Radiofrequency Ablation Effective Against Barrett Esophagus
Barrett esophagus with dysplasia or metaplasia, esophageal adenocarcinoma, radiofrequency ablation, endoscopy, esophagectomy. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)
In a randomized multicenter phase II study, endoscopy with radiofrequency ablation (RFA) resulted in much higher rates of eradication of both high- and low-grade dysplasia associated with Barrett esophagus (BE) than did endoscopy with a sham procedure. The study did not investigate whether radiofrequency ablation was superior to other treatments commonly used for Barrett esophagus and had too few patients to determine accurately whether the RFA decreased the risk of progression to cancer.
New England Journal of Medicine, May 28, 2009 (see the journal abstract).
Gastroesophageal reflux disease (GERD) affects between 3 and 7 percent of the US population. In patients with GERD, stomach contents, including food and acid, are pushed backward from the stomach to the lower end of the esophagus. About 10 percent of patients with GERD develop a condition called Barrett esophagus, in which the cells lining the interior wall of the lowest portion of the esophagus are replaced by abnormal cells known as intestinal metaplasia. Intestinal metaplasia cells may become more abnormal over time, progressing to low-grade dysplasia and then to high-grade dysplasia. In a small minority of patients with dysplasia, especially high-grade dysplasia, these cells may gradually progress to esophageal adenocarcinoma (EA), a cancer that can be very difficult to cure. Clinicians have long sought treatments that would prevent BE from progressing to EA.
Patients with Barrett esophagus generally receive daily oral anti-acid medicine as well as regular check-ups during which a physician passes an endoscope (a flexible tube with a light and a viewing lens) from the throat down to the lower esophagus and stomach to inspect the esophageal lining for cellular abnormalities and to take samples for biopsy examination. Professional guidelines differ as to how to treat Barrett esophagus. Some guidelines call for surgical removal of the lower esophagus for individuals with the high-grade dysplastic form of the condition. Some recommend non-surgical procedures that kill the lining cells in place, a technique called ablation. Ablation has been done as an outpatient procedure using lasers (phototherapy) or, more recently, radio waves (radiofrequency ablation, RFA). It remains unclear whether ablation should be recommended just for those Barrett esophagus patients with the highest risk of developing esophageal cancer, i.e., those with high-grade dysplasia, or for patients with low-grade dysplasia as well.
At 19 sites in the United States, 127 patients with either high- or low-grade dysplastic Barrett esophagus were enrolled in a phase II randomized clinical trial to evaluate the value of RFA in treating the condition. Patients were first stratified (assigned to subgroups) based on whether they had low- or high-grade dysplasia. Patients in each group were then assigned at random (in a 2:1 ratio) to receive either endoscopy with RFA (84 patients total) or sham endoscopy alone, that is, without RFA treatment (43 patients total).
With RFA, after the endoscope was inserted through the throat into the lower esophagus, a small balloon attached to the endoscope was inflated and then positioned against the esophageal lining. Controlled energy from radio waves was delivered through the balloon wall, burning the cells in contact with it. In some patients, the balloon was repositioned for a second or third application in order to treat all abnormal cells.
Patients in the ablation group were allowed to receive up to three additional ablation sessions at 2, 4, and 9 months after the first procedure, if needed. Altogether, the 84 patients in the RFA group received a total of 298 treatments.
Patients in both groups were evaluated with repeat endoscopic biopsy procedures for 12 months following their initial procedure. For patients with low-grade dysplasia at study entry, these examinations were performed at 6-month intervals. For patients with high-grade dysplasia at study entry, the examinations were performed at 3-month intervals. After 12 months, control group patients were allowed to receive RFA treatments if they wished.
The main goal of the study was to determine the presence or absence of any intestinal metaplasia as well as of high- or low-grade dysplasia at 12 months after the initial procedure with and without RFA.
The study's principal investigator was Nicholas J. Shaheen, M.D., M.P.H., of the University of North Carolina School of Medicine at Chapel Hill. All patients received esomeprazole--a proton pump inhibitor to reduce acid reflux--twice daily throughout the trial, which was provided by AstraZeneca, a pharmaceutical company that has provided support to some of the researchers. The trial was sponsored by BÂRRX Medical, a medical device company that developed and supplied the technology used in the trial and that has also provided support to a number of the study researchers.
After 12 months of follow-up, among patients with low-grade dysplasia at study entry, dysplasia was eradicated in 90 percent of patients treated with RFA and 23 percent of those treated with the sham procedure. Among patients with high-grade dysplasia at study entry, dysplasia was eradicated in 81 percent and 19 percent of patients, respectively. Among all patients, complete eradication of all intestinal metaplasia was found in 77 percent of patients in the RFA group and 2.3 percent of those in the control group.
There were too few patients in the study to accurately measure the effect of RFA on preventing progression of pre-malignant lesions or the progression of pre-malignant lesions to esophageal cancer. Nonetheless, the study did find that 9.3 percent of patients in the control group but only 1.2 percent of those in the RFA group had progression to cancer. Among patients with high-grade dysplasia, 19 percent of those in the control group (4 of 43) but only 2.4 percent of those in the ablation group (1 of 84) developed cancer.
Key side effects were evaluated after the first RFA treatment. Only three serious adverse events requiring hospitalization were seen, all after RFA. On the first day after treatment, RFA patients reported a chest discomfort level of 23 on a 100-point scale, but the control group reported no chest discomfort. RFA-related discomfort resolved by the eighth day in all patients.
Even though some clinicians advocate short-interval endoscopic follow-up with biopsy alone for patients with only low-grade dysplasia, the authors of this study suggested that their results suggest that "the application of ablative therapy in patients with low-grade dysplasia is worth further investigation and consideration."
This phase II study was designed primarily to determine how effective RFA was in eradicating metaplasia overall and low- and high-grade dysplasia at 12 months. Longer-term data are not available. Although RFA effects on limiting disease progression were also observed, no definitive conclusions can be drawn because of the small patient numbers and the short follow-up time. It also remains unknown whether any procedure that eradicates metaplasia or dysplasia, or even decreases progression among the phases of BE, will ultimately reduce deaths from esophageal cancer.
In an editorial that accompanied the study, Jacques J.G.H.M. Bergman, M.D., Ph.D., from the Academic Medical Center in Amsterdam, in the Netherlands, wrote that "the decreased risk of cancer incidence should be looked at with some caution," because the study was not designed to study this outcome and the numbers of cancer cases were very small". He also noted that allowing control patients to cross over to RFA treatment after 12 months complicates longer term comparisons.
Editorialist Bergman also said that although the trial did not formally compare RFA ablation to other ablation techniques or surgery, the very high success rate and low morbidity with RFA show that this technique is very promising. He also suggested that, based on the results of this trial, individuals with high-grade dysplasia might consider choosing RFA first followed by surgical treatment later, if the ablation is unsuccessful.
These results of the study are "promising," agreed Nurse Consultant Ellen Richmond, Program Director for Barrett esophagus in NCI's Division of Cancer Prevention. "And reducing the number of surveillance endoscopies is always a good thing," she added, because of the cost and potential risks associated with that procedure. However, more and larger studies are needed to confirm the value of RFA to patients at different stages of Barrett esophagus.