REVIEW URRENT C OPINION
Radiofrequency ablation for Barrett’s esophagus Pavlos Z. Kaimakliotis and Gary W. Falk
Purpose of review Several studies published in the last year that have provided evidence on the efficacy, durability and safety of radiofrequency ablation (RFA) in Barrett’s esophagus are highlighted in this review. Recent findings RFA is well tolerated and efficacious in most but not all Barrett’s esophagus patients with dysplasia and esophageal adenocarcinoma (EAC). Recent reports have described highly variable rates of disease recurrence. Disease progression may occur during initial therapy or after complete eradication in a small, difficult to identify subset of patients. Studies are underway to help determine the predictors of response and recurrence. Modifications in technique and target populations have been described in the last year as well. Summary Endoscopic mucosal resection and RFA are the cornerstones in the management of dysplasia and early EAC in Barrett’s esophagus patients today. Despite the encouraging data on the effectiveness and safety of RFA, recurrence and progression of disease remain an issue in a subset of patients who are treated. Keywords Barrett’s esophagus, dysplasia, esophageal adenocarcinoma, radiofrequency ablation
INTRODUCTION Barrett’s esophagus with intestinal metaplasia is a risk factor for the development of esophageal adenocarcinoma (EAC), and the risk for this cancer increases substantially as the metaplasia progresses to low-grade dysplasia and high-grade dysplasia [1,2]. Prior to the introduction of ablative therapies for dysplastic Barrett’s esophagus, the management options consisted of intensive endoscopic surveillance or esophagectomy. Radiofrequency ablation (RFA) has revolutionized the management of dysplastic Barrett’s esophagus and early EAC and, in conjunction with endoscopic mucosal resection (EMR), has provided a less-invasive alternative to esophagectomy [3–6]. RFA offers the opportunity to eradicate the intestinal metaplasia of Barrett’s esophagus, thereby eliminating the underlying mucosa at risk for progression to cancer. However, the durability of this intervention remains uncertain, and current data suggest that regular endoscopic surveillance will be required even for patients who have complete eradication of intestinal metaplasia by RFA. The last year has offered further insight into the questions regarding RFA efficacy, durability, risk of recurrence and disease progression after ablation. The purpose of this article is to discuss these developments.
EFFICACY OF RADIOFREQUENCY ABLATION RFA has been shown in a randomized controlled trial to safely and effectively eradicate intestinal metaplasia and dysplasia in Barrett’s esophagus, and to decrease the rate of progression from dysplasia to cancer (Fig. 1) [7]. This study found reversal of high-grade dysplasia in 74% of treated patients at 1 year, and a follow-up study found that the response was durable in 93% of cases at 2 years [7,8]. Several studies in the last year have examined the effectiveness of RFA in large numbers of patients (Table 1) [9 ,10 ,11 ,12]. Bulsiewicz et al. [9 ] showed eradication of intestinal metaplasia in 80% of 244 Barrett’s patients with dysplasia or early EAC treated with RFA. Eradication of dysplasia was achieved in 87% of patients. Strictures were the most common &
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Division of Gastroenterology, Hospital of the University of Pennsylvania, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA Correspondence to Gary W. Falk, MD, MS, Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, 9 Penn Tower, One Convention Avenue, Philadelphia, PA 19104, USA. Tel: +1 215 615 4452; fax: +1 215 349 5915; e-mail: [email protected] Curr Opin Gastroenterol 2014, 30:415–421 DOI:10.1097/MOG.0000000000000087
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KEY POINTS RFA in combination with endoscopic mucosal resection provides well tolerated, effective and durable treatment for Barrett’s esophagus with dysplasia and early adenocarcinoma. Barrett’s patients with initial response to RFA may develop recurrence of intestinal metaplasia and dysplasia, or may even progress to adenocarcinoma. Postablation surveillance remains an integral part of the management of Barrett’s patients with dysplasia or early adenocarcinoma treated with RFA and EMR.
complication, seen in 8.2% of patients treated with RFA, and were more likely to develop in patients with a history of nonsteroidal anti-inflammatory drug use, prior antireflux surgery or erosive esophagitis. Orman et al. [13 ] performed a systematic review that included 3802 patients in 18 studies, and found that eradication of intestinal metaplasia was achieved in 78% of patients [95% confidence interval (CI) 70–86%] and eradication of dysplasia was achieved in 91% (95% CI 87–95%). Progression to cancer occurred in 0.2% of patients during &&
treatment (i.e. before complete eradication of intestinal metaplasia) and in 0.7% of patients after eradication of intestinal metaplasia had been achieved. The meta-analysis was, however, limited by significant heterogeneity and variability in the quality of the included studies. One study analyzed RFA data on 448 Barrett’s patients from three major tertiary referral centers in the USA [10 ]. Seventy-one percent of those patients had high-grade dysplasia or EAC, 15% low-grade dysplasia, 14% nondysplastic Barrett’s esophagus, and 55% had undergone EMR prior to RFA. Eradication of intestinal metaplasia was achieved in only 56% of patients at 24 months and 71% at 36 months. Recurrence of intestinal metaplasia was seen in 33% at 24 months, with 22% of all recurrences showing dysplasia. No factors could be identified to predict recurrence. Only one patient (3%) who was found to have a subsquamous EAC had a worse grade of histology at recurrence than prior to ablation. All patients with recurrent dysplastic Barrett’s esophagus had high-grade dysplasia on entry histology, and the recurrent dysplasia was treated successfully with endoscopic interventions in all but the one patient with cancer described above. Stricture formation occurred in &&
(a)
(b)
(c)
(d)
FIGURE 1. (a) Barrett’s esophagus C8M8 Prague Classification with high-grade dysplasia. (b) Same area of Barrett’s esophagus examined using narrow-band imaging. (c) Radiofrequency ablation with HALO360. (d) Follow-up with reestablishment of neosquamous epithelium and eradication of intestinal metaplasia. 416
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Barrett’s esophagus Kaimakliotis and Falk Table 1. Summary of the recent data on the efficacy of radiofrequency ablation for eradicating intestinal metaplasia and dysplasia No. of patients
Author
Length of BE median/mean (cm)
Complete eradication of IM
Complete eradication of dysplasia
Disease progression
87%
1.6%
Bulsiewicz et al. [9 ]
210
4 cm
80%
Gupta et al. [10 ]
448
4.3 cm
26% at 1 year
&
&&
3% (EAC)
56% at 2 years 71% at 3 years Haidry et al. [11 ] &&
335
5.8 cm
62% at 1 year
81% at 1 year
72
4.7 cm
82% LSBE
88% LSBE
10.8 cm
77% ULSBE
90% ULSBE
5.1% 3% (invasive cancer)
Dulai et al. [12]
n/a
BE, Barrett’s esophagus; EAC, esophageal adenocarcinoma; IM, intestinal metaplasia; LSBE, long-segment Barrett’s esophagus; ULSBE, ultralong-segment Barrett’s esophagus.
6.5% of patients, all of whom were managed effectively with dilation. The low rates of complete eradication and high rates of recurrence in this study may be explained by the requirement for two consecutive endoscopies without histologic or endoscopic evidence of intestinal metaplasia to define complete eradication, inclusion of patients with Barrett’s esophagus lengths greater than 8 cm, and a biopsy protocol that mandated that specimens be taken from the gastroesophageal junction (GEJ). Recurrences occurred equally as often at the GEJ as within the tubular esophagus, and the most common place for dysplasia recurrence was at the GEJ. The studies by Shaheen et al. [7,8], in contrast, sampled the area proximal to the neosquamocolumnar junction after RFA, but did not target the GEJ specifically. A study from The United Kingdom National Halo RFA registry included 335 Barrett’s esophagus patients with dysplasia or early adenocarcinoma (72% high-grade dysplasia, 24% EAC, and 4% lowgrade dysplasia) who were treated with EMR and RFA [11 ]. At 12 months, 86% of patients were free of high-grade dysplasia and 62% were free of intestinal metaplasia. Progression to invasive cancer occurred in 3% at 12 months. Progression to a worse &&
histology occurred in 5.1% of patients after a median follow-up of 19 months. Strictures developed in 9% of patients. Table 2 summarizes the data on RFA complications.
LONG-SEGMENT VERSUS ULTRALONGSEGMENT BARRETT’S ESOPHAGUS Until recently, most RFA studies included only patients with a Barrett’s esophagus segment less than 8 cm in length. Dulai et al. [12] reported on the treatment of Barrett’s esophagus at least 8 cm, termed ‘ultralong-segment Barrett’s esophagus’ (ULSBE), in a single-center study of 72 patients. Eradication rates for dysplasia were similar for ULSBE vs. long-segment Barrett’s esophagus (LSBE) (90 vs. 88%, P ¼ 1) and intestinal metaplasia (77 vs. 82%, P ¼ 0.77). Mean number of RFA sessions and time to eradication of dysplasia were also similar, 2.4 vs. 2 (P ¼ 0.180) and 8.3 vs. 8.5 months (P ¼ 0.470), respectively. However, eradication of intestinal metaplasia required significantly more RFA sessions in ULSBE vs. LSBE (2.9 vs. 2.2, P ¼ 0.008), but not more time (11.7 vs. 9.7 months, P ¼ 0.430). There was no recurrence of dysplasia. Intestinal metaplasia eradication was maintained at 3 years in 82% for
Table 2. Summary of data on RFA complications No. of patients
Author
All complications
Complication requiring hospitalization
Stricture
Bleeding
Bulsiewicz et al. [9 ]
244
9.4%
1.6%
8.2%
1.6%
Gupta et al. [10 ]
448
6.5%
0.3%
4.5%
1.4%
Haidry et al. [11 ]
335
9.3%
9%
72
14%
14%
&
&&
&&
Dulai et al. [12]
Mucosal tear
0.3% 0.3% (perforation)
RFA, radiofrequency ablation.
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LSBE, compared to 65% for ULSBE. This study showed RFA in ULSBE and LSBE had similar efficacy and safety profiles, but patients with ULSBE required more RFA sessions to achieve eradication of intestinal metaplasia, and RFA may be less durable in maintaining eradication in the ULSBE patients.
RADIOFREQUENCY ABLATION AFTER FUNDOPLICATION Barrett’s metaplasia is a complication of gastroesophageal reflux disease (GERD), but the indications for fundoplication to treat GERD generally are not influenced by the presence of Barrett’s esophagus. However, it is not known whether fundoplication influences the effectiveness of RFA therapy in Barrett’s esophagus. Shaheen et al. [14] studied the impact of fundoplication on RFA in 301 patients, and found similar rates of efficacy and adverse events. Eradication of intestinal metaplasia and dysplasia were achieved in 71 and 87% of fundoplication patients, and in 73 and 87% of patients without fundoplication, respectively. There was no difference in eradication of intestinal metaplasia or dysplasia in the two groups at 1 year. However, it remains unclear whether fundoplication should be considered in individuals refractory to RFA therapy, an issue that merits further investigation.
DURABILITY RFA clearly is effective for the treatment of dysplastic Barrett’s esophagus in the short term, but the treatment durability is not well defined. Data from the AIM Dysplasia Trial provided information on the durability of RFA in Barrett’s esophagus patients with dysplasia, allowing for additional RFA therapy as needed. At 2-year follow-up, compete eradication of dysplasia was reported in 95% of patients and complete eradication of intestinal metaplasia in
93% [8]. At 3 years, 98% of patients were free of dysplasia and 91% were free of intestinal metaplasia. Several studies this last year provided additional information on the recurrence rates after RFA and identified potential risk factors for recurrence (see Table 3) [10 ,11 ,12,13 ,15 ]. Orman et al. [16] reported the results of a single-center study on patients who had endoscopic surveillance after completing RFA for Barrett’s esophagus with dysplasia or early adenocarcinoma. Eradication of dysplasia was achieved in 119 patients, of whom 85% remained free of dysplasia at a median follow-up of 393 days with no additional therapy. Dysplasia recurred in patients with high-grade dysplasia and early adenocarcinoma at a rate of 4.2% per year. No patients with low-grade dysplasia had recurrent dysplasia. In patients with compete eradication of intestinal metaplasia, 80% remained free of intestinal metaplasia at a median follow-up of 397 days. In patients with preablation low-grade dysplasia, recurrent intestinal metaplasia occurred at a rate of 2.4% per year, whereas in patients with preablation highgrade dysplasia and intramucosal carcinoma, recurrent intestinal metaplasia occurred at rates of 5.5% per year and 9.4% per year, respectively. Among the patients with recurrent intestinal metaplasia, progression to early adenocarcinoma occurred in three of the eight patients, all of whom had preablation high-grade dysplasia. Any recurrence of intestinal metaplasia or worse histology occurred in 5.2% of patients per year during a total of 155 patient-years of observation. The rate of recurrence of high-grade dysplasia or worse histology was 2.6% per year, and the rate of adenocarcinoma was 1.3% per year. No clinical characteristics could be identified that predicted disease recurrence, perhaps because the number of recurrences was so small. A prospective, single-center study from Amsterdam of 54 patients with 5-year follow-up after treatment of Barrett’s esophagus with high-grade &&
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Table 3. Summary of data on the durability of RFA Author
No. of patients
Free of IM
Gupta et al. [10 ]
448
67%
Haidry et al. [11 ]
270
Dulai et al. [12]
34
&&
&&
Free of dysplasia
2 Years 94%
19 Months
82% LSBE
100% LSBE
3 Years
65% ULSBE
100% ULSBE
Orman et al. [13 ]
119 CE-D 112 CE-IM
Rate of progression 1.9%/year
Phoa et al. [15 ]
54
90%
&&
&
Follow-up duration
Recurrence rate of IM/dysplasia 5.2%/year
155 Patient-years observation
5 Years
CE-D, complete eradication of dysplasia; CE-IM, complete eradication of intestinal metaplasia; IM, intestinal metaplasia; LSBE, long-segment Barrett’s esophagus; RFA, radiofrequency ablation; ULSBE, ultralong-segment Barrett’s esophagus.
