Esophagus

Subject Category: Esophagus

Am J Gastroenterol 2013; 108:197–199; doi:10.1038/ajg.2012.415

Editorial: Endpoints for Radiofrequency Ablation in Barrett's Dysplasia

Emmanuel C Gorospe MD, MPH, CNSC1, Gang Sun MD, PhD1 and Kenneth K Wang MD, FACG1

1Barrett's Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA

Correspondence: Kenneth K. Wang, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA. E-mail: wang.kenneth@mayo.edu

Received 27 July 2012; Accepted 21 October 2012

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Abstract

The need to combat the rising incidence of esophageal adenocarcinoma with its dismal prognosis has led to increasing development of many endoscopic treatments for Barrett's esophagus (BE). Radiofrequency ablation (RFA) has been shown to be a safe and effective endoscopic treatment modality for dysplastic BE. The durability of successful eradication of dysplastic BE has been reported by earlier studies with limited sample size, follow-up time, and inadequate cohort of patients with high-grade dysplasia or intramucosal cancer. In this issue, Orman and colleagues present their findings from their single center, retrospective cohort of patients who underwent RFA with post-treatment surveillance. They report a low recurrence rate of 5.2% per year. There were no clinical characteristics found to be associated with BE recurrence in terms of length of segment or degree of dysplasia. Complete eradication of dysplasia (CE-D) or intestinal metaplasia was determined after a single post-RFA endoscopic examination with biopsies. This is an area of controversy as previous studies have used a minimum of two negative examinations before CE can be claimed. There are also limitations from sampling error during surveillance biopsies and the loss of a third of all post-RFA patients during surveillance. Multicenter, prospective studies with adequate follow-up are still needed before we can draw recommendations when to adequately cease post-treatment surveillance and to identify patients with increased risk of either recurrence or progression.

Radiofrequency ablation (RFA) has become an established endoscopic treatment for dysplasia in Barrett’s esophagus (BE). RFA was designed to produce a controlled superficial thermal injury directed specifically to the esophageal mucosa (1). Among the available endoscopic ablative modalities, RFA has been adopted the most due to its commercial availability, ease of use, and effective outcomes in eradicating dysplastic BE (2). For BE with high-grade dysplasia (HGD) or intramucosal cancer, RFA in conjunction with endoscopic mucosal resection for visible lesions provides a safe and cost-effective alternative to esophagectomy (3,4).

The efficacy of RFA in achieving either complete eradication of dysplasia (CE-D) or intestinal metaplasia (CE-IM) has been encouraging. In the 1-year follow-up of the AIM Dysplasia trial, almost 86% of patients treated with RFA achieved CE-D while 77% had CE-IM (5). However, the definitions of CE-D and CE-IM are all based on biopsies that suffer from sampling error. The analysis in the trial was based upon the findings at biopsy at a pre-determined time. If IM or dysplasia was detected subsequently, then additional treatment was performed. The 2-year interim, intention-to-treat analysis of the same prospective study demonstrated 85 and 83% CE-D and CE-IM rates, respectively. However, 55% of patients already required repeat RFA treatment after the first year (6). These issues concerning what is dysplasia recurrence, disease progression, and recommended surveillance after CE are becoming more important as more patients undergo ablative therapy with prospects for long-term follow-up.

In this issue of the American Journal of Gastroenterology, the study by Orman et al. (7) adds to the growing body of evidence that support RFA as an effective, safe, and likely durable treatment modality for BE complicated with dysplasia. Their aim was to assess the rates and risk factors for recurrence of dysplasia and IM after successful post-RFA therapy. The investigators conducted a retrospective cohort study of patients who underwent RFA and surveillance at their tertiary referral center. Appropriate options for the management of BE based on the degree of dysplasia were discussed and offered to all patients. Nodular lesions within the BE segment were also treated by endoscopic mucosal resection.

From a total of 188 patients who completed RFA, there were 183 patients who achieved CE-D and 168 with CE-IM. However, only 119 (65%) and 112 (67%) patients who achieved CE-D and CE-IM, respectively, continued with surveillance at the same tertiary center. The rest (>30%) were followed by their local or referring gastroenterologists and were not included in the analysis for rates of recurrence. Among the 119 patients who achieved CE-D and underwent surveillance, 85% did not have recurrence of dysplasia with a median follow-up of 393 days without requiring any additional RFA treatment. Similarly, 80% of the 112 patients who attained CE-IM and underwent surveillance did not have recurrence of IM. The outcomes of this study are comparable with previously reported rates of successful response to RFA (3,5,8). The conclusion highlights the low recurrence of IM (5.2% per year) in patients who achieved CE-IM after RFA. There were no identifiable clinical or endoscopic factors associated with recurrence after achieving CE-IM.

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Overall, Orman and colleagues have performed an important analysis on the rate and factors of IM or dysplasia recurrence after successful RFA in patients with dysplastic BE. However, several important limitations of this study should be considered. In the study, both CE-D and CE-IM were determined after a single upper endoscopy (EGD) with Seattle-protocol biopsies. Patients were deemed to be on surveillance after undergoing at least one EGD after the post-RFA endoscopy and biopsies that demonstrated CE-D or CE-IM status. In contrast, prior studies have assessed the attainment of CE-D and CE-IM usually after two consecutive, negative surveillance endoscopies with Seattle-protocol biopsies to minimize the number of patients with persistent dysplasia or IM missed due to sampling error during biopsy acquisition (9,10).

Of note, the follow-up intervals during post-RFA surveillance changed within the study period. From 2006 to 2009, the investigators performed surveillance based on pre-RFA histology. By 2009, patients with CE-IM underwent biannual surveillance for 1 year and then yearly afterwards, regardless of baseline histology. The American College of Gastroenterology guidelines recommend follow-up with endoscopy and biopsies at intervals based on the prior grade of dysplasia. Although this recommendation is associated with increased cost and invasiveness, an intensive surveillance protocol would provide closer follow-up and possible early treatment of patients at high risk for malignant progression. In the retrospective cohort of Orman et al., there were three patients with pre-RFA HGD who had histologic progression, of which two developed esophageal adenocarcinoma.

In spite of its limitations as a retrospective study, Orman and colleagues present one of the largest cohorts of post-RFA patients with HGD and intramucosal cancer who were evaluated for recurrence. A multicenter retrospective study from an NIH-sponsored BE study consortium recently reported 592 patients of whom 355 had pre-RFA HGD (11). Complete remission was assessed after two negative endoscopies with biopsies. In 24 months after achieving CR-IM, 33% of patients had recurrence of IM. Unlike the single center cohort presented by Orman et al., multivariate analysis of this multicenter study demonstrated advanced age and length of BE segment to be significant risk factors for failing to achieve remission of IM. Given the rate of IM recurrence in post-RFA patients cited in previous studies, the term “remission” from IM or dysplasia is more appropriate in describing the outcomes of RFA rather than declaring a definitive eradication (12).

In summary, there is good evidence supporting the use of RFA as an effective and safe therapeutic modality for dysplasia in BE (2,13,14). It is clear in all prospective cohort studies that repeated treatments with RFA will be required during follow-up (5,15,16). With the limitations due to sampling errors during biopsy acquisition, the possibility of buried metaplasia, and lack of evidence-based consensus recommendations, we suggest that patients receiving RFA for BE dysplasia should be kept in surveillance until definitive long-term, prospective data can provide further recommendations on the post-RFA endoscopic surveillance. In the same line, there are several studies that suggest enhanced patient survival if early esophageal neoplasia is detected by endoscopic surveillance as compared with symptomatic detection (17). To date, it is still unclear if RFA can maintain lifetime remission of dysplasia in certain patients. We still do not know how much buried metaplasia we are missing with surveillance biopsies (18). More importantly, we do not have definitive data to determine the duration of surveillance in post-RFA patients after achieving CE-IM. In the future, predictive biomarkers may become available for clinical application that would facilitate risk stratification of either pre- or post-ablation patients who may require long-term surveillance and extensive endoscopic evaluation with biopsies (19). Until then, endoscopic surveillance directed at the gastroesophageal junction and the original BE segment should be continued in post-ablation patients, especially in those with HGD or intramucosal cancer.

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Conflict of interest

Guarantors of the article: Emmanuel C. Gorospe, MD, MPH, CNSC and Kenneth K. Wang, MD, FACG.

Specific author contributions: All authors contributed to the concept and writing of the manuscript.

Financial support: None.

Potential competing interests: E.C. Gorospe and G. Sun have nothing to declare. K. K. Wang declares that he receives grant/research support from the following companies: Abbott Diagnostics, Barrx Medical, CSA Medical, Fujinon, NinePoint Medical, Oncoscope and Pinnacle Pharma.

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