute’s Division of Cancer Prevention.



View larger version (113K):
[in this window]
[in a new window]
 
Dr. Ernest Hawk

 
Physicians often order endoscopies for patients who have prolonged or pronounced GERD to see what the problems might be. It is during these endoscopies that Barrett’s esophagus or more advanced disease is often first diagnosed.

Glenn Eisen, M.D., Vanderbilt University Medical Center, Nashville, Tenn., noted that some researchers think that the incidence of Barrett’s esophagus may be less than previously thought, but autopsy studies have shown that only one in 20 cases of Barrett’s are diagnosed prior to death. Yet Barrett’s esophagus is a key signal that a more serious problem could develop, so regardless of the actual incidence numbers, the disease still requires a search for a solution.

"Among the many problems we have in trying to determine the quality of data regarding Barrett’s esophagus are first, sampling errors in biopsies and variability in pathologic interpretation that may misclassify low (and even high) grade dysplasia; second, erosive esophagitis that can obscure a diagnosis of Barrett’s; and third, great uncertainty about when Barrett’s starts to develop." Some scientists think that the time from inception to diagnosis of Barrett’s could be up to 25 years.

Brian Reid, M.D., Ph.D., Fred Hutchinson Cancer Research Center, Seattle, said he feels that the best way to get a handle on GERD and Barrett’s esophagus is to assemble a panel of biomarkers that can define the disease progression from dysplasia to cancer. He noted that although an estimated 15% to 27% of high-grade dysplasias go on to cancer, only about 2% to 8% of low-grade dysplasias progress. Most importantly, 10 times as many low-grade dysplasias may regress to normal tissue.

Some key biomarkers Reid suggests looking at include p16 abnormalities, which are found in 88% of patients; APC methylation, which is found in 40% of patients with metaplasia and in 92% of cancer patients; and p53 mutations, which are found in nearly all patients with cancer of the esophagus.

Given current estimates of a high prevalence of Barrett’s esophagus, but low incidence of cancer evolving from Barrett’s esophagus (about 0.4%), questions arise about the cost effectiveness of screening. In a detailed study, Dawn Provenzale, M.D., Duke University Medical Center, Durham, N.C., found that "with the cost of an endoscopy running upwards from $600, the most effective screening might be every 3 years, but we found, based on our models, that the most cost-effective screening in reducing overall mortality is every 5 years." Yet even this study did not provoke a consensus on screening recommendations.

Treating Symptoms

Even if GERD does not lead directly to Barrett’s esophagus, most people want relief from GERD symptoms. There are already a number of treatments on the market for GERD, but it is not known if they will help prevent adenocarcinoma.

Jon Spechler, M.D., Department of Veteran Affairs Medical Center, Dallas, noted that proton pump inhibitors such as omeprazole (Prilosec, AstraZeneca) relieve symptoms and there are even indications of disease regression, but squamous cell islands can develop and acid reflux still can occur.

In addition to these quandaries, Spechler said that complete blockage of acid reflux would require multiple dosing and pH monitoring and would result in bacterial overgrowth in the stomach. There have not been any definitive studies that show that GERD therapy, whether pharmacological or surgical, prevents cancer.

In addressing the difficulty of how to answer many of the questions about GERD and Barrett’s esophagus, Steven Piantadosi, M.D., Ph.D., Johns Hopkins Oncology Center, Baltimore, said that "Barrett’s has a low frequency of clinical events (progression to cancer), which makes it difficult to find surrogate markers and design effective clinical trials of cancer prevention." He estimates that a trial would take 10 years and require up to 10,000 patients.

Most participants at the workshops agreed that the best way around this dilemma was to create a multicenter, multidisciplinary clinical infrastructure to facilitate risk assessment and clinical trials, and focus on prevention and treatment of Barrett’s dysplasia, rather than cancer.

But what about those cases that do progress to adenocarcinoma? Many researchers seem to agree that, once diagnosed, esophageal adenocarcinoma is largely treatable because it is characterized by slow, recognizable epithelial changes. However, according to Raj Goyal, M.D., Veterans Administration Medical Center, West Roxbury, Mass., "95% of adenocarcinomas present silently, so we currently recommend that Barrett’s patients without dysplasia be monitored endoscopically every 2 to 3 years."

For patients who want treatment, Sampliner noted that the risks associated with surgery can be high in some facilities. Goyal noted that treatment ablation therapies, such as lasers, photodynamic techniques, and others "can’t eradicate all mucosal abnormalities and while they may help prevent reflux, we don’t know if they can prevent progression to cancer." He added that gastric acid suppression, the alternative to surgery, may even spur progression to cancer, "but we really don’t have an answer to that question either at this point in time."

Some scientists believe that they can no longer discern the natural history of Barrett’s esophagus, since most patients with symptoms of GERD are treated with some sort of acid blocker. For this reason, an animal model is high on a list of funding priorities for many researchers. A trial design similar to that of the multicenter AIDS cohort studies has also been suggested as a model for a lower cost Barrett’s trial, wherein high-risk patients with and without Barrett’s esophagus would be followed for years to study exposure and possible conversion to disease.

Reid suggested simpler observational studies, which would also be less costly, because, as he said, "we need to identify and develop validated intermediate end points that can be reasonably relied upon, since the risk of Barrett’s progressing to cancer is low." Dietary intervention studies that focus on increased consumption of fruits and vegetables, reductions in fat and reflux-inducing foods, and weight control, offer other options for potentially effective, yet safe, trials to effect a reduction in cancer risk, Reid added.



             
Copyright © 2001 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement