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1 Eur Surg (2009) 41/1: DOI /s z Springer-Verlag 2009 european surgery ACA Acta Chirurgica Austriaca Printed in Austria Radiofrequency ablation of Barrett's esophagus G. Arora 1;2, S. Basra 3, A. K. Roorda 4, G. Triadafilopoulos 5 1 Division of Gastroenterology, Hepatology and Nutrition, University of Texas Medical School, Houston, TX, USA 2 MD Anderson Cancer Center, Division of Gastroenterology, Hepatology and Nutrition, Houston, TX, USA 3 Department of Medicine, University of Texas Medical Branch, Galveston, TX, USA 4 Section of Digestive Diseases, West Virginia University, WV, USA 5 Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA Received January 9, 2009; accepted after revision January 26, 2009 Radiofrequenzablation bei Barrett-Ösophagus Zusammenfassung. Grundlagen: Barrett-Ösophagus (BE) besitzt ein erhöhtes Krebsrisiko und nimmt deutlich an Häufigkeit zu. Die Radiofrequenz-Ablation (RFA) stellt eine neue, vielversprechende Methode zur Barrett-Ablation dar. Methodik: Übersicht zu RFA bei Barrett-Ösophagus (Literatur: PubMed, Abstrakts der wichtigen Gastroenterologen-Kongresse 2007 und 2008). Ergebnisse: RFA erlaubt eine wirksame Behandlung des BE (auch bei Dysplasie) und erzielt hohe Heilungsraten mit minimalen Komplikationen. Eine Normalisierung des ph-wertes in der Speiseröhre (medikamentös oder chirurgisch) ist wichtig, um die Wirksamkeit zu verbessern und ein Rezidiv zu verhindern. Schlussfolgerungen: RFA ist eine äußerst wirksame, endoskopische Methode zur Entfernung von BE ( Dysplasie) und wird wohl die erste Therapie der Wahl bei BE werden. Wir benötigen aber weitere Daten, die den Stellenwert von RFA im Vergleich zu anderen Therapieoptionen vergleichen. Schlüsselwörter: Barrett-Ösophagus, Ablation, Radiofrequenz. Summary. Background: Barrett s esophagus (BE) is an important risk factor for esophageal carcinoma and its incidence is likely rising. Amongst the various available endoscopic ablative therapies, radiofrequency ablation (RFA) is a very promising new one. Methods: We performed a comprehensive review of the literature on the treatment of BE using RFA. We searched for published articles on Pubmed and also Correspondence: George Triadafilopoulos, M.D., D.Sc., Clinical Professor of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Always Building, Room M 211, 300 Pasteur Drive, MC: 5187, Stanford, CA , USA. Fax: þþ vagt@stanford.edu reviewed the abstracts from the major gastroenterological society meetings of 2007 and Results: RFA is an effective option in treating BE, especially when dysplastic changes are present, achieving high eradication rates with minimal complications. Prior control of intra-esophageal ph by either pharmacologic therapy or fundoplication is important in maximizing efficacy and preventing relapse. Conclusions: RFA is a very well tolerated therapy for non-dysplastic and dysplastic BE and will likely become a first-line treatment. More data, however, will be needed to compare the various existing modalities of endoscopic ablative and resection therapies for BE. Keywords: Barrett s, ablation, radiofrequency. Barrett's esophagus Barrett s esophagus (BE), a replacement of the normal squamous mucosa of the distal esophagus by an abnormal intestine-like mucosa (metaplasia), occurs as a result of chronic gastro-esophageal reflux disease (GERD). BE is the most important risk factor for the development of esophageal adenocarcinoma (EAC). The prevalence of BE has varied widely, likely because of different populations and definitions used to estimate it; it ranges from 0.9% to 4.5% [1, 2]. The incidence of BE might be rising, as highlighted by an Australian study that found that the number of cases of BE increased from 2.9 to 18.9 per 1000 endoscopies from 1990 to 2002 (p<0.001) [3]. BE is classified as long-segment (3 cm) or short-segment (<3 cm) based on the distance between the squamo-columnar junction (Z-line) and the gastro-esophageal junction (top aspect of gastric folds). Endoscopy, combined with multiple biopsies is reliable in up to 80% of the patients in detecting the presence of BE [4]. High levels of acid exposure, low resting lower esophageal sphincter pressure and poor esophageal motility are some of the risk factors associated with the development of BE. BE is also more common in patients with severe esophagitis Eur Surg Radiofrequency ablation of Barrett s esophagus 1/

2 Fig. 1: (A) Low-grade dysplasia in BE. (B) High-grade dysplasia in BE (Courtesy of Dr. Robert Odze, Brigham and Womens' Hospital, Boston, MA, USA) on barium study (e.g., stricture, ulcers), in those with longstanding GERD symptoms (>5 years),and in those with scleroderma [5]. The risk of dysplasia associated with short-segment BE is estimated to be 6 8% compared to 15 24% for long-segment BE [1, 6, 7]. The annual incidence of esophageal adenocarcinoma (EAC) in patients with BE varies from 0.2 to 2% [8 12]. EAC carries a dismal 5-year overall survival rate of 15%. Because of the lethal nature of EAC and evidence supporting the progression of BE to EAC via the stages of low-grade dysplasia (LGD) (Fig. 1A) and high-grade dysplasia (HGD) (Fig. 1B), early intervention in BE is of paramount significance. Patients with BE are advised to undergo regular endoscopic surveillance for dysplasia. Endoscopy with fourquadrant biopsy sampling at intervals of 1 2 cm of the entire length of the visibly abnormal epithelium remains the current standard for the detection of dysplasia or cancer in patients with BE. In turn, the management of BE depends on the histology of the biopsy specimens obtained during the endoscopy, and it can include intestinal metaplasia (IM), LGD, HGD and EAC. Therapeutic options for HGD in BE once confirmed by a second, expert pathologist include esophagectomy, endoscopic ablative therapies, endoscopic mucosal resection (EMR), and intensive endoscopic surveillance (usually every 3 months to detect progression to cancer). Out of these, esophagectomy is the only definitive treatment option, albeit the one with the highest rates of procedure-related mortality and long-term morbidity and impairment of life quality. The mortality rate for esophagectomy varies inversely with the volume of cases performed at any particular institution. In a study of 340 esophagectomies performed at 25 different hospitals, the mortality rate was 3.0% for patients who had the surgery at institutions that did 5 or more esophagectomies per year, compared to 12.2% for patients treated at institutions where the surgery was performed less frequently [13]. Surgical literature, showing a 43% prevalence of occult carcinoma in resection specimens of patients sent to surgery for HGD, is cited as evidence to support resective surgery [14]. Some authorities recommend that patients with HGD in BE should have expectant management with intensive endoscopic surveillance (i.e., endoscopic examinations every 3 6 months), and that definitive treatment should be withheld until biopsy specimens reveal EAC [15]. This practice has been endorsed as a management option by the American College of Gastroenterology [16], but few published data directly support the safety and efficacy of intensive surveillance for HGD. In patients with EAC limited to the mucosa (maximum T1, M1-3), endoscopic therapy (EMR and ablation) is an acceptable therapy. However, when EAC involves the submucosa or deeper layers, esophagectomy should be performed. Endoscopic ablative therapy of Barrett's esophagus Ablation can be accomplished with laser, multi-polar electrocoagulation, photodynamic therapy, or radiofrequency (RF) energy. Following ablation, patients are given potent anti-secretory therapy, and the injured mucosa heals with the growth of new squamous epithelium. The goals of ablative therapy are to arrest disease progression or eliminate it, increase survival by decreasing cancerrelated and surgery-related death, and reduce or eliminate the need for life-long surveillance. Prior to any ablative treatment, careful white-light endoscopic exam should be performed to note the full extent of the BE segment, measured as distance from the incisors of the Z-line and the top of the gastric folds. In addition, biopsies should be obtained from four quadrants from each 1 2 cm level of the BE, as also from any areas -nodular or eroded- that appear suspicious for dysplasia. To increase the yield from the biopsies, chromo-endoscopy, narrow band imaging, magnification endoscopy, auto-fluorescence or high-definition endoscopy may be employed. Prior to consideration for ablative therapy, anti-secretory therapy with a PPI should be used to fully control GERD symptoms. Some authors recommend the performance of ph monitoring on such therapy to ascertain control of the intra-esophageal ph even in patients who are symptomfree on PPI therapy. EMR should be used to resect any visible abnormality within the BE mucosa. In EMR, a diathermy snare or endoscopic knife is used to remove an entire segment of esophageal mucosa (down to the submucosa). Endoscopic ultrasonography (EUS) is performed first, especially if HGD is present, to estimate the depth of 20 1/2009 Radiofrequency ablation of Barrett s esophagus Eur Surg

3 the neoplastic lesion, since extension into the submucosa is a contraindication to EMR. A period of 8 weeks should be allowed after EMR for healing, before ablation is performed. Radiofrequency ablation (RFA) can be performed circumferentially or focally. Focal RFA is used for islands of abnormal mucosa that may remain after circumferential treatment or as a primary treatment for short-segment BE. Radiofrequency ablation for BE Circumferential RFA is delivered using the commercially available HALO 360 ablation system (BARRX Medical Inc., Sunnyvale, CA). This consists of an energy generator (Fig. 2A), a sizing balloon catheter (Fig. 2B), and balloon-based ablation catheters in various sizes (outer diameter 22, 25, 28, 31 or 34 mm) (Fig. 2C). The generator with its integrated pressure-volume system is used to inflate the sizing and ablation catheters, to calculate the inner diameter of the esophagus, and finally to deliver high-power, ultra-short burst of radiofrequency energy to the ablation catheter. To select the appropriately sized ablation catheter, a sizing balloon catheter is first used within the BE segment to measure the inner diameter of the esophagus in the BE segment. Subsequently, the ablation catheter is placed just proximal to the most proximal extent of the BE segment and RF energy is delivered from the generator to the catheter, using a foot-activated pedal (Fig. 2 left and middle panels). This is done in a proximal to distal fashion until the whole segment of BE has been ablated. Uniformity of the ablative energy, secondary to standardized power and energy density setting, electrode spacing and inflation pressure, ensures that the muscularis mucosae is not injured [17 19]. This procedure is simple enough that it can be performed on an outpatient basis and may require a mean of 2 sessions for complete ablation. Focal RFA is done using the HALO 90 ablation system. It consists of an energy generator and an electrode that delivers the RF energy and can be mounted on the endoscope (Fig. 2D and Fig. 3 right panel). To perform RFA, this electrode is placed into close contact with the abnormal mucosa and RF energy is delivered using the generator. The electrode is activated twice in succession and subsequent sessions may be performed if needed, at intervals of 2 3 months until all of the BE has been eradicated, as seen endoscopically (Fig. 3, right panel) and confirmed histologically (Fig. 4). Patients should be continued on high dose PPI (given twice daily, for most patients). Fig. 2: (A) HALO Energy Generator. (B) Dilation balloon catheter. (C) HALO-360 ablation catheter. (D) HALO-90 ablation catheter Outcomes of RFA for BE A multi-phase study evaluated the effect of a balloonbased bipolar radiofrequency electrode on esophageal epithelium. Phases I through III, performed using a porcine model, studied the energy density necessary to completely ablate the esophageal epithelium, the depth of ablation and possible stricture formation rate at each energy setting. In phase IV, the extent and degree of ablation was quantified histologically in human patients undergoing esophagectomy for EAC. Phase I showed that energy density settings of 9.7 to 29.5 Joules per square-centimeter surface area (J=cm 2 ) completely eliminated the esophageal epithelium. Phase II showed that the severity and frequency of stricture formation was directly proportional to the energy density, with an energy density >20 J=cm 2 Fig. 3: Endoscopic examples of radiofrequency ablation. Left panel: Un-inflated HALO-360 ablation catheter positioned on the top of BE. Middle panel: Immediately after ablation, a white coagulum is seen. Right panel: HALO-90 ablative therapy of a short-segment BE Eur Surg Radiofrequency ablation of Barrett s esophagus 1/

4 Fig. 4: Post-ablation histology: (A) Residual buried glands underneath neo-squamous epithelium, requiring follow-up ablation therapy. (B) Mixed mucus=oxyntic mucosa without goblet cells, not requiring further ablation (Courtesy of Dr. Robert Odze, Brigham and Womens' Hospital, Boston, MA, USA) resulting in stricture formation in all subjects, but settings 10.6 J=cm 2 or lower not causing any stricture formation. Phase III showed that the energy density provided was directly proportional to the depth of ablation confirmed histologically. Phase IV suggested that energy densities of 10 and 12 J=cm 2 were adequate to completely ablate the epithelium without any direct injury to the submucosa or stricture formation [17]. To determine the optimal RFA parameters (energy density and number of applications) required to completely ablate normal, squamous esophageal epithelium, without any trauma to the deeper layers, 13 patients with EAC underwent RFA prior to an esophagectomy [18]. These subjects were randomized to receive one of three energy density settings (8, 10, or 12 J=cm 2 ). The area proximal to the EAC was ablated once and the area distally twice. After the surgery, the esophageal adventitia and mediastinum were inspected for the depth and completeness of ablation and the thickness of residual ablation effect after tissue slough using hematoxylin and eosin, and diaphorase stains. The results showed that complete epithelial ablation was reliably achieved at 10 J=cm 2 and 12 J=cm 2,whereas8J=cm 2 and 10 J=cm 2 only partly ablated the epithelium. Thus, the maximum ablation depth was directly related to the energy density setting and that a second treatment did not change the depth of ablation significantly. For evaluation of the optimal treatment parameters for the ablation of IM containing HGD, 8 patients with a histopathological diagnosis of IM-HGD underwent RFA prior to esophagectomy and they were randomly treated with 10, 12, or 14 J=cm 2 for 2, 3, or 4 applications respectively [19]. After resection, multiple sections from the ablation zones were microscopically inspected for the maximum ablation depth and complete ablation of all IM-HGD. This study showed that the maximum ablation depth increased with the amount of energy density and the number of applications. None of the specimens showed any submucosal ablation. The deepest ablation was achieved at 14 J=cm 2 4 applications that led to edema of the superficial submucosa. Complete ablation was achieved in 9 of 10 ablation zones. At 12 J=cm 2 2applications, there was a single focus of HGD that remained at the margin of 1 out of 10 ablation zones. This was attributed to incomplete overlap of the second ablation application. The Ablation of Intestinal Metaplasia (AIM) trial enrolled patients from 8 U.S. Centers between 2003 and 2005, diagnosed with BE (without dysplasia) and who would retain their esophagus after RFA [17]. This trial comprised two phases: the dosimetry phase (n ¼ 32) and the effectiveness phase (n ¼ 70). The dosimetry phase aimed to determine the dose-response and the safety of delivering 6 to 12 J=cm 2 with only one application. There were no dose-related adverse events and the outcomes at 1and3monthsallowedfortheselectionof10J=cm 2 for the subsequent effectiveness phase of the trial. This latter phase used 10 J=cm 2 delivered twice, followed by endoscopy with biopsies at 1, 3, 6, and 12 months. At 12 months, a complete response, defined as all biopsy specimens being negative for BE, was seen in 70% of patients. There were no adverse events, such as stricture formation, or buried glandular mucosa. A U.S. multi-center uncontrolled prospective, clinical trial, assessed the long-term 2.5-year follow-up of the AIM-II patient population [20]. The goal of this trial was to assess the long-term safety and efficacy of stepwise circumferential ablation, followed by focal ablation. Seventy patients with 2 to 6 cm of BE and histological evidence of IM underwent circumferential ablation at baseline and the procedure was repeated at 4 months if there was any residual IM. Follow-up biopsy specimens were obtained at 1, 3, 6, 12, and 30 months. Focal ablation was performed if there was any IM present on either the 12-month biopsy or if there was endoscopic appearance of columnar-lined esophagus. At 12 months, a CR-IM was achieved in 48 of 69 patients. At 30 months, CR-IM was attained in 60 of 61 patients after the focal ablation (98% per protocol analysis). There were no strictures or buried glands at either 12 or 30 months. Roorda et al., used a combination of optimal ph control with twice daily PPI and circumferential RFA 22 1/2009 Radiofrequency ablation of Barrett s esophagus Eur Surg

