effective treatment of early barrett’s neoplasia with stepwise circumferential and focal ablation...

Effective treatment of early Barrett’s neoplasia withstepwise circumferential and focal ablation using theHALO system

Authors J. J. Gondrie1, R. E. Pouw1, C. M. T. Sondermeijer1, F. P. Peters1, W. L. Curvers1, W. D. Rosmolen1, F. Ten Kate2,P. Fockens1, J. J. Bergman1

Institutions 1 Department of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands2 Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands

submitted 21 January 2008accepted after revision23 January 2008

BibliographyDOI 10.1055/s−2007−995589Published online:10 March 2008Endoscopy 2008; 40:370±379 � Georg ThiemeVerlag KG Stuttgart ´ New YorkISSN 0013−726X

Corresponding authorJ. J. Bergman, MDDepartment of Gastro−enterology and HepatologyAcademic Medical CenterMeibergdreef 91105 AZ, AmsterdamThe NetherlandsFax: +31−20−[email protected]

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Introduction!

Stepwise circumferential and focal ablation usingthe HALO ablation system is a relatively new en−doscopic treatment for Barrett’s esophagus [1±4]. In circumferential ablation, radiofrequencyenergy is delivered via a specially designed bal−loon (HALO360), which contains multiple electro−des encircling its outer surface. For focal ablationof residual areas of Barrett’s esophagus, an ar−ticulated, cap−based electrode using the sametechnology is used (HALO90).Recent studies suggest that stepwise circumfer−ential and focal ablation is highly effective in re−moving Barrett’s mucosa and its associated dys−plasia without the known drawbacks of other ab−lation techniques, such as residual dysplasia and

intestinal metaplasia, esophageal stenosis, or re−sidual subsquamous Barrett’s mucosa (“buriedBarrett’s”) [1, 2].We have recently published the results of a studyin which stepwise circumferential and focal abla−tion was used for treatment of 11 patients withBarrett’s esophagus presenting with either flathigh−grade dysplasia (HGD) or residual dysplasiaafter prior endoscopic resection for HGD or intra−mucosaal cancer (IMC) [2]. Ablation was found tobe a highly effective. All patients achieved com−plete clearance of dysplasia as well as completeendoscopic and histological clearance of all intes−tinal metaplasia. All ablation sessions were per−formed as outpatient procedures, there were nosevere complications, and post−ablation symp−toms were generally mild and short−lasting [2].

Study aims: The aim of the current study was toevaluate the efficacy and safety of stepwisecircumferential and focal ablation using theHALO system for Barrett’s esophagus containingflat, high−grade dysplasia (HGD) or residualdysplasia after endoscopic resection for HGD orintramucosal cancer (IMC).Methods: Visible abnormalities were removedwith endoscopic resection prior to ablation. Per−sistence of dysplasia and absence of IMC wereconfirmed with biopsy after endoscopicresection. A balloon−based electrode was usedfor primary circumferential ablation and anendoscope−mounted electrode was used forsecondary focal ablation.Results: Twelve patients (nine men; median age70 years) were treated (median Barrett’s length7 cm). Visible abnormalities were removed byendoscopic resection in seven patients. The worstpathological grade of residual Barrett’s esopha−gus after resection and prior to ablation waslow−grade dysplasia (LGD) (n = 1) and HGD(n = 11). Patients underwent a median of onecircumferential and two focal ablation sessions.

Complete remission of dysplasia was achieved in12/12 patients (100%). Complete endoscopic andhistological removal of Barrett’s esophagus wasachieved in 12/12 patients (100%). There wereno ablation−related stenoses, and nosubsquamous Barrett’s esophagus was observedin 363 biopsies obtained from post−ablationneo−squamous mucosa. Protocolized cleaning ofthe ablation zone and electrode in betweenablations resulted in superior regression ofBarrett’s esophagus compared with previousstudies. During a median follow−up of 14 monthsno recurrence of dysplasia or Barrett’s esophaguswas observed.Conclusions: Stepwise circumferential and focalablation for Barrett’s esophagus with flat HGD orfor Barrett’s with residual dysplasia afterendoscopic resection for HGD/IMC is a safe andeffective treatment modality. Its success rateand safety profile compare favorably withalternatives such as esophagectomy, widespreadendoscopic resection or photodynamic therapy.

