New Therapy for Barrett's Esophagus and Prevention of Esophageal Adenocarcinoma

Clinical Scenario: Mr. W. is a 54-year-old male with a longstanding history of gastroesophageal reflux disease and HTN. He was diagnosed with Barrett's esophagus 2 years ago and is currently being followed by his gastroenterologist. He currently undergoes surveillance with annual endoscopies to detect the transformation of the Barrett's esophagus to dysplasia. On his last endoscopy, he was diagnosed with high grade dysplasia, which is known to have an increased rate of developing esophageal adenocarcinoma. He now comes in for a follow-up visit to review his options for the management of esophageal dysplasia in hopes to minimize his risk of developing adenocarcinoma.

Gastroesophageal reflux disease (GERD) is a widely prevalent illness. Chances are that most people will know someone who suffers from an acid reflux problem. While the symptoms can be bothersome to those who have it, we do not generally perceive it as a life threatening illness. As you may know, in about 10% of people, the natural history of GERD is progression to Barrett's esophagus, where the normal squamous epithelial lining of the esophagus is displaced by columnar epithelium from the intestine (intestinal metaplasia). In a small number of patients, this can further progress to low-grade dysplasia. In the unfortunate few, this can progress to high-grade dysplasia, and eventually, to esophageal adenocarcinoma. It is a fact that in preceding decades, the incidence of esophageal carcinoma has increased dramatically. Moreover, this is undoubtedly one of the cancers with the worst prognosis, with a 5-year survival quoted to be less than 15%. Therefore, it comes as no surprise that much effort has been placed in finding effective ways to manage this illness and prevent progression to cancer.

The current standard of care for patients who have Barrett's esophagus and low-grade dysplasia is to follow closely with serial endoscopies once or twice a year. If they transition to high-grade dysplasia, there is an estimated 15-20% chance per year of progression to cancer, with some studies quoting up to 50% chance of progression over a 3-year period. Currently, they have two options: either they continue on with endoscopic surveillance every three months or they undergo esophagectomy. In the first option, there is a risk of sampling errors with random biopsies which can make detection of submucosal malignancy challenging and result in underdiagnosis. On the flip side, mild dysplasia can be misinterpreted as high-grade or worse, resulting in unnecessary surgery. Overall, it is quite variable from center to center depending on the expertise of the endoscopist and pathologist. Needless to say, the second option, and esophagectomy, is a high risk procedure with significant morbidity and mortality.

In the May 28, 2009 issue of New England Journal of Medicine (NEJM), Shaheen and colleagues provide us with a whole new management strategy in the prevention of esophageal adenocarcinoma, "Radiofrequency Ablation in Barrett's Esophagus with Dysplasia." This article reports the results of a multicenter, sham-controlled trial in which 127 patients with Barrett's esophagus with either low or high grade dysplasia are randomly assigned to receive either endoscopic radiofrequency ablation (RFA) or sham procedure. Following is a brief review of the results of this study, gained mostly from the abstract of the article: Among patients with low grade dysplasia, there was complete eradication in 90% of the ablation group versus 22% in control/sham group. Among patients with high grade dysplasia, there was complete eradication in 81% of ablation group compared with only 19% in control group. Overall, there as complete eradication in 77% of ablation group compared to 2.3% in control group. This resulted in less disease progression (3.6% vs 16.3%) and fewer cancers (1.2% vs 9.3%) in the ablation group. Compared to the risks of intensive endoscopic surveillance and esophagectomy, the risks of RFA, which include post-procedure chest pain and esophageal stricture in a few, are mild, and thus much more acceptable.

This is not the first attempt to finding non-operative, less invasive ways to manage esophageal dysplasia. In the past, there was a multicenter, randomized trial conducted by Overholt and colleagues, in which patients with high grade dysplasia were randomized to either photodynamic therapy or endoscopic surveillance. In this study, the cure rate of high grade dysplasia was only 50% in the photodynamic group, with 13% of patients progressing to cancer. These findings are clearly inferior to the efficacy of RFA, in which the cure rates were much higher and the disease progression much lower (3.6%). Furthermore, over 90% of patients developed adverse events related to the treatment, which included esophageal stricture (up to 36%) and a significant risk of photosensitivity reaction (69%) to the chemosensitizing agent.

While this present study shows promise in utilizing RFA as a management option in the prevention of esophageal adenocarcinoma, we have to be careful not to over-utilize this option to include all patients with Barrett's or low grade dysplasia. Since only a small number of patients with Barrett's or low-grade dysplasia actually progress to high grade dysplasia or adenocarcinoma (less than 1%), we have to balance the risks, albeit low, of the procedure as well as the cost-effectiveness of expanding this treatment to a much larger population. In the same issue in NEJM, Dr. Berman wrote an insightful editorial reviewing the natural history of Barrett's, what this study means to the current standards of care in managing Barrett's and dysplasia, and cost-effectiveness of expanding this treatment option to all patients with Barrett's, including those with no dysplasia or low-grade dysplasia.

So what can we do for Mr. W., who was found to have high-grade dysplasia on his last endoscopy? As mentioned above, there is a high rate of progression from high-grade dysplasia to cancer. Our current options are intensive surveillance endoscopies, esophagectomy, photodynamic therapy, or RFA. Aside from subjecting the patient to an invasive procedure every 3-4months, the option of surveillance endoscopies with random biopsies, carries a real risk of missing this transformation, especially since many cancers originate submucosally and may be missed by random biopsies. In addition, there can be much operator bias from center to center, which makes this option even less reliable. Alongside, with this ground-breaking study, we should expect that there will be a lot fewer esophagectomies; it doesn't make sense to subject a patient to a procedure with such a high risk of complications and mortality, not to mention the greatly adverse effect on quality of life, when we can have the option of an office based procedure with a low complication rate.

References:

1. Shaheen NJ, Sharma P, Overholt BF, et al. Radiofrequency Ablation in Barrett's Esophagus with Dysplasia. N Engl J Med 2009;360:2277-87.
2. Bergman JJ. Radiofrequency Ablation-Great for Some or Justified for Many? N Engl J Med 2009;360:2353-2354.