5 (without focal RFA) to treat BE [21]. A total of 13 patients were treated in a single community-based, BE referral center, 3 with HGD, 4 with LGD, and 6 with IM. Circumferential RFA was followed by twice daily PPI and surveillance every 3 months for a total of 12 months. Patients received a second ablation if any metaplasia or dysplasia was present at follow-up. A 24-hr ambulatory esophageal ph of less than 4 was seen less than 4% of time in only 5 of 13 patients. After a mean ablation session of 1.4, CR was achieved in 6=13 patients with IM without dysplasia and 5=7 with IM with dysplasia. Their data support the notion that better ph control leads to more favorable response to RFA. A large, 16 US-center trial assessed the safety and effectiveness of circumferential ablation for treating BE- HGD [22]. One hundred forty two patients with BE-HGD (median length 6 cm) received circumferential ablation by using RFA with 1 median number of treatment sessions and a median follow-up of 12 months. Follow-up biopsies were assessed for complete histological response, defined as negative for HGD (CR-HGD), negative for any dysplasia (CR-D), and negative for IM (CR-IM). There were no serious adverse events, 1 patient developed an asymptomatic stricture, and no patients exhibited buried glands. A CR-HGD was achieved in 90.2% of patients, CR-D in 80.4%, and CR-IM in 54.3%. However, this trial was limited by its non-randomized study design, the lack of a control arm and a centralized pathology review, and for its lack of follow-up beyond 12 months. A single-center prospective study evaluated a stepwise approach of circumferential and focal ablation for eradicating IM and LGD over a 2-year follow-up [23]. Ten patients with LGD underwent circumferential ablation at baseline with repeat circumferential ablation at 4 months for any residual IM. Endoscopy with 4-quadrant biopsies every 1 cm was performed at 1, 3, 6, 12 and 24 months. After 1 year, focal ablation was performed for any residual IM. Patients also received lansoprazole 30 mg twice daily. At 2 years, CR for dysplasia was 100% and CR for IM was 90%. There were no strictures or evidence of buried glands. The single patient with persistent IM at 2 years received one additional focal ablation (off-trial) and was eventually IM-free. The safety and effectiveness of stepwise circumferential and focal RFA treating BE with HGD was assessed in a prospective cohort study of 10 patients without limiting the use of any prior endoscopic resection of visible lesions [24]. After any visible abnormalities were resected (in 6 patients), there were 2 patients with LGD and 9 with HGD. After undergoing a median of 2 circumferential and 2 focal ablations and an additional escape EMR in one patient, all patients had complete eradication of dysplasia and complete endoscopic and histological eradication of BE. Another study published by the same group evaluated the safety and efficacy of using stepwise circumferential and focal RFA for BE containing flat HGD or BE with residual dysplasia after EMR for HGD=intra-mucosal carcinoma (IMC) [25]. Twelve patients were enrolled, 11 with HGD and 1 with IMC after 7 patients underwent EMR for visible abnormalities. After a median of 1 circumferential and 2 focal ablations and an additional escape EMR in one patient, CR-IM was achieved in 12=12 patients. In both studies, there were no adverse events, strictures or buried glands in contrast to other ablation techniques (i.e. photodynamic therapy), which have a much higher rate of stricture formation. Moreover, scraping the coagulated tissues off using a cap thereby re-exposing the surface of the ablation zone and cleaning the electrode in between ablations probably contributed to better results. Two clinical studies assessed the effect of RFA on genetic abnormalities present in the metaplastic epithelium. In the first, 16 patients with BE-LGD received a single ablation and 5 received 2 ablations [26]. After a 2.5-year follow-up, 51 micro-dissection specimens were analyzed for a panel of 16 allelic imbalance mutational markers affecting 1p, 3p, 5q, 9p, 10q, 17p, 17q, 21q, and 22q using quantitative fluorescent PCR with capillary electrophoresis. RFA achieved a CR-IM in 15=16 patients (94%) and in all patients, previously present mutations were no longer detectable. In that one patient with persistent disease, only highly expanded mutations remained, indicating that highly clonally expanded mutations were more resistant to regression and required follow-up ablation treatment. Also, it was noted that mutational regression was time-dependent and could occur 6 12 months following treatment. In another study, Gondrie et al., assessed the successful elimination of all pre-existing genetic abnormalities in BE-HGD after step-wise use of circumferential and focal ablations [27]. Ten patients with BE-HGD with abnormal Ki67 and p53 staining along with fluorescent in-situ hybridization (FISH) abnormalities at baseline underwent stepwise