Radiofrequency Ablation of Nondysplastic or Low-Grade Dysplastic Barrett's Esophagus
Executive Summary
Background
Barrett’s esophagus is a pathologic condition in which normal squamous epithelial tissues undergo inappropriate cell differentiation resulting in intestinal metaplasia manifested by replacement of normal epithelial cells by the specialized columnar type. This process occurs in response to chronic inflammatory irritation and injury caused by gastroesophageal reflux disease (GERD). The prevalence of Barrett’s esophagus is 10% to 15% in patients undergoing endoscopy for GERD symptoms and 1% to 2% in asymptomatic adults in the U.S. It develops in the distal esophagus and varies in length. Intestinal metaplasia is considered to be a precursor to esophageal adenocarcinoma; therefore, patients with Barrett’s esophagus are at an increased risk (i.e., 30- to 40-fold) for developing this disease in their lifetime compared to the general population. In patients diagnosed with Barrett’s esophagus with high-grade dysplasia, risk of progression to cancer is relatively high and esophageal adenocarcinoma is associated with poor morbidity and a 5-year survival rate of 13% or less. Therefore, intervention with esophagectomy or radiofrequency ablation may be strongly indicated. However, in Barrett’s esophagus with intestinal metaplasia, or low-grade dysplasia, which are the issues being addressed in this Assessment, it is not clear whether intervention with an endoscopic procedure to remove affected tissue would improve health outcomes.
Objective
This Assessment evaluates the outcomes of radiofrequency ablation plus surveillance versus surveillance alone in the treatment of nondysplastic or low-grade dysplastic Barrett’s esophagus. The key concern is whether radiofrequency ablation reduces the rate of disease progression while producing an acceptable risk of adverse events. The ideal way to investigate this is with randomized, comparative trials of these two approaches with long-term follow-up for disease progression or disease-specific mortality.
Search Strategy
A MEDLINE® search (via PubMed) was performed through September 2010, to obtain references to original reports on ablation of Barrett’s esophagus using a textword search for “radiofrequency” and “Barrett*” (truncated). In addition, clinicaltrials.gov was searched for completed studies. The queries were limited to English-language studies of human subjects. Review articles provided background information. The bibliographies of retrieved articles were consulted to identify references that may have been overlooked by the electronic search.
An additional search of studies on surveillance of Barrett’s esophagus was also conducted, focusing on systematic reviews, meta-analyses, decision analyses, and cost-effectiveness analyses.
Selection Criteria
Studies were selected for inclusion in the Assessment if they were full-length, peer-reviewed articles published in an English-language journal and studied Barrett’s esophagus treated with radiofrequency ablation in a comparative study of any size or single-arm study of at least 40 patients. Evidence for surveillance was sought from recent systematic reviews and meta-analyses.
Main Results
Of the 6 studies reviewed that met study selection criteria, only the single randomized trial systematically reported data on disease progression at 12 months for 66 patients with low-grade dysplasia. The trial found no cases progressing to cancer and 2 radiofrequency ablation cases (5%) versus 3 sham procedure cases (14%) progressing to high-grade dysplasia, a difference that was not statistically significant. A meta-analysis of 51 studies on surveillance alone provided ample evidence on disease progression. The individual risk of developing esophageal adenocarcinoma is 0.6% per year and the risk of mortality due to esophageal adenocarcinoma is 0.3% per year.
Follow-up histologic response is an intermediate outcome, a possible surrogate for disease progression. The randomized trial showed significantly higher probabilities of complete eradication of intestinal metaplasia and dysplasia for radiofrequency ablation than the sham procedure. Single-arm studies showed that probabilities of complete response for any signs of Barrett’s esophagus were 59% or higher at 12 months or longer, with higher complete response rates for more restrictive definitions of response. There was no evidence from the selected studies on symptoms, function, quality of life, or disease-specific mortality.
Adverse events include stricture, seen in 6% of radiofrequency ablation patients in the randomized trial. Strictures were also seen in 6.8% in one single-arm study, in 6.1% of a second study, 2.1% of a third, and in no patients in two other studies. Stricture typically requires endoscopic dilation that carries a risk of esophageal perforation and mortality. It is difficult to quantify the mortality risk associated with stricture, but it is likely greater than zero. Chest pain can occur immediately after ablation. One case of esophageal perforation was reported in these studies. Other adverse events include bleeding and mucosal injury or scarring.