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dysplasia or early adenocarcinoma showed sustained remission of neoplasia and intestinal metaplasia in 90% of patients [15 ]. EMR had been performed in 72% of patients prior to RFA. Neoplasia recurrence was detected in three patients and was managed endoscopically. Subsquamous intestinal metaplasia (SSIM) was detected in only three patients in followup biopsies from the neosquamous epithelium, but subsequent endoscopies did not detect SSIM again. Tissue sampling at 5 years, including EMR samples in 30 patients, showed no evidence of SSIM in any patient. This study highlights the favorable longterm results that can be achieved with EMR and RFA of Barrett’s esophagus with high-grade dysplasia or early adenocarcinoma. It also demonstrates the need for long-term follow-up and careful inspection for focal areas of recurrence. It is not clear why Barrett’s metaplasia persists or recurs after RFA. Zeki et al. [17 ] hypothesized that RFA may select for the clonal expansion of mutated epithelial populations. In a case series of 19 Barrett’s patients with high-grade dysplasia or early adenocarcinoma, DNA was extracted from Barrett’s glands before and after RFA. Eight patients had detectable TP53 or CDKN2A mutations before and after treatment with EMR and RFA. Three of five patients with persistent disease had a single mutation present throughout the disease course. None of the patients with recurrent disease had persistent mutations, but developed new mutations after treatment. Jovov et al. [18] found that, compared with native squamous epithelium, the neosquamous epithelium exhibits defective barrier function with dilated intercellular spaces and abnormal permeability. This defective barrier function may render the neosquamous epithelium vulnerable to reflux damage and recurrent Barrett’s esophagus. This issue is clinically important because the underlying pathophysiologic defects that led to the development of Barrett’s esophagus are still present after RFA, and abnormal acid reflux can persist after RFA despite the use of high-dose proton pump inhibitors (PPIs). &
&
SUBSQUAMOUS INTESTINAL METAPLASIA Following endoscopic ablation of Barrett’s metaplasia, the reported frequency of SSIM (which can exhibit dysplasia and invasive carcinoma) ranges from 0 to 28% [19,20]. Phoa et al. [15 ] recently reported SSIM in 5.5% of patients during followup. None of these patients were found to have SSIM on subsequent surveillance biopsies, and there was no SSIM found in EMR samples taken specifically to detect SSIM in 30 patients. Prior reports may have underestimated the prevalence of SSIM because of &
biopsy sampling error. EMR offers greater tissue depth and surface area for histopathology compared with forceps biopsy. Other studies have reported SSIM present in 28–98% of patients referred for the endoscopic management of high-grade dysplasia or early adenocarcinoma in Barrett’s esophagus [21–23]. Thus, the prevalence of SSIM before and after RFA remains unclear. The presence of SSIM, however, has important potential implications for surveillance sampling and for planning the extent of endotherapy, given the potential for this mucosa to progress to adenocarcinoma. It remains unclear whether newer technologies, such as three-dimensional optical coherence tomography, will be helpful with this issue.
PREDICTORS OF RESPONSE Despite the effectiveness of RFA, not all Barrett’s esophagus patients achieve complete eradication of dysplasia and intestinal metaplasia. Barrett’s segment length, hiatal hernia size and uncontrolled weakly acidic reflux despite twice-daily PPI prior to RFA have been associated with persistent intestinal metaplasia after ablation [24]. Further insights into the predictive factors for initial treatment response after circumferential RFA (c-RFA) were obtained in a multicenter study of 278 patients with Barrett’s esophagus and high-grade dysplasia [25 ]. Poor initial response, defined as less than 50% regression of the Barrett’s surface area 3 months after initial RFA, was identified in 13% of patients. Poor initial responders required a median treatment period of 13 months with a median of four RFA sessions, compared with 7 months and three RFA sessions in good initial responders. Active reflux esophagitis at baseline despite PPI therapy was the strongest predictor of poor initial response to RFA. Other predictors included regeneration with Barrett’s epithelium instead of squamous epithelium after EMR, esophageal narrowing prior to RFA and years of neoplasia prior to RFA. Table 4 summarizes the factors associated with failure to achieve eradication of intestinal metaplasia. &
ALTERNATIVE RADIOFREQUENCY ABLATION REGIMENS Initial RFA of Barrett’s esophagus typically involves two consecutive, circumferential applications of radiofrequency energy using the HALO360 catheter, with a time-consuming step of removing the ablation catheter, reinserting the endoscope and ‘cleaning’ the ablated coagulum between energy applications. A multicenter randomized clinical trial compared this standard regimen to two simplified c-RFA
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Esophagus Table 4. Factors associated with failure to achieve eradication of intestinal metaplasia Author
Factors associated with failure to achieve eradication of IM
Bulsiewicz et al. [9 ]
Female sex
&
Longer length of BE Incomplete healing between treatment sessions Haidry et al. [11 ]
Each additional 1 cm of BE length reduces the chances of CE-D by 15.7%
Dulai et al. [12]
Increasing BE length associated with reduced likelihood of CE-IM (not dysplasia)
&&
Krishnan et al. [24]
Length of BE Hiatal hernia size Uncontrolled acid reflux despite twice daily PPI therapy
Van Vilsteren et al. [25 ] &
Active esophagitis at baseline despite PPI therapy BE regeneration at the EMR scar Esophageal narrowing prior to RFA Number of years with neoplasia prior to RFA
BE, Barrett’s esophagus; CE-D, complete eradication of dysplasia; CE-IM, complete eradication of intestinal metaplasia; EMR, endoscopic mucosal resection; IM, intestinal metaplasia; PPI, proton pump inhibitor; RFA, radiofrequency ablation.
regimens for patients with high-grade dysplasia [26]. In both simplified ablation regimens, the Barrett’s treatment zone was flushed with tap water. For one simplified regimen, the ablation zone coagulum was cleaned without removing the ablation catheter. In the second simplified regimen, two consecutive circumferential ablations were performed with no cleaning in between. There were no significant differences in the complication rates or in ablation results at 3 months among the three treatment groups. However, the time required to complete the RFA procedure was 20 min for the standard group, 13 min for the simple-with-cleaning group, and 5 min for the simple-no-cleaning group (P < 0.01). This study suggests that simplification of the current time-consuming RFA regimen is feasible. Further randomized studies comparing the simplified regimens to the standard approach are necessary to determine the long-term safety and efficacy. A multicenter study by the same group described a simplified RFA regimen for the treatment of focal areas of Barrett’s esophagus using the HALO90 catheter [27]. This regimen comprises three consecutive applications of RFA at 15 J/cm2 instead of the standard 12 J/cm2. A total of 41 patients, 83% with high-grade dysplasia or early adenocarcinoma were included in the study for the focal treatment of at least two Barrett’s islands. The two islands were randomized to the standard or the simplified ablation regimen. The proportion of completely ablated Barrett’s areas at 2 months after HALO90 RFA was 67% for the standard regimen and 73% for the simplified regimen, showing noninferiority of the simplified regimen. This study did not take into account the differences in the size and baseline 420
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histology of the Barrett’s islands treated with the two different regimens. This study did not compare the adverse events of the two regimens. Despite these limitations, the simplified regimen does appear promising.
CONCLUSION The last year has provided additional data to support the use of RFA for the treatment of patients with Barrett’s esophagus with dysplasia and early adenocarcinoma. These data show that RFA is a well tolerated, effective and durable technique for the management of most such patients. However, some patients require longer duration of therapy, and some will not achieve complete eradication of intestinal metaplasia or dysplasia. Some may even have disease progression despite apparently successful ablation. There is also a considerable risk of recurrence of both intestinal metaplasia and dysplasia after achieving complete eradication, which has implications for postablation surveillance. Of particular concern are the reports of SSIM with progression to subsquamous dysplasia and adenocarcinoma. There remains a need to identify better predictors of both response to RFA and recurrence after successful ablation. Consequently, our current endoscopic ablative techniques cannot yet be considered a cure for intestinal metaplasia with dysplasia and early adenocarcinoma, confirming the need for meticulous long-term surveillance and retreatment. Further studies are needed to provide more information on unanswered questions regarding posttreatment surveillance, predictors of response and disease progression or recurrence. Volume 30 Number 4 July 2014
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Acknowledgements None. Conflicts of interest None declared.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Sharma P, Falk GW, Weston AP, et al. Dysplasia and cancer in a large multicenter cohort of patients with Barrett’s esophagus. Clin Gastroenterol Hepatol 2006; 4:566–572. 2. Shaheen NJ, Richter JE. Barrett’s oesophagus. Lancet 2009; 373:850– 861. 3. Bennett C, Vakil N, Bergman J. Consensus statements for management of Barrett’s dysplasia and early-stage esophageal adenocarcinoma, based on a Delphi process. Gastroenterology 2012; 143:336–346. 4. Peters FP, Kara MA, Rosmolen WD, et al. Endoscopic treatment of high-grade dysplasia and early stage cancer in Barrett’s esophagus. Gastrointest Endosc 2005; 61:506–514. 5. Pech O, Behrens A, May A, et al. Long-term results and risk factor analysis for recurrence after curative endoscopic therapy in 349 patients with high-grade intraepithelial neoplasia and mucosal adenocarcinoma in Barrett’s oesophagus. Gut 2008; 57:1200–1206. 6. Alvarez Herrero L, Pouw RE, van Vilsteren FG, et al. Risk of lymph node metastasis associated with deeper invasion by early adenocarcinoma of the esophagus and cardia: study based on endoscopic resection specimens. Endoscopy 2010; 42:1030–1036. 7. Shaheen NJ, Sharma P, Overholt BF, et al. Radiofrequency ablation in Barrett’s esophagus with dysplasia. N Engl J Med 2009; 360:2277–2288. 8. Shaheen NJ, Overholt BF, Sampliner RE, et al. Durability of radiofrequency ablation in Barrett’s esophagus with dysplasia. Gastroenterology 2011; 141:460–468. 9. Bulsiewicz WJ, Kim HP, Dellon ES, et al. Safety and efficacy of endoscopic & mucosal therapy with radiofrequency ablation for patients with neoplastic Barrett’s esophagus. Clin Gastroenterol Hepatol 2013; 11:636–642. A retrospective study of 244 patients treated with RFA for Barrett’s esophagus with dysplasia or early EAC showed 80% eradication of intestinal metaplasia and 87% eradication of dysplasia. 10. Gupta M, Iyer PG, Lutzke L, et al. Recurrence of esophageal intestinal && metaplasia after endoscopic mucosal resection and radiofrequency ablation of Barrett’s esophagus: results from a US Multicenter Consortium. Gastroenterology 2013; 145:79.e1–86.e1. A multicenter consortium cohort study shows high rates of intestinal metaplasia recurrence and emphasizes the need for ongoing surveillance after RFA. 11. Haidry RJ, Dunn JM, Butt MA, et al. Radiofrequency ablation and endoscopic && mucosal resection for dysplastic Barrett’s esophagus and early esophageal adenocarcinoma: outcomes of the UK National Halo RFA Registry. Gastroenterology 2013; 145:87–95. A large UK experience found that dysplasia was cleared from 81% of patients by 12 months.
12. Dulai PS, Pohl H, Levenick JM, et al. Radiofrequency ablation for long- and ultralong-segment Barrett’s esophagus: a comparative long-term follow-up study. Gastrointest Endosc 2013; 77:534–541. 13. Orman ES, Li N, Shaheen NJ. Efficacy and durability of radiofrequency && ablation for Barrett’s esophagus: systematic review and meta-analysis. Clin Gastroenterol Hepatol 2013; 11:1245–1255. A systematic review and meta-analysis with significant study heterogeneity provides data on efficacy, durability and complications of radiofrequency ablation. 14. Shaheen NJ, Kim HP, Bulsiewicz WJ, et al. Prior fundoplication does not improve safety or efficacy outcomes of radiofrequency ablation: results from the U.S. RFA Registry. J Gastrointest Surg 2013; 17:21–28; discussion 28–29. 15. Phoa KN, Pouw RE, van Vilsteren FG, et al. Remission of Barrett’s esophagus & with early neoplasia 5 years after radiofrequency ablation with endoscopic resection: a Netherlands cohort study. Gastroenterology 2013; 145:96–104. A five-year follow-up of patients with HGD and early EAC showed a sustained remission rate of 90%. 16. Orman ES, Kim HP, Bulsiewicz WJ, et al. Intestinal metaplasia recurs infrequently in patients successfully treated for Barrett’s esophagus with radiofrequency ablation. Am J Gastroenterol 2013; 108:187–195; quiz 196. 17. Zeki SS, Haidry R, Graham TA, et al. Clonal selection and persistence in & dysplastic Barrett’s esophagus and intramucosal cancers after failed radiofrequency ablation. Am J Gastroenterol 2013; 108:1584–1592. A case series of 19 patients sheds light on the cause of persistent and recurrent dysplastic Barrett’s esophagus, and suggests that clonal expansion of persistent mutations postablation may account for persistent post-RFA disease. 18. Jovov B, Shaheen NJ, Orlando GS, et al. Defective barrier function in neosquamous epithelium. Am J Gastroenterol 2013; 108:386–391. 19. Titi M, Overhiser A, Ulusarac O, et al. Development of subsquamous highgrade dysplasia and adenocarcinoma after successful radiofrequency ablation of Barrett’s esophagus. Gastroenterology 2012; 143:564–660. 20. Gray NA, Odze RD, Spechler SJ. Buried metaplasia after endoscopic ablation of Barrett’s esophagus: a systematic review. Am J Gastroenterol 2011; 106:1899–1908; quiz 1909. 21. Chennat J, Ross AS, Konda VJ, et al. Advanced pathology under squamous epithelium on initial EMR specimens in patients with Barrett’s esophagus and high-grade dysplasia or intramucosal carcinoma: implications for surveillance and endotherapy management. Gastrointest Endosc 2009; 70:417–421. 22. Yachimski P, Shi C, Slaughter JC, Washington MK. Endoscopic mucosal resection of Barrett’s esophagus detects high prevalence of subsquamous intestinal metaplasia. World J Gastrointest Endosc 2013; 5:590–594. 23. Anders M, Lucks Y, El-Masry MA, et al. Subsquamous extension of intestinal metaplasia is detected in 98% of cases of neoplastic Barrett’s esophagus. Clin Gastroenterol Hepatol 2014; 12:405–410. 24. Krishnan K, Pandolfino JE, Kahrilas PJ, et al. Increased risk for persistent intestinal metaplasia in patients with Barrett’s esophagus and uncontrolled reflux exposure before radiofrequency ablation. Gastroenterology 2012; 143:576–581. 25. Van Vilsteren FG, Alvarez Herrero L, Pouw RE, et al. Predictive factors for & initial treatment response after circumferential radiofrequency ablation for Barrett’s esophagus with early neoplasia: a prospective multicenter study. Endoscopy 2013; 45:516–525. A prospective multicenter study showed patients with poor initial response to RFA have lower final success for eradication of intestinal metaplasia and dysplasia in Barrett’s esophagus, and require a longer treatment period. 26. Van Vilsteren FG, Phoa KN, Alvarez Herrero L, et al. Circumferential balloonbased radiofrequency ablation of Barrett’s esophagus with dysplasia can be simplified, yet efficacy maintained, by omitting the cleaning phase. Clin Gastroenterol Hepatol 2013; 11:491.e1–498.e1. 27. Van Vilsteren FG, Phoa KN, Alvarez Herrero L, et al. A simplified regimen for focal radiofrequency ablation of Barrett’s mucosa: a randomized multicenter trial comparing two ablation regimens. Gastrointest Endosc 2013; 78:30–38.
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Radiofrequency ablation for Barrett’s esophagus Pavlos Z. Kaimakliotis and Gary W. Falk
Purpose of review Several studies published in the last year that have provided evidence on the efficacy, durability and safety of radiofrequency ablation (RFA) in Barrett’s esophagus are highlighted in this review. Recent findings RFA is well tolerated and efficacious in most but not all Barrett’s esophagus patients with dysplasia and esophageal adenocarcinoma (EAC). Recent reports have described highly variable rates of disease recurrence. Disease progression may occur during initial therapy or after complete eradication in a small, difficult to identify subset of patients. Studies are underway to help determine the predictors of response and recurrence. Modifications in technique and target populations have been described in the last year as well. Summary Endoscopic mucosal resection and RFA are the cornerstones in the management of dysplasia and early EAC in Barrett’s esophagus patients today. Despite the encouraging data on the effectiveness and safety of RFA, recurrence and progression of disease remain an issue in a subset of patients who are treated. Keywords Barrett’s esophagus, dysplasia, esophageal adenocarcinoma, radiofrequency ablation
INTRODUCTION Barrett’s esophagus with intestinal metaplasia is a risk factor for the development of esophageal adenocarcinoma (EAC), and the risk for this cancer increases substantially as the metaplasia progresses to low-grade dysplasia and high-grade dysplasia [1,2]. Prior to the introduction of ablative therapies for dysplastic Barrett’s esophagus, the management options consisted of intensive endoscopic surveillance or esophagectomy. Radiofrequency ablation (RFA) has revolutionized the management of dysplastic Barrett’s esophagus and early EAC and, in conjunction with endoscopic mucosal resection (EMR), has provided a less-invasive alternative to esophagectomy [3–6]. RFA offers the opportunity to eradicate the intestinal metaplasia of Barrett’s esophagus, thereby eliminating the underlying mucosa at risk for progression to cancer. However, the durability of this intervention remains uncertain, and current data suggest that regular endoscopic surveillance will be required even for patients who have complete eradication of intestinal metaplasia by RFA. The last year has offered further insight into the questions regarding RFA efficacy, durability, risk of recurrence and disease progression after ablation. The purpose of this article is to discuss these developments.
EFFICACY OF RADIOFREQUENCY ABLATION RFA has been shown in a randomized controlled trial to safely and effectively eradicate intestinal metaplasia and dysplasia in Barrett’s esophagus, and to decrease the rate of progression from dysplasia to cancer (Fig. 1) [7]. This study found reversal of high-grade dysplasia in 74% of treated patients at 1 year, and a follow-up study found that the response was durable in 93% of cases at 2 years [7,8]. Several studies in the last year have examined the effectiveness of RFA in large numbers of patients (Table 1) [9 ,10 ,11 ,12]. Bulsiewicz et al. [9 ] showed eradication of intestinal metaplasia in 80% of 244 Barrett’s patients with dysplasia or early EAC treated with RFA. Eradication of dysplasia was achieved in 87% of patients. Strictures were the most common &
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Division of Gastroenterology, Hospital of the University of Pennsylvania, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA Correspondence to Gary W. Falk, MD, MS, Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, 9 Penn Tower, One Convention Avenue, Philadelphia, PA 19104, USA. Tel: +1 215 615 4452; fax: +1 215 349 5915; e-mail: [email protected] Curr Opin Gastroenterol 2014, 30:415–421 DOI:10.1097/MOG.0000000000000087
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KEY POINTS RFA in combination with endoscopic mucosal resection provides well tolerated, effective and durable treatment for Barrett’s esophagus with dysplasia and early adenocarcinoma. Barrett’s patients with initial response to RFA may develop recurrence of intestinal metaplasia and dysplasia, or may even progress to adenocarcinoma. Postablation surveillance remains an integral part of the management of Barrett’s patients with dysplasia or early adenocarcinoma treated with RFA and EMR.
complication, seen in 8.2% of patients treated with RFA, and were more likely to develop in patients with a history of nonsteroidal anti-inflammatory drug use, prior antireflux surgery or erosive esophagitis. Orman et al. [13 ] performed a systematic review that included 3802 patients in 18 studies, and found that eradication of intestinal metaplasia was achieved in 78% of patients [95% confidence interval (CI) 70–86%] and eradication of dysplasia was achieved in 91% (95% CI 87–95%). Progression to cancer occurred in 0.2% of patients during &&
treatment (i.e. before complete eradication of intestinal metaplasia) and in 0.7% of patients after eradication of intestinal metaplasia had been achieved. The meta-analysis was, however, limited by significant heterogeneity and variability in the quality of the included studies. One study analyzed RFA data on 448 Barrett’s patients from three major tertiary referral centers in the USA [10 ]. Seventy-one percent of those patients had high-grade dysplasia or EAC, 15% low-grade dysplasia, 14% nondysplastic Barrett’s esophagus, and 55% had undergone EMR prior to RFA. Eradication of intestinal metaplasia was achieved in only 56% of patients at 24 months and 71% at 36 months. Recurrence of intestinal metaplasia was seen in 33% at 24 months, with 22% of all recurrences showing dysplasia. No factors could be identified to predict recurrence. Only one patient (3%) who was found to have a subsquamous EAC had a worse grade of histology at recurrence than prior to ablation. All patients with recurrent dysplastic Barrett’s esophagus had high-grade dysplasia on entry histology, and the recurrent dysplasia was treated successfully with endoscopic interventions in all but the one patient with cancer described above. Stricture formation occurred in &&
(a)
(b)
(c)
(d)
FIGURE 1. (a) Barrett’s esophagus C8M8 Prague Classification with high-grade dysplasia. (b) Same area of Barrett’s esophagus examined using narrow-band imaging. (c) Radiofrequency ablation with HALO360. (d) Follow-up with reestablishment of neosquamous epithelium and eradication of intestinal metaplasia. 416
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Barrett’s esophagus Kaimakliotis and Falk Table 1. Summary of the recent data on the efficacy of radiofrequency ablation for eradicating intestinal metaplasia and dysplasia No. of patients
Author
Length of BE median/mean (cm)
Complete eradication of IM
Complete eradication of dysplasia
Disease progression
87%
1.6%
Bulsiewicz et al. [9 ]
210
4 cm
80%
Gupta et al. [10 ]
448
4.3 cm
26% at 1 year
&
&&
3% (EAC)
56% at 2 years 71% at 3 years Haidry et al. [11 ] &&
335
5.8 cm
62% at 1 year
81% at 1 year
72
4.7 cm
82% LSBE
88% LSBE
10.8 cm
77% ULSBE
90% ULSBE
5.1% 3% (invasive cancer)
Dulai et al. [12]
n/a
BE, Barrett’s esophagus; EAC, esophageal adenocarcinoma; IM, intestinal metaplasia; LSBE, long-segment Barrett’s esophagus; ULSBE, ultralong-segment Barrett’s esophagus.