circumferential and focal ablation. Two months after the focal ablation, CR-dysplasia and CR-IM were achieved in all patients (100%) and biopsy revealed the growth of neo-squamous epithelium without any abnormalities of Ki67, p53 or FISH. A randomized, sham-controlled trial assessed the utility of RFA in patients with dysplasia [28]. Patients were randomized to RFA or sham (2:1), HGD vs. LGD, and BE length (<4 vs. 4 8 cm). The results showed that at one-year interim follow-up, 74% (ITT, or intentionto-treat analysis) of patients randomized to RFA had no evidence of IM and 85% had no dysplasia (94% PP, or per protocol analysis). Moreover, compared to 0% progression of dysplasia in RFA-treated patients, 3 sham subjects had progression to HGD or CA. Five patients (6%) developed esophageal strictures all of which were removed with a mean of 2 endoscopic dilations. This trial, although still in progress, has shown that RFA is effective in eradicating IM and dysplasia in patients with LGD and flat HGD. Follow-up after RFA After RFA, some patients experience mild and transient discomfort which typically lasts less than 4 days [29]. Medications post-ablation usually include high-dose PPI, liquid acetaminophen with codeine, liquid antacid= lidocaine, sucralfate, and anti-emetics. Patients are advised to be on soft diet for one week and to avoid non-steroidal anti-inflammatory drugs, anticoagulants, or aspirin for at Eur Surg Radiofrequency ablation of Barrett s esophagus 1/

6 least a week before and after RFA. Follow-up endoscopies with a strict biopsy protocol may be repeated at 2 and 6 months after the last treatment and then annually if there is no endoscopically visible BE. Patients should be put on lifelong PPI therapy to prevent any GERD symptoms and recurrence of the metaplasia. Discussion The aforementioned published experience suggests that RFA is an effective option in treating BE, especially when dysplastic=neoplastic changes are present, achieving high eradication rates with minimal complications. To more effectively target areas for biopsies, application of technologies such as narrow-band imaging may be helpful. Prior control of intra-esophageal ph by either pharmacologic therapy or fundoplication is important in maximizing efficacy and preventing relapse (Fig. 5). Circumferential, followed by focal RFA, uniformly and rapidly treats large BE surface areas while limiting the maximum ablation depth to the muscularis mucosae. Preliminary studies suggest that endoscopic mucosal resection of visible neoplasia, followed by the combined use of circumferential and focal ablation, is the strategy most likely to achieve the best results (Fig. 6) [25]. Importantly, repeat treatments are possible, allowing for the continued maintenance of a IM-free esophagus over the lifetime of the patient [18]. Furthermore, the technique is nearly operator-independent, in regard to dosing, depth of ablation and targeting. Cost-effectiveness studies have shown RFA to be cost-effective compared to other interventions, such Fig. 6: Stepwise management of Barrett's esophagus containing either high-grade or low-grade dysplasia. Recognition of endoscopically visible lesions and their endoscopic resection is followed, 2 months later, by complete ablation of residual metaplasia and non-visible dyplasia by RFA therapy as surveillance alone, or esophagectomy [30]. Future studies would hopefully elucidate the optimal combination of currently available treatment modalities including ablation, endoscopic resection, surveillance, and surgery. Abbreviations BE, Barrett s Esophagus; CR, Complete Response; EAC, Esophageal Adenocarcinoma; EMR, Endoscopic Mucosal Resection; GERD, Gastro-esophageal Reflux Disease; HGD, High Grade Dysplasia; IM, Intestinal Metaplasia; IMC, Intramucosal carcinoma; ITT, Intention-to-treat; LGD, Low Grade Dysplasia; PP, Per Protocol; PPI, Proton Pump Inhibitor; RF, Radiofrequency; RFA, Radiofrequency Ablation. Fig. 5: Intra-esophageal ph control in BE prior to ablation. Optimal, long-term, intra-esophageal ph control is desirable prior to ablation of metaplasia, with or without dysplasia, in order to enhance the ablation efficacy and reduce the likelihood of BE recurrence Competing interests GT is a consultant and a member of the speakers bureau of BARRx, Takeda, Astra-Zeneca, and XenoPort, and has received honoraria for such activities. SB, GA and AR have no conflicts of interest. 24 1/2009 Radiofrequency ablation of Barrett s esophagus Eur Surg

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