Gondrie JJ et al. Stepwise circumferential and focal ablation for early Barrett’s neoplasia ¼ Endoscopy 2008; 40: 370 ± 379

In the study, the maximum allowable length of Barrett’s esopha−gus was 7 cm and a relatively high number of ablation proce−dures were required to achieve the impressive success rate: allpatients underwent two circumferential ablations and up tothree focal ablations sessions. This was partially due to the factthat the focal ablation technology only became available mid−way into the study period, which required us to treat small resi−dual islands with circumferential ablation whereas focal abla−tion would have been a more logical choice. In addition, thiswas the first study in which the focal ablation device was usedin clinical trials, and the optimal energy settings had to beadjusted during the study period [2].The aim of the current study was therefore to use the knowledgedeveloped in our first study to treat patients with Barrett’sesophagus with HGD or IMC under more optimal circumstances,now also allowing the inclusion of patients with a Barrett’s seg−ment of > 7 cm.

Patients and methods!

Patients selectionPatients were eligible if they met all of the following inclusioncriteria:1. Barrett’s esophagus defined as a columnar−lined esophagus

on endoscopy showing intestinal metaplasia upon biopsy;endoscopic Barrett’s length between 2 and 10 cm;

2. at baseline, HGD or IMC diagnosed at two separate endosco−pies and assessed by an experienced gastrointestinal pathol−ogist (FtK);

3. any visible endoscopic abnormality on high−resolution en−doscopy removed with endoscopic resection prior to abla−tion;

4. in cases of prior endoscopic resection, documented presenceof residual low−grade dysplasia (LGD) or HGD in biopsies ob−tained after endoscopic resection;

5. age between 18 and 85 years;6. written informed consent.

Patients were excluded in cases where one of the following ex−clusion criteria was present:1. in cases of a prior endoscopic resection: vertical resection

margin positive for cancer, submucosal invading cancer,poorly differentiated cancer, or presence of lymphatic/vascu−lar invasion;

2. baseline esophageal stenosis with resistance to passage of atherapeutic endoscope (Olympus ITQ160 or IT140, OlympusEurope, Hamburg, Germany, outer diameter of 11.7 mm);

3. visible abnormalities after endoscopic resection, but prior toablation;

4. invasive cancer in any biopsy obtained after endoscopic re−section, but prior to ablation;

5. absence of residual dysplasia (i. e. LGD or HGD) after endo−scopic resection, but prior to ablation.

Endoscopic work−up and management prior to ablationAll patients underwent at least two separate endoscopic proce−dures for mapping of the Barrett’s segment, performed withhigh−resolution endoscopes with narrow band imaging (NBI)capabilities (GIF−Q240Z, Lucera 260 system, Olympus, Tokyo, Ja−pan or GIF−H180, Excera II−system and a high−definition monitor,Olympus Europe, Hamburg, Germany).

The length of the Barrett’s section was determined according tothe Prague classification system [5]. The maximum proximal ex−tent of the Barrett’s mucosa (i. e. including islands) was alsodocumented, as isolated islands are not categorized in the Pra−gue system. In addition, the location of the diaphragmatic pinchand the presence of a hiatal hernia were recorded. Visible lesionswere classified according to the Japanese Classification of EarlyGastric Carcinoma [6], and targeted biopsies were taken fol−lowed by random 4−quadrant biopsies at 2−cm intervals.All patients underwent endoscopic ultrasonography (EUS) usingelectronic radial endoscopes (GF−UE160, Olympus GmbH, Ham−burg, Germany) in conjunction with an Aloka SSD−5000 Pro−Sound processor (Aloka, Meerbusch, Germany).All patients with endoscopically visible abnormalities had theirlesions removed by endoscopic resection for diagnostic purposesprior to ablation and to ensure that ablation was performed onan endoscopically flat mucosa.Endoscopic resection was performed with the cap technique orwith the multiband mucosectomy technique [7, 8]. After endo−scopic resection, all resection specimens were collected for his−topathological analysis. High−resolution endoscopy was per−formed 6 weeks after endoscopic resection to exclude the pres−ence of visible abnormalities prior to ablation, and to obtainbiopsies to evaluate the presence of residual dysplasia in the re−maining Barrett’s esophagus. Ablation was performed within 3months after the last mapping endoscopy and at least 6 weeksafter endoscopic resection.

The HALO360 and HALO90 system (l" Fig. 1)Both ablation systems used in this trial (HALO Ablation Systems,B�RRX Medical Inc., Sunnyvale, California, USA) have 510(k)clearance by the Food and Drug Administration in the USA andthe CE Mark for Europe for the treatment of Barrett’s esophagus.Circumferential ablation is performed using the HALO360 system,consisting of an energy generator, ablation catheter, and sizingballoon (l" Fig. 1). The sizing balloon is used for measuring theinner diameter of the esophagus prior to ablation. The noncom−pliant balloon has a length of 4 cm and a central lumen for guidewire passage. Upon activation, the balloon is automaticallyinflated to 4 psi (0.28 atm) and the esophageal inner diameteris automatically calculated based on the baseline balloon vol−ume/geometry and the inflated pressure/volume. The sizing bal−loon can measure esophageal diameters in the range of approxi−mately 18± 33.7 mm, and each measuring cycle takes approxi−mately 6 seconds. The esophageal inner diameter is measuredfor every 1 cm of the Barrett’s segment and an appropriatelysized HALO360 ablation catheter is selected based on these meas−urements.The ablation catheter consists of a noncompliant balloon with a3−cm long bipolar electrode on its outer surface (l" Fig. 1). Theelectrode contains 60 250−�m−wide electrode rings, which com−pletely encircle the balloon, each ring being 250 �m apart fromits neighboring rings. The ablation catheter is available in fiveouter diameter sizes (22, 25, 28, 31, and 34 mm), and is intro−duced over a guide wire. Ablation settings were 12 J/cm2 and 40W/cm2.Focal ablation is performed using the HALO90 system, consistingof an energy generator and a cap−based device that is mountedon the distal tip of an endoscope (compatible with endoscopeouter diameter in the range of 8.6 ± 12.8 mm). The device(l" Fig. 1) has a 20 � 15−mm articulated platform on its uppersurface with an electrode array identical to that of HALO360. The

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focal device is mounted with the electrode surface positioned atthe 12 o’clock position in the video image, and is used for abla−tion of tongues and islands with a maximum length of 2 cm andless than 50 % of the circumference. Ablation settings were 12±15 J/cm2 and 40 W/cm2.

Endoscopic procedures and medicationEndoscopic treatments were performed under conscious seda−tion with midazolam and/or fentanyl. Patients were clinicallyobserved for 3 ±4 hours after the ablation procedures and thendischarged. Patients were prescribed esomeprazole 40 mg bidas a maintenance dosage and ranitidine 300 mg at bedtime plus5 mL sucralfate suspension (200 mg/mL) qid for a period of 2weeks after each treatment endoscopy.

Circumferential ablation techniqueIn the first ablation session the whole circumference of the Bar−rett’s segment was treated using the HALO360 device (l" Fig. 2).The Barrett’s segment was first flushed with 10± 20 mL of acetyl−cysteine (1 %) for mucolysis followed by flushing with 40± 60 mLof tap water. Subsequently, a 0.035−inch guide wire (Amplatz ex−tra stiff, Cook Endoscopy, Limerick, Ireland) was introduced intothe duodenum and the endoscope was removed. The sizing bal−loon was then introduced over the guide wire and positioned 3±5 cm above the proximal margin of the Barrett’s esophagus. Theinner diameter of the esophagus was then measured at 1−cm lin−ear increments along the Barrett’s length. Based on this sizingprocedure an ablation catheter with the appropriate diameterwas chosen and introduced over the guide wire. Alongside theablation catheter the endoscope was then introduced and, undervisual control, the Barrett’s esophagus was ablated, starting 1 cmabove the most proximal extent of the Barrett’s segment (includ−ing islands) and continuing into the hiatal hernia (l" Fig. 2). Eachablation resulted in a 3−cm mucosal segment being treated, anda small overlap (i. e. < 1 cm) between ablation zones was accept−ed. After the entire Barrett’s segment was treated, the endoscopewas removed followed by removal of the ablation balloon. Whilethe balloon electrode was cleaned manually outside the patientto remove adherent tissue, the endoscope was reintroduced toremove all ablated and sloughing tissue from the ablation zoneby a combination of suctioning and vigorous flushing with tapwater (l" Fig. 2). The stomach was then emptied and deflated,the endoscope was removed followed by reintroduction of theablation catheter and the endoscope to repeat the whole abla−

tion procedure so that all areas received two applications of en−ergy (l" Fig. 2).

Focal ablation technique system (l" Fig. 3)At subsequent ablation sessions, the Barrett’s segment was firstevaluated for the presence of strictures and the presence of resi−dual Barrett’s mucosa using white light and NBI endoscopy. TheBarrett’s segment was flushed with acetylcysteine (1%) followedby flushing with tap water. The endoscope was subsequentlywithdrawn and the proximal esophagus was thoroughlyinspected to exclude the presence of a Zenker’s diverticulumthat might impair subsequent introduction of the focal ablationcatheter.The focal ablation catheter was then mounted on the tip of theendoscope and introduced into the distal esophagus. Targetedareas were positioned at the 12 o’clock position in the videoen−doscopic image, the endoscope deflected upwards so as to bringthe ablation surface into firm contact with the tissue, and abla−tion delivered successively two times to each area in anautomated manner (l" Fig. 3). In cases where the squamocolum−nar junction (SCJ) had an irregular appearance, suggesting possi−ble residual Barrett’s mucosa, the SCJ was treated circumferen−tially using the same technique. After all targeted areas hadbeen treated, the ablated tissue was cleaned of adherent coagu−lum using the leading edge of the device. The device and the en−doscope were subsequently removed to clean the electrode sur−face and then reintroduced to treat all areas a second time (againwith two successive ablations to each area).

Study protocol system (l" Fig. 4)After the endoscopic work−up (with or without endoscopic re−section for removal of visible lesions), the primary circumferen−tial ablation was performed within 3 months after the last map−ping endoscopy and at least 6 weeks after any endoscopic resec−tion. Subsequent ablation sessions were scheduled at 2−monthintervals, using high−resolution endoscopy with NBI. Islandswith a maximum length of 2 cm and less than 50 % of the circum−ference were treated with focal ablation using the “double−dou−ble 12 J/cm2 regimen” described above. For larger areas of resi−dual Barrett’s mucosa, circumferential ablation was repeated.After a maximum of two circumferential ablation sessions andtwo focal ablation sessions using the double−double 12 J/cm2 re−gimen, mapping of the original Barrett’s segment was repeated(l" Fig. 4). After this was completed, all patients underwent ahigh−resolution endoscopy with NBI to evaluate the presence of

Fig. 1 Set−up of the HALO360 and HALO90 system.a HALO360 sizing balloon. b Generator with footpedal. c HALO360 ablation balloon for circumferen−tial ablation. d HALO90 catheter for focal ablationmounted on an endoscope.

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residual Barrett’s mucosa and to estimate the percentage surfaceregression. Targeted biopsies were taken of any residual Barrett’smucosa present and random biopsies (4Q Bx/1cm) were takenfrom neo−squamous epithelium throughout the full extent ofthe original Barrett’s esophagus and from the area immediatelydistal to the neo−SCJ. No additional ablation was performed atthis time point.Patients who demonstrated residual intestinal metaplasia at thisstage were eligible for an additional focal ablation using theaforementioned double−double regimen, but now performed atan energy density setting of 15 J/cm2. This was again followedby a high−resolution endoscopy with NBI at 2 months. If therewas residual Barrett’s mucosa at that point, it was removedwith endoscopic resection using the multiband mucosectomytechnique as an escape treatment.Final outcome was assessed 2 months after the last treatment byhigh−resolution endoscopy with NBI and biopsies from any visi−ble islands or tongues of columnar−appearing mucosa, neo−squamous mucosa, and immediately distal to the neo−SCJ.Subsequent follow−up endoscopies were scheduled at 6 and 12months and yearly after the last treatment session with EUS forthose patients who were treated for an invasive cancer initially.

Histopathological reviewAll biopsies and endoscopic resection specimens were routinelyprocessed and stained with hematoxylin and eosin. They wereevaluated by a junior pathologist supervised by a senior gastro−intestinal pathologist. For the purpose of this study, all speci−mens were further reviewed by an experienced pathologist(FtK) and scored on standardized case report forms. Endoscopicresection specimens were evaluated for the presence of intes−tinal metaplasia, LGD, HGD, and invasive cancer. In cases of inva−sive cancer, tumor differentiation, penetration depth, and lym−phatic/vascular invasion were assessed. In addition, the verticaland lateral margins of the resection specimens were evaluatedfor the presence of dysplasia or cancer. Biopsy specimens wereevaluated for the presence of intestinal metaplasia, LGD, HGDor IMC as well as for the presence of residual glands underneathneo−squamous epithelium (buried Barrett’s), irrespective ofwhether such glands communicated with the epithelial surface.

Outcome measuresThe primary endpoint of the study was the complete histologicalclearance of dysplasia and cancer after treatment. In addition,the following secondary endpoints were assessed: the rate of

Fig. 3 Endoscopic appearance of a focal ablationprocedure using the HALO90 system. a Four residualislands of Barrett’s mucosa remaining after primarycircumferential ablation. b Corresponding viewwith narrow band imaging. c Effect immediatelyafter the ablation: there is necrotic debris coveringthe ablation zone; the distal edge of the HALO90

catheter can be seen at the 12 o’clock position ofthe endoscopic view.

Fig. 2 Endoscopic appearance of a circumferential ablation procedureusing the HALO360 system. a C10M11 Barrett’s esophagus with high−gradedysplasia. b HALO360 ablation balloon positioned 1 cm above the maximumextent of the Barrett’s esophagus. c Effect immediately after the first abla−tion. d View after removal of the balloon catheter. There is necrotic debris

covering the ablation zone. e View after cleaning the ablation zone by suc−tioning and water rinses in preparation for the second ablation pass. f Effect6 weeks later: 99 % surface area regression with only small residual islandsremaining for focal ablation using the HALO90 system.



complete endoscopic and histological eradication of intestinalmetaplasia (including biopsies obtained from neo−squamousmucosa and distal to the neo−SCJ), the rate of acute and late com−plications of ablation, and the number of treatment sessions re−quired.

Ethical considerations and statisticsThe study was approved by the Medical Ethics Committee of ourinstitute, and informed consent was obtained from all partici−pants.Data were analyzed using the SPSS statistical software package(SPSS Inc., Chicago, USA). For descriptive statistics, the mean(� SD) was used in cases of a normal distribution of variables,and the median (25 % ±75 %) was used for variables with askewed distribution. Where appropriate, the Mann±Whitneytest and Fisher exact test were used.

Results!

Patients system (l" Table 1)Eligible patients were recruited between September 2005 andJanuary 2006, during which period endoscopic work−up and en−doscopic resection (if required) were carried out. All patientswere then treated with their first ablation session in February2006. Twelve patients (nine men; median age 70 years [range,53±76 years]) were included. The median length of the Barrett’ssegment was 7 cm (range, 6.5 ± 8 cm). Seven patients (58 %) un−derwent endoscopic resection for focal removal of visible ab−normalities prior to ablation. There were six piecemeal proce−dures with a median of 2 resections (IQR 2±3). There were no im−mediate resection−related complications. The resection speci−mens showed IMC (n = 2) and HGD (n = 5). The worst pathologi−cal grade after endoscopic resection and prior to ablation wasLGD (n = 1) and HGD (n = 11).

Clearance of dysplasia and intestinal metaplasia system(l" Fig. 5)Complete histological eradication of dysplasia was finallyachieved in all patients (100%; l" Fig. 6). In eleven patients(92 %) this endpoint was reached after one circumferential abla−tion and two focal ablation sessions. One patient underwent twocircumferential ablations and two focal ablation sessions butstill had residual HGD in the distal part of the esophagus(l" Fig. 7). Subsequent focal ablation at 2 � 2 15 J/cm2 did not re−sult in complete removal of Barrett’s esophagus and he was fi−nally treated with three endoscopic resection sessions untilcomplete removal of all Barrett’s esophagus and dysplasia wasachieved (l" Fig. 7). The resection specimens of the first two es−cape resection procedures contained HGD and IMC; the resec−tion specimens of the third resection contained only gastric−type mucosa.Complete endoscopic and histological eradication of intestinalmetaplasia (including biopsies obtained from neo−squamousmucosa and distal to the neo−SCJ) was achieved in all patients

Table 1 Patient demographics

Number of patients 12

Sex (M/F) 9/3

Median age, years (IQR) 70 (53 ± 76)

Median length Barrett’s esophagus, cm (IQR) 7 (6.5 ± 8)

Worst histology at inclusion, HGD/IMC 11/1

Number of patients with endoscopic resectionprior to RFA (%) 7 (58)

Number of patients with piecemeal resection,n/N (%) 6/7 (86)

Histology of resected specimen, HGD/IMC 5/2

Worst histology after resection prior to ablation,LGD/HGD 1/11

HGD = high−grade dysplasia; IMC = intramucosal cancer; IQR = interquartilerange; LGD = low−grade dysplasia; RFA, radiofrequency ablation.

Mapping Barrett’s esophagus with HGD/IMC

Endoscopic resection Endoscopic resection of visible lesions

Post-endoscopic resection Mapping Histology prior to ablation

At inclusion HALO360 (2 x12 J/cm2)

2 months intervals

Outcome I EGD, biopsies

Follow-up I EGD, biopsies at 6 months after last treatment

Follow-up II EGD, biopsies and EUS at 12 months after last treatment

HALO360 (2 x12 J/cm2) or HALO90 (2x12 J/cm2)Maximum of 2 HALO360 and 2 HALO90 sessions

2 months interval HALO90 (2 x12 J/cm2) Only for persisting Barrett’s esophagus

2 months interval Escape endoscopic resection. Only for persisting Barrett’s esophagus

Final Outcome EGD, biopsies

Fig. 4 Flow chart illustrating the study protocol.EGD, esophagogastroduodenoscopy; EUS, endo−scopic ultrasonography; HGD, high−grade dyspla−sia; IMC, intramucosal cancer.

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(100%; l" Fig. 5). In eight patients (67%) this endpoint wasreached after one circumferential ablation and two focal abla−tion sessions. Three other patients had small residual Barrett’sislands or an irregular Z−line left; the median percentage surfaceregression being 100% (IQR 99 ±100). These three patients wereeffectively treated with an additional focal ablation at 2 � 2 15 J/cm2. Finally, one patient had 85% surface area regression aftertwo circumferential ablations and two focal ablation sessionsbut still had a significant amount of Barrett’s esophagus leftthat was found to contain HGD upon biopsy. As mentionedabove he was treated with an additional focal ablation at 2 � 215 J/cm2 but finally required endoscopic resection for completeremoval of all Barrett’s esophagus and dysplasia.Patients were followed up for a median period of 14 months (IQR13± 15) after the first ablation session and 9.5 months (IQR 8 ±10) after the last treatment session. All patients underwent the6−month follow−up assessment whereas three patients under−went the 12−month follow−up assessment. After a median num−ber of 2 follow−up endoscopies, none of the patients showed re−currence of dysplasia or endoscopic signs of recurrent Barrett’smucosa. A total of 363 biopsies were obtained from normal−ap−pearing neo−squamous mucosa (median number per patient 30[IQR 22± 39]). In none of these biopsies was intestinal metapla−sia encountered, neither at the surface epithelium nor buried be−low the neo−squamous mucosa (buried Barrett’s).

Number of treatment sessions and complicationsEleven patients underwent a single circumferential ablation;one patient was treated twice with circumferential ablation.Eight patients had two focal ablations and four patients hadthree focal ablations. Only one patient underwent endoscopicresection as escape treatment (three sessions).

All ablation sessions were performed as outpatient procedures.There were no severe complications. One patient initially under−went endoscopic resection with resection of two specimens(l" Fig. 8), with relative narrowing of the esophagus noted atthe 6−week follow−up (without dysphagia). At the time of pri−mary circumferential ablation 6 weeks later, we noted an 8−mmnodule. We ablated and then performed a focal endoscopic re−section with the multiband mucosectomy technique in thesame session, with the specimen showing HGD. Due, perhaps,to the previous narrowing and simultaneous endoscopic resec−tion and ablation, the patient developed dysphagia that resolvedafter one Savary dilatation procedure.No other complications occurred during the treatment protocolor follow−up period.

Discussion!

HGD or IMC in Barrett’s esophagus can be effectively treatedwith a combined approach of endoscopic resection followed bystepwise circumferential and focal ablation [2]. Endoscopic re−section removes thicker, visible lesions and enables proper pa−tient selection based on the histological assessment of the resec−tion specimen: patients showing submucosal invasion are refer−red for surgery and those with mucosal neoplasia are amendablefor endoscopic management [8 ±11]. As endoscopic resectiongenerally only results in removal of focal lesions, recurrent le−sions may develop elsewhere in the Barrett’s segment duringfollow−up [10± 13]. Endoscopic resection is therefore often com−bined with ablative techniques for removal of residual dysplasiaas well as removing the entire remaining nondysplastic Barrett’smucosa. Ablation techniques, such as photodynamic therapy(PDT) and argon plasma coagulation (APC) are, however, asso−

Barrett’s esophagus with HGD/IMC (n = 12)

Endoscopic resection of visible lesions (n = 7)IMC (n = 2); HGD (n = 5)

Histology prior to ablationHGD (n = 11); LGD (n = 1)

Clearance of dysplasia 11/12HGD 1/12Clearance of intestinal metaplasia 8/12Surface regression 99.9 %

3 ablations (n = 11), 4 ablations (n = 1)

Clearance of dysplasia 12/12Clearance of intestinal metaplasia 12/12Intestinal metaplasia of cardia 0/12Surface regression 100%

Additional HALO90 (n = 4), escape endoscopic resection (n = 1)

Clearance of dysplasia 12/12Clearance of intestinal metaplasia 12/12Intestinal metaplasia of cardia 0/12Surface regression 100%

Follow up since start therapy (months) 14Follow up since last treatment (months) 9.5Number follow up endoscopies 2Number follow up biopsies 30

Pre-assessment

Outcome I

Final outcome

Follow-up

Fig. 5 Summary of the clinical outcome of 12 pa−tients with high−grade dysplasia (HGD) or intramu−cosal cancer (IMC) who where treated with step−wise circumferential and focal ablation using theHALO ablation system after focal endoscopic re−moval of visible abnormalities.



ciated with significant drawbacks [14 ±20]. PDT and APC oftendo not result in complete removal of the whole Barrett’s segmentand/or require multiple treatment sessions [14 ± 18]. In addition,PDT and APC may cause residual areas of intestinal metaplasia tobecome hidden underneath the neo−squamous mucosa that re−generates after treatment (i. e. buried Barrett’s), and anecdotalreports have suggested that these foci can progress to cancer[21 ± 23]. Furthermore, areas of Barrett’s mucosa remaining afterPDT or APC have been found to contain the same genetic ab−normalities as those present prior to treatment, suggesting per−sistent malignant potential [24,25]. Finally, significant compli−cations may occur after APC and PDT, of which esophageal steno−sis is the most frequently reported [15, 26].Recent studies suggest that stepwise circumferential and focalablation using the HALO ablation system is a highly effective ab−lation technique that, due to its design and metered dosing, isnot associated with the aforementioned drawbacks [1,2]. Wehave recently published the first study on the use of this ablationtechnique for treatment of 11 Barrett’s patients with either flatHGD or with residual dysplasia after prior endoscopic resectionfor HGD or IMC [2]. In that trial, all patients had complete clear−ance of dysplasia and complete endoscopic and histological re−moval of all Barrett’s mucosa. These impressive results were re−produced in the current study: all 12 patients had complete era−

dication of dysplasia and complete endoscopic and histologicalclearance of intestinal metaplasia. All treatment sessions wereperformed as outpatient procedures, and there were no severecomplications or hospital admissions.Patients in the current study had a longer Barrett’s segment thanthe ones included in our first study (median Barrett’s length7 cm [IQR 6.5 ± 8] vs. 5 cm [IQR 4 ±7], P = 0.07). Despite the largersurface area to be treated, patients required fewer ablation ses−sions than in the previous study (mean 3.4 sessions vs. 4.2 ses−sions; P = 0.02). The apparently higher efficacy in the currentstudy has three plausible explanations. First, the current studyincorporated the use of the focal ablation system from the begin−ning of the study, whereas it was incorporated only halfway intothe previous study [2]. Second, our present study avoided thelearning curve and dose−escalation issues that were worked outin the first study. Nevertheless, four of our patients still requireda step up of focal ablation to double−double 15 J/cm2. As this wasnot associated with any significant complications or side effects,we suggest that this double−double 15 J/cm2 setting is used forsubsequent ablation studies. Third, in the current study we in−cluded in the protocol the technical step of removing the adher−ent coagulum of the ablation zone and cleaning of the electrodebetween the two ablation passes of the circumferential ablationprocedure. In our first study, this was done by just superficially

Fig. 6 Endoscopic appearance of a C7M8 Barrett’sesophagus with high−grade dysplasia. a, b Appear−ance of the Barrett’s esophagus prior to ablation.c, d After complete endoscopic removal of all Bar−rett’s esophagus. e ,f Corresponding view with nar−row band imaging.

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cleaning the ablation zone with the ablation balloon beingpassed into the stomach. In the current study the ablation bal−loon was removed from the esophagus and extensive water rin−ses and suctioning were used to clean the ablated segment be−fore applying the second ablation (l" Fig. 2). When we comparedthe amount of surface regression after just one primary circum−ferential ablation session between the two studies, the currentstudy had a superior outcome (median percentage surface re−gression 99% vs. 90 %; P = 0.04). In our opinion, cleaning the elec−trode and ablation zone after the first pass provides a more as−sured eradication allowing for more optimal focal ablation ofany residual Barrett’s esophagus at follow−up sessions.The current study also differs from the first study in a higher rateof piecemeal resections in patients who underwent an endo−scopic resection prior to ablation (6/7 vs. 0/6; P < 0.05). This im−plies that patients with larger visible lesions and thus a morewidespread resection were included in the present study. Onepatient suffered from a symptomatic stenosis after a piecemeal

resection procedure was followed by a session in which a smalllesion located opposite the original resection site was resectedimmediately after circumferential ablation (l" Fig. 8). Althoughwe can not exclude the possibility that the ablation contributedto the esophageal narrowing, we speculate that the stenosismainly resulted from damage incurred by the subsequent resec−tions at this site. This premise is strengthened by the results oftrials of ablation as single therapy for nondysplastic Barrett’sesophagus or LGD, in which no strictures have been reported inover 100 patients treated [1].In this study, we required that all endoscopically visible abnorm−alities had to be removed by endoscopic resection prior to abla−tion. This allowed for optimal staging of patients and ensuredthat only flat mucosa was ablated, preventing possible under−treatment of patients with deeper invading lesions. The resultsof the current study again suggest that stepwise circumferentialand focal ablation can be applied safely after a prior endoscopicresection. The extent of the prior endoscopic resection in the cur−

Fig. 7 C7M8 Barrett’s esophagus with high−grade dysplasia (HGD) andintramucosal cancer (IMC) treated with endoscopic resection of visible ab−normalities followed by stepwise circumferential and focal ablation usingthe HALO ablation system. a ± c Prior to treatment: C7M8 Barrett’s esoph−agus with subtle mucosal abnormalities (b) that were resected endoscopi−cally, showing IMC and HGD. d ± f Effect after two circumferential and three

focal ablation sessions: surface area regression is 85 % but a nearly circum−ferential segment of Barrett’s esophagus remains distally with biopsiesshowing HGD. g ± i Result after stepwise endoscopic resection of residualBarrett’s mucosa with the multiband mucosectomy technique: completeendoscopic and histological removal of dysplasia and Barrett’s esophagus.



rent study, however, did not encompass more than 50% of thecircumference or measure more than 2 cm in length. Performingan endoscopic resection is inevitably associated with esophagealscarring. Depending on the extent of the resection this may ei−ther lead to just a small visible scar, a relative narrowing of theesophageal lumen, or a clearly visible stenosis causing dyspha−gia. From a theoretical standpoint, a significant stenosis after en−doscopic resection may impair the efficacy and safety of subse−quent ablation procedures. More studies have to be conducted toevaluate the combined use of endoscopic resection and this ab−lation technique to continue to optimize this endoscopic treat−ment strategy.The current study also shows that Barrett’s mucosa that persistsafter multiple ablation sessions can be easily treated by usingendoscopic resection as an escape treatment. In one of our pa−tients, five ablation sessions resulted in 85% surface regressionof a C7M8 Barrett’s with persistent HGD. This was easily resect−

ed without any submucosal lifting using the multiband muco−sectomy technique (l" Fig. 7). This again illustrates the lack ofsignificant submucosal scarring after stepwise circumferentialand focal ablation therapy with the HALO system, which is animportant advantage over other ablation techniques that gener−ally do not allow subsequent use of endoscopic resection as anescape treatment.Another unique feature of this ablation technique is the lack ofsubsquamous intestinal metaplasia after treatment, a findingcommonly associated with other ablation therapies. In the cur−rent study we obtained a total number of 363 biopsies fromneo−squamous epithelium after ablation without detecting anyareas of buried Barrett’s. These results are in accordance withboth our previous study on the use of this technique for Barrett’sneoplasia [2] the AIM study, in which stepwise circumferentialand focal ablation was used for ablation of nondysplastic Bar−

Fig. 8 C2M5 Barrett’s esophagus with high−grade dysplasia (HGD) and avisible abnormality treated with endoscopic resection and stepwise cir−cumferential and focal ablation using the HALO ablation system. a ± c Pie−cemeal endoscopic resection with resection of two pieces that healed withrelative narrowing of the esophagus. d ± f At the primary circumferentialablation session 6 weeks later, an 8−mm slightly elevated lesion was de−

tected contralateral to the previous resection site; the lesion was resectedimmediately after the circumferential ablation during the same session.g ± i The patient subsequently developed dysphagia, which resolved fol−lowing a single endoscopic dilatation. Complete removal of dysplasia andBarrett’s esophagus was finally achieved in this patient.

Original article378


rett’s esophagus, and where 473 and 4306 biopsies, respectively,were obtained from neo−squamous mucosa [1,2].This study suffers from the same limitations as our previousstudy: the sample size was relatively small, the duration of fol−low−up was relatively short, and the study was performed in acenter with an international referral function for early Barrett’sneoplasia. Large−scale multicenter studies in Europe and theUSA are currently underway, which will allow us to further de−termine the role of stepwise circumferential and focal ablationfor the treatment of Barrett’s neoplasia.In summary, this is the second prospective study from our centeron the use of stepwise circumferential and focal ablation usingthe HALO ablation system for treatment of either flat HGD inBarrett’s esophagus or treatment of residual dysplasia after en−doscopic resection for HGD or IMC. All 12 patients had completeeradication of dysplasia and complete endoscopic and histologi−cal removal of all Barrett’s mucosa. All treatment sessions wereperformed on an outpatient basis with no significant complica−tions. There were no ablation−related stenoses, and no subsqua−mous intestinal metaplasia was observed in over 363 biopsiestaken from neo−squamous mucosa. Compared to our first study,the efficacy of the circumferential ablation was improved bycleaning the electrode and ablation zone between ablation pas−ses. This more−assured regression after primary circumferentialablation allows more optimal focal ablation of any residual Bar−rett’s mucosa, and achieves complete eradication in fewer treat−ment sessions.These results confirm the findings from our recent study andstrongly suggest that, in expert hands, stepwise circumferentialand focal ablation using the HALO ablation system is a highly ef−fective and safe treatment for early Barrett’s neoplasia.

Competing interests: J. J. Bergman has received research supportin the form of grants and materials for conducting studies for thefollowing companies: B�RRX Medical, Sunnyvale, California,USA; and Olympus Endoscopy Tokyo Japan.

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