6.5% of patients, all of whom were managed effectively with dilation. The low rates of complete eradication and high rates of recurrence in this study may be explained by the requirement for two consecutive endoscopies without histologic or endoscopic evidence of intestinal metaplasia to define complete eradication, inclusion of patients with Barrett’s esophagus lengths greater than 8 cm, and a biopsy protocol that mandated that specimens be taken from the gastroesophageal junction (GEJ). Recurrences occurred equally as often at the GEJ as within the tubular esophagus, and the most common place for dysplasia recurrence was at the GEJ. The studies by Shaheen et al. [7,8], in contrast, sampled the area proximal to the neosquamocolumnar junction after RFA, but did not target the GEJ specifically. A study from The United Kingdom National Halo RFA registry included 335 Barrett’s esophagus patients with dysplasia or early adenocarcinoma (72% high-grade dysplasia, 24% EAC, and 4% lowgrade dysplasia) who were treated with EMR and RFA [11 ]. At 12 months, 86% of patients were free of high-grade dysplasia and 62% were free of intestinal metaplasia. Progression to invasive cancer occurred in 3% at 12 months. Progression to a worse &&
histology occurred in 5.1% of patients after a median follow-up of 19 months. Strictures developed in 9% of patients. Table 2 summarizes the data on RFA complications.
LONG-SEGMENT VERSUS ULTRALONGSEGMENT BARRETT’S ESOPHAGUS Until recently, most RFA studies included only patients with a Barrett’s esophagus segment less than 8 cm in length. Dulai et al. [12] reported on the treatment of Barrett’s esophagus at least 8 cm, termed ‘ultralong-segment Barrett’s esophagus’ (ULSBE), in a single-center study of 72 patients. Eradication rates for dysplasia were similar for ULSBE vs. long-segment Barrett’s esophagus (LSBE) (90 vs. 88%, P ¼ 1) and intestinal metaplasia (77 vs. 82%, P ¼ 0.77). Mean number of RFA sessions and time to eradication of dysplasia were also similar, 2.4 vs. 2 (P ¼ 0.180) and 8.3 vs. 8.5 months (P ¼ 0.470), respectively. However, eradication of intestinal metaplasia required significantly more RFA sessions in ULSBE vs. LSBE (2.9 vs. 2.2, P ¼ 0.008), but not more time (11.7 vs. 9.7 months, P ¼ 0.430). There was no recurrence of dysplasia. Intestinal metaplasia eradication was maintained at 3 years in 82% for
Table 2. Summary of data on RFA complications No. of patients
Author
All complications
Complication requiring hospitalization
Stricture
Bleeding
Bulsiewicz et al. [9 ]
244
9.4%
1.6%
8.2%
1.6%
Gupta et al. [10 ]
448
6.5%
0.3%
4.5%
1.4%
Haidry et al. [11 ]
335
9.3%
9%
72
14%
14%
&
&&
&&
Dulai et al. [12]
Mucosal tear
0.3% 0.3% (perforation)
RFA, radiofrequency ablation.
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LSBE, compared to 65% for ULSBE. This study showed RFA in ULSBE and LSBE had similar efficacy and safety profiles, but patients with ULSBE required more RFA sessions to achieve eradication of intestinal metaplasia, and RFA may be less durable in maintaining eradication in the ULSBE patients.
RADIOFREQUENCY ABLATION AFTER FUNDOPLICATION Barrett’s metaplasia is a complication of gastroesophageal reflux disease (GERD), but the indications for fundoplication to treat GERD generally are not influenced by the presence of Barrett’s esophagus. However, it is not known whether fundoplication influences the effectiveness of RFA therapy in Barrett’s esophagus. Shaheen et al. [14] studied the impact of fundoplication on RFA in 301 patients, and found similar rates of efficacy and adverse events. Eradication of intestinal metaplasia and dysplasia were achieved in 71 and 87% of fundoplication patients, and in 73 and 87% of patients without fundoplication, respectively. There was no difference in eradication of intestinal metaplasia or dysplasia in the two groups at 1 year. However, it remains unclear whether fundoplication should be considered in individuals refractory to RFA therapy, an issue that merits further investigation.
DURABILITY RFA clearly is effective for the treatment of dysplastic Barrett’s esophagus in the short term, but the treatment durability is not well defined. Data from the AIM Dysplasia Trial provided information on the durability of RFA in Barrett’s esophagus patients with dysplasia, allowing for additional RFA therapy as needed. At 2-year follow-up, compete eradication of dysplasia was reported in 95% of patients and complete eradication of intestinal metaplasia in
93% [8]. At 3 years, 98% of patients were free of dysplasia and 91% were free of intestinal metaplasia. Several studies this last year provided additional information on the recurrence rates after RFA and identified potential risk factors for recurrence (see Table 3) [10 ,11 ,12,13 ,15 ]. Orman et al. [16] reported the results of a single-center study on patients who had endoscopic surveillance after completing RFA for Barrett’s esophagus with dysplasia or early adenocarcinoma. Eradication of dysplasia was achieved in 119 patients, of whom 85% remained free of dysplasia at a median follow-up of 393 days with no additional therapy. Dysplasia recurred in patients with high-grade dysplasia and early adenocarcinoma at a rate of 4.2% per year. No patients with low-grade dysplasia had recurrent dysplasia. In patients with compete eradication of intestinal metaplasia, 80% remained free of intestinal metaplasia at a median follow-up of 397 days. In patients with preablation low-grade dysplasia, recurrent intestinal metaplasia occurred at a rate of 2.4% per year, whereas in patients with preablation highgrade dysplasia and intramucosal carcinoma, recurrent intestinal metaplasia occurred at rates of 5.5% per year and 9.4% per year, respectively. Among the patients with recurrent intestinal metaplasia, progression to early adenocarcinoma occurred in three of the eight patients, all of whom had preablation high-grade dysplasia. Any recurrence of intestinal metaplasia or worse histology occurred in 5.2% of patients per year during a total of 155 patient-years of observation. The rate of recurrence of high-grade dysplasia or worse histology was 2.6% per year, and the rate of adenocarcinoma was 1.3% per year. No clinical characteristics could be identified that predicted disease recurrence, perhaps because the number of recurrences was so small. A prospective, single-center study from Amsterdam of 54 patients with 5-year follow-up after treatment of Barrett’s esophagus with high-grade &&
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Table 3. Summary of data on the durability of RFA Author
No. of patients
Free of IM
Gupta et al. [10 ]
448
67%
Haidry et al. [11 ]
270
Dulai et al. [12]
34
&&
&&
Free of dysplasia
2 Years 94%
19 Months
82% LSBE
100% LSBE
3 Years
65% ULSBE
100% ULSBE
Orman et al. [13 ]
119 CE-D 112 CE-IM
Rate of progression 1.9%/year
Phoa et al. [15 ]
54
90%
&&
&
Follow-up duration
Recurrence rate of IM/dysplasia 5.2%/year
155 Patient-years observation
5 Years
CE-D, complete eradication of dysplasia; CE-IM, complete eradication of intestinal metaplasia; IM, intestinal metaplasia; LSBE, long-segment Barrett’s esophagus; RFA, radiofrequency ablation; ULSBE, ultralong-segment Barrett’s esophagus.