Authors’ Conclusions and Comments
The available evidence is insufficient to show that radiofrequency ablation plus surveillance achieves a better net health outcome than surveillance alone among patients with nondysplastic or low-grade dysplastic Barrett’s esophagus.
Stricture occurs in up to 6% of patients. Stricture carries difficult to quantify risks of esophageal perforation and death, but these events are likely to have a nonzero probability. If the risk of procedure-related mortality is more than zero, evidence is needed to show that it is offset by a sufficiently large reduction in disease progression. Thus, it cannot be concluded that radiofrequency ablation of nondysplastic or low-grade dysplastic Barrett’s esophagus improves the net health outcome.
There is considerable variation in the technique of performing radiofrequency ablation. Both circumferential and focal ablation devices are typically used to treat a patient. It is unclear if circumferential ablation should be used more than once. It is also unclear how many follow-up ablation treatments are needed. Endoscopic mucosal resection may contribute toward any effects ablation may have on disease progression.
Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel made the following judgments about whether radiofrequency ablation of nondysplastic or low-grade dysplastic Barrett’s esophagus meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria.
1. The technology must have final approval from the appropriate governmental regulatory bodies.
The HALO system, the only radiofrequency ablation device currently represented by outcome studies, was developed by BÂRRX Medical, Inc. (Sunnyvale, Calif.). It is an automated device that uses radiofrequency energy and consists of two components: an energy generator and an ablation catheter. The generator provides rapid (i.e., less than 1 second) delivery of a predetermined amount of radiofrequency energy to the catheter. Both the HALO90 and HALO360 are inserted into the esophagus with an endoscope, using standard techniques. The HALO90 catheter is plate-based and used for focal ablation of areas of Barrett’s esophagus up to 3 cm. The HALO360 uses a balloon catheter that is sized to fit the individual esophagus, and is inflated to allow for circumferential ablation. The ablation with radiofrequency affects only the most superficial layer of the esophagus (the mucosa), with the intent of leaving the underlying tissues unharmed.
The HALO360 received U.S. Food and Drug Administration (FDA) marketing clearance via 510(k) in 2005 and the HALO90 in 2006. The FDA-cleared indications are use in coagulation of bleeding and nonbleeding sites in the gastrointestinal tract, and include the treatment of Barrett’s esophagus.
2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.
The key concern is whether radiofrequency ablation reduces the rate of disease progression while producing an acceptable risk of adverse events. The body of evidence on disease progression is too small and of too short a duration to permit conclusions about the effects of radiofrequency ablation on this outcome among patients with nondysplastic or low-grade dysplastic Barrett’s esophagus.
3. The technology must improve the net health outcome.
Stricture occurs in up to 6% of patients. Stricture carries difficult to quantify risks of esophageal perforation and death, but these events are likely to have a nonzero probability. If the risk of procedure-related mortality is more than zero, evidence is needed to show that it is offset by a sufficiently large reduction in disease progression. Without clear evidence of reduced disease progression, it cannot be concluded that radiofrequency ablation of nondysplastic or low-grade dysplastic Barrett’s esophagus achieves beneficial outcomes that outweigh harms.
4. The technology must be as beneficial as any established alternatives.
A meta-analysis of 51 studies on surveillance alone provided ample evidence on disease progression. The individual risk of developing esophageal adenocarcinoma is 0.6% per year and the risk of mortality due to esophageal adenocarcinoma is 0.3% per year.
Evidence does not support conclusions about the effects of radiofrequency ablation plus surveillance on health outcomes among patients with nondysplastic or low-grade dysplastic Barrett’s esophagus. Therefore, it is unclear whether radiofrequency ablation plus surveillance is as beneficial as surveillance alone.
5. The improvement must be attainable outside the investigational settings.
Whether radiofrequency ablation plus surveillance improves health outcomes in any setting has not been established.
Based on the above, radiofrequency ablation of nondysplastic or low-grade dysplastic Barrett’s esophagus does not meet the TEC criteria.
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ablation; adenocarcinoma; balloon; buried glands; circumferential; columnar; dysplasia; endoluminal; endoscopic; endosonography; epithelium; eradication; focal; intramucosal; meta-analysis; metaplasia; resection;