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dysplasia or early adenocarcinoma showed sustained remission of neoplasia and intestinal metaplasia in 90% of patients [15 ]. EMR had been performed in 72% of patients prior to RFA. Neoplasia recurrence was detected in three patients and was managed endoscopically. Subsquamous intestinal metaplasia (SSIM) was detected in only three patients in followup biopsies from the neosquamous epithelium, but subsequent endoscopies did not detect SSIM again. Tissue sampling at 5 years, including EMR samples in 30 patients, showed no evidence of SSIM in any patient. This study highlights the favorable longterm results that can be achieved with EMR and RFA of Barrett’s esophagus with high-grade dysplasia or early adenocarcinoma. It also demonstrates the need for long-term follow-up and careful inspection for focal areas of recurrence. It is not clear why Barrett’s metaplasia persists or recurs after RFA. Zeki et al. [17 ] hypothesized that RFA may select for the clonal expansion of mutated epithelial populations. In a case series of 19 Barrett’s patients with high-grade dysplasia or early adenocarcinoma, DNA was extracted from Barrett’s glands before and after RFA. Eight patients had detectable TP53 or CDKN2A mutations before and after treatment with EMR and RFA. Three of five patients with persistent disease had a single mutation present throughout the disease course. None of the patients with recurrent disease had persistent mutations, but developed new mutations after treatment. Jovov et al. [18] found that, compared with native squamous epithelium, the neosquamous epithelium exhibits defective barrier function with dilated intercellular spaces and abnormal permeability. This defective barrier function may render the neosquamous epithelium vulnerable to reflux damage and recurrent Barrett’s esophagus. This issue is clinically important because the underlying pathophysiologic defects that led to the development of Barrett’s esophagus are still present after RFA, and abnormal acid reflux can persist after RFA despite the use of high-dose proton pump inhibitors (PPIs). &
&
SUBSQUAMOUS INTESTINAL METAPLASIA Following endoscopic ablation of Barrett’s metaplasia, the reported frequency of SSIM (which can exhibit dysplasia and invasive carcinoma) ranges from 0 to 28% [19,20]. Phoa et al. [15 ] recently reported SSIM in 5.5% of patients during followup. None of these patients were found to have SSIM on subsequent surveillance biopsies, and there was no SSIM found in EMR samples taken specifically to detect SSIM in 30 patients. Prior reports may have underestimated the prevalence of SSIM because of &
biopsy sampling error. EMR offers greater tissue depth and surface area for histopathology compared with forceps biopsy. Other studies have reported SSIM present in 28–98% of patients referred for the endoscopic management of high-grade dysplasia or early adenocarcinoma in Barrett’s esophagus [21–23]. Thus, the prevalence of SSIM before and after RFA remains unclear. The presence of SSIM, however, has important potential implications for surveillance sampling and for planning the extent of endotherapy, given the potential for this mucosa to progress to adenocarcinoma. It remains unclear whether newer technologies, such as three-dimensional optical coherence tomography, will be helpful with this issue.
PREDICTORS OF RESPONSE Despite the effectiveness of RFA, not all Barrett’s esophagus patients achieve complete eradication of dysplasia and intestinal metaplasia. Barrett’s segment length, hiatal hernia size and uncontrolled weakly acidic reflux despite twice-daily PPI prior to RFA have been associated with persistent intestinal metaplasia after ablation [24]. Further insights into the predictive factors for initial treatment response after circumferential RFA (c-RFA) were obtained in a multicenter study of 278 patients with Barrett’s esophagus and high-grade dysplasia [25 ]. Poor initial response, defined as less than 50% regression of the Barrett’s surface area 3 months after initial RFA, was identified in 13% of patients. Poor initial responders required a median treatment period of 13 months with a median of four RFA sessions, compared with 7 months and three RFA sessions in good initial responders. Active reflux esophagitis at baseline despite PPI therapy was the strongest predictor of poor initial response to RFA. Other predictors included regeneration with Barrett’s epithelium instead of squamous epithelium after EMR, esophageal narrowing prior to RFA and years of neoplasia prior to RFA. Table 4 summarizes the factors associated with failure to achieve eradication of intestinal metaplasia. &
ALTERNATIVE RADIOFREQUENCY ABLATION REGIMENS Initial RFA of Barrett’s esophagus typically involves two consecutive, circumferential applications of radiofrequency energy using the HALO360 catheter, with a time-consuming step of removing the ablation catheter, reinserting the endoscope and ‘cleaning’ the ablated coagulum between energy applications. A multicenter randomized clinical trial compared this standard regimen to two simplified c-RFA
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Factors associated with failure to achieve eradication of IM
Bulsiewicz et al. [9 ]
Female sex
&
Longer length of BE Incomplete healing between treatment sessions Haidry et al. [11 ]
Each additional 1 cm of BE length reduces the chances of CE-D by 15.7%
Dulai et al. [12]
Increasing BE length associated with reduced likelihood of CE-IM (not dysplasia)
&&
Krishnan et al. [24]
Length of BE Hiatal hernia size Uncontrolled acid reflux despite twice daily PPI therapy
Van Vilsteren et al. [25 ] &
Active esophagitis at baseline despite PPI therapy BE regeneration at the EMR scar Esophageal narrowing prior to RFA Number of years with neoplasia prior to RFA
BE, Barrett’s esophagus; CE-D, complete eradication of dysplasia; CE-IM, complete eradication of intestinal metaplasia; EMR, endoscopic mucosal resection; IM, intestinal metaplasia; PPI, proton pump inhibitor; RFA, radiofrequency ablation.
regimens for patients with high-grade dysplasia [26]. In both simplified ablation regimens, the Barrett’s treatment zone was flushed with tap water. For one simplified regimen, the ablation zone coagulum was cleaned without removing the ablation catheter. In the second simplified regimen, two consecutive circumferential ablations were performed with no cleaning in between. There were no significant differences in the complication rates or in ablation results at 3 months among the three treatment groups. However, the time required to complete the RFA procedure was 20 min for the standard group, 13 min for the simple-with-cleaning group, and 5 min for the simple-no-cleaning group (P < 0.01). This study suggests that simplification of the current time-consuming RFA regimen is feasible. Further randomized studies comparing the simplified regimens to the standard approach are necessary to determine the long-term safety and efficacy. A multicenter study by the same group described a simplified RFA regimen for the treatment of focal areas of Barrett’s esophagus using the HALO90 catheter [27]. This regimen comprises three consecutive applications of RFA at 15 J/cm2 instead of the standard 12 J/cm2. A total of 41 patients, 83% with high-grade dysplasia or early adenocarcinoma were included in the study for the focal treatment of at least two Barrett’s islands. The two islands were randomized to the standard or the simplified ablation regimen. The proportion of completely ablated Barrett’s areas at 2 months after HALO90 RFA was 67% for the standard regimen and 73% for the simplified regimen, showing noninferiority of the simplified regimen. This study did not take into account the differences in the size and baseline 420
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histology of the Barrett’s islands treated with the two different regimens. This study did not compare the adverse events of the two regimens. Despite these limitations, the simplified regimen does appear promising.
CONCLUSION The last year has provided additional data to support the use of RFA for the treatment of patients with Barrett’s esophagus with dysplasia and early adenocarcinoma. These data show that RFA is a well tolerated, effective and durable technique for the management of most such patients. However, some patients require longer duration of therapy, and some will not achieve complete eradication of intestinal metaplasia or dysplasia. Some may even have disease progression despite apparently successful ablation. There is also a considerable risk of recurrence of both intestinal metaplasia and dysplasia after achieving complete eradication, which has implications for postablation surveillance. Of particular concern are the reports of SSIM with progression to subsquamous dysplasia and adenocarcinoma. There remains a need to identify better predictors of both response to RFA and recurrence after successful ablation. Consequently, our current endoscopic ablative techniques cannot yet be considered a cure for intestinal metaplasia with dysplasia and early adenocarcinoma, confirming the need for meticulous long-term surveillance and retreatment. Further studies are needed to provide more information on unanswered questions regarding posttreatment surveillance, predictors of response and disease progression or recurrence. Volume 30 Number 4 July 2014
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Acknowledgements None. Conflicts of interest None declared.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Sharma P, Falk GW, Weston AP, et al. Dysplasia and cancer in a large multicenter cohort of patients with Barrett’s esophagus. Clin Gastroenterol Hepatol 2006; 4:566–572. 2. Shaheen NJ, Richter JE. Barrett’s oesophagus. Lancet 2009; 373:850– 861. 3. Bennett C, Vakil N, Bergman J. Consensus statements for management of Barrett’s dysplasia and early-stage esophageal adenocarcinoma, based on a Delphi process. Gastroenterology 2012; 143:336–346. 4. Peters FP, Kara MA, Rosmolen WD, et al. Endoscopic treatment of high-grade dysplasia and early stage cancer in Barrett’s esophagus. Gastrointest Endosc 2005; 61:506–514. 5. Pech O, Behrens A, May A, et al. Long-term results and risk factor analysis for recurrence after curative endoscopic therapy in 349 patients with high-grade intraepithelial neoplasia and mucosal adenocarcinoma in Barrett’s oesophagus. Gut 2008; 57:1200–1206. 6. Alvarez Herrero L, Pouw RE, van Vilsteren FG, et al. Risk of lymph node metastasis associated with deeper invasion by early adenocarcinoma of the esophagus and cardia: study based on endoscopic resection specimens. Endoscopy 2010; 42:1030–1036. 7. Shaheen NJ, Sharma P, Overholt BF, et al. Radiofrequency ablation in Barrett’s esophagus with dysplasia. N Engl J Med 2009; 360:2277–2288. 8. Shaheen NJ, Overholt BF, Sampliner RE, et al. Durability of radiofrequency ablation in Barrett’s esophagus with dysplasia. Gastroenterology 2011; 141:460–468. 9. Bulsiewicz WJ, Kim HP, Dellon ES, et al. Safety and efficacy of endoscopic & mucosal therapy with radiofrequency ablation for patients with neoplastic Barrett’s esophagus. Clin Gastroenterol Hepatol 2013; 11:636–642. A retrospective study of 244 patients treated with RFA for Barrett’s esophagus with dysplasia or early EAC showed 80% eradication of intestinal metaplasia and 87% eradication of dysplasia. 10. Gupta M, Iyer PG, Lutzke L, et al. Recurrence of esophageal intestinal && metaplasia after endoscopic mucosal resection and radiofrequency ablation of Barrett’s esophagus: results from a US Multicenter Consortium. Gastroenterology 2013; 145:79.e1–86.e1. A multicenter consortium cohort study shows high rates of intestinal metaplasia recurrence and emphasizes the need for ongoing surveillance after RFA. 11. Haidry RJ, Dunn JM, Butt MA, et al. Radiofrequency ablation and endoscopic && mucosal resection for dysplastic Barrett’s esophagus and early esophageal adenocarcinoma: outcomes of the UK National Halo RFA Registry. Gastroenterology 2013; 145:87–95. A large UK experience found that dysplasia was cleared from 81% of patients by 12 months.
12. Dulai PS, Pohl H, Levenick JM, et al. Radiofrequency ablation for long- and ultralong-segment Barrett’s esophagus: a comparative long-term follow-up study. Gastrointest Endosc 2013; 77:534–541. 13. Orman ES, Li N, Shaheen NJ. Efficacy and durability of radiofrequency && ablation for Barrett’s esophagus: systematic review and meta-analysis. Clin Gastroenterol Hepatol 2013; 11:1245–1255. A systematic review and meta-analysis with significant study heterogeneity provides data on efficacy, durability and complications of radiofrequency ablation. 14. Shaheen NJ, Kim HP, Bulsiewicz WJ, et al. Prior fundoplication does not improve safety or efficacy outcomes of radiofrequency ablation: results from the U.S. RFA Registry. J Gastrointest Surg 2013; 17:21–28; discussion 28–29. 15. Phoa KN, Pouw RE, van Vilsteren FG, et al. Remission of Barrett’s esophagus & with early neoplasia 5 years after radiofrequency ablation with endoscopic resection: a Netherlands cohort study. Gastroenterology 2013; 145:96–104. A five-year follow-up of patients with HGD and early EAC showed a sustained remission rate of 90%. 16. Orman ES, Kim HP, Bulsiewicz WJ, et al. Intestinal metaplasia recurs infrequently in patients successfully treated for Barrett’s esophagus with radiofrequency ablation. Am J Gastroenterol 2013; 108:187–195; quiz 196. 17. Zeki SS, Haidry R, Graham TA, et al. Clonal selection and persistence in & dysplastic Barrett’s esophagus and intramucosal cancers after failed radiofrequency ablation. Am J Gastroenterol 2013; 108:1584–1592. A case series of 19 patients sheds light on the cause of persistent and recurrent dysplastic Barrett’s esophagus, and suggests that clonal expansion of persistent mutations postablation may account for persistent post-RFA disease. 18. Jovov B, Shaheen NJ, Orlando GS, et al. Defective barrier function in neosquamous epithelium. Am J Gastroenterol 2013; 108:386–391. 19. Titi M, Overhiser A, Ulusarac O, et al. Development of subsquamous highgrade dysplasia and adenocarcinoma after successful radiofrequency ablation of Barrett’s esophagus. Gastroenterology 2012; 143:564–660. 20. Gray NA, Odze RD, Spechler SJ. Buried metaplasia after endoscopic ablation of Barrett’s esophagus: a systematic review. Am J Gastroenterol 2011; 106:1899–1908; quiz 1909. 21. Chennat J, Ross AS, Konda VJ, et al. Advanced pathology under squamous epithelium on initial EMR specimens in patients with Barrett’s esophagus and high-grade dysplasia or intramucosal carcinoma: implications for surveillance and endotherapy management. Gastrointest Endosc 2009; 70:417–421. 22. Yachimski P, Shi C, Slaughter JC, Washington MK. Endoscopic mucosal resection of Barrett’s esophagus detects high prevalence of subsquamous intestinal metaplasia. World J Gastrointest Endosc 2013; 5:590–594. 23. Anders M, Lucks Y, El-Masry MA, et al. Subsquamous extension of intestinal metaplasia is detected in 98% of cases of neoplastic Barrett’s esophagus. Clin Gastroenterol Hepatol 2014; 12:405–410. 24. Krishnan K, Pandolfino JE, Kahrilas PJ, et al. Increased risk for persistent intestinal metaplasia in patients with Barrett’s esophagus and uncontrolled reflux exposure before radiofrequency ablation. Gastroenterology 2012; 143:576–581. 25. Van Vilsteren FG, Alvarez Herrero L, Pouw RE, et al. Predictive factors for & initial treatment response after circumferential radiofrequency ablation for Barrett’s esophagus with early neoplasia: a prospective multicenter study. Endoscopy 2013; 45:516–525. A prospective multicenter study showed patients with poor initial response to RFA have lower final success for eradication of intestinal metaplasia and dysplasia in Barrett’s esophagus, and require a longer treatment period. 26. Van Vilsteren FG, Phoa KN, Alvarez Herrero L, et al. Circumferential balloonbased radiofrequency ablation of Barrett’s esophagus with dysplasia can be simplified, yet efficacy maintained, by omitting the cleaning phase. Clin Gastroenterol Hepatol 2013; 11:491.e1–498.e1. 27. Van Vilsteren FG, Phoa KN, Alvarez Herrero L, et al. A simplified regimen for focal radiofrequency ablation of Barrett’s mucosa: a randomized multicenter trial comparing two ablation regimens. Gastrointest Endosc 2013; 78:30–38.
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