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Endoscopic radiofrequency ablation for Barrett's esophagus: 5-year outcomes from a prospective multicenter trial

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The AIM-II Trial included patients with nondysplastic Barrett's esophagus (NDBE) treated with radiofrequency ablation (RFA). Complete eradication of NDBE (complete response-intestinal metaplasia [CR-IM]) was achieved in 98.4 % of patients at 2.5 years. We report the proportion of patients demonstrating CR-IM at 5-year follow-up. Prospective, multicenter US trial (NCT00489268). After endoscopic RFA of NDBE up to 6 cm, patients with CR-IM at 2.5 years were eligible for longer-term follow-up. At 5 years, we obtained four-quadrant biopsies from every 1 cm of the original extent of Barrett's esophagus. All specimens were reviewed by one expert gastrointestinal pathologist, followed by focal RFA and repeat biopsy if NDBE was identified. Primary outcomes were (i) proportion of patients demonstrating CR-IM at 5-year biopsy, and (ii) proportion of patients demonstrating CR-IM at 5-year biopsy or after the single-session focal RFA. Of 60 eligible patients, 50 consented to participate. Of 1473 esophageal specimens obtained at 5 years 85 % contained lamina propria or deeper tissue (per patient, mean 30 , standard deviation [SD] 13). CR-IM was demonstrated in 92 % (46 / 50) of patients, while 8 % (4 / 50) had focal NDBE; focal RFA converted all these to CR-IM. There were no buried glands, dysplasia, strictures, or serious adverse events. Kaplan-Meier CR-IM survival analysis showed probability of maintaining CR-IM for at least 4 years after first durable CR-IM was 0.91 (95 % confidence interval [CI] 0.77 - 0.97) and mean duration of CR-IM was 4.22 years (standard error [SE] 0.12). In patients with NDBE treated with RFA, CR-IM was demonstrated in the majority of patients (92 %) at 5-year follow-up, biopsy depth was adequate to detect recurrence, and all failures (4 / 4, 100 %) were converted to CR-IM with single-session focal RFA.
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Reprint
Endoscopy 2010
October
Volume 42
Page 781789
Endoscopic radiofrequency
ablation for Barrett’s
esophagus: 5-year outcomes
from aprospective
multicenter trial
D. E. Fleischer, B. F.Overholt, V.K.Sharma,
A. Reymunde, M. B. Kimmey, R. Chuttani,
K. J. Chang, R. Muthasamy, C. J. Lightdale,
N. Santiago, D. K. Pleskow, P. J. Dean,
K. K. Wang
Endoscopy
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Endoscopy_Sonder_silbern_1c_u1u4:Muster_Sonder_silbern_1c_u1u4.qxd 30.09.2010 10:49 Seite 1
Endoscopic radiofrequency ablation for Barretts
esophagus: 5-year outcomes from a prospective
multicenter trial*
Authors D. E. Fleischer1, B. F. Overholt2, V. K. Sharma1, A. Reymunde3, M. B. Kimmey4, R. Chuttani5, K. J. Chang6, R. Muthasamy6,
C. J. Lightdale7, N. Santiago3, D. K. Pleskow5,P.J.Dean
8, K. K. Wang9
Institutions Institutions are listed at the end of article.
submitted 23 April 2010
accepted after revision
16 May 2010
Bibliography
DOI http://dx.doi.org/
10.1055/s-0030-1255779
Published online
20 September 2010
Endoscopy 2010; 42:
781789 © Georg Thieme
Verlag KG Stuttgart · New York
ISSN 0013-726X
Corresponding author
D. E. Fleischer, MD
Mayo Clinic, Scottsdale
13400 East Shea Boulevard
Scottsdale, AZ 85259-5499
USA
Fax: +1-480-301-8673
Fleischer.David@mayo.edu
Original article 781
Introduction
!
Barretts esophagus occurs as a result of chronic
injury to the esophageal epithelium by reflux of
gastroduodenal contents associated with gastro-
esophageal reflux disease (GERD) [1, 2]. A diagno-
sis of Barretts esophagus is suspected upon dis-
covery of salmon-colored epithelium in the
esophagus and is confirmed by mucosal biopsy
that demonstrates intestinal epithelium contain-
ing goblet cells, referred to as intestinal metapla-
sia [3]. Barretts esophagus is categorized endo-
scopically by length and histologically according
to the absence or presence/severity of dysplastic
cellular changes: nondysplastic, low grade dys-
plasia (LGD), or high grade dysplasia (HGD). These
morphological categories represent surrogate
markers of increasing risk of developing esopha-
geal adenocarcinoma (EAC). Hence, medical so-
ciety guidelines have commonly recommended a
strategy of surveillance endoscopy with biopsy
for patients with nondysplastic and LGD Barretts
esophagus, to: (i) detect neoplastic progression
prior to EAC, or (ii) detect EAC at a treatable stage
[37].
A surveillance strategy for nondysplastic and LGD
Barretts esophagus has many recognized limita-
tions: biopsy sampling errors, lack of compliance
with surveillance protocols, cost, cost-utility con-
siderations, and failure to avert EAC in many
cases. Therefore, endoscopic therapies intended
to completely remove or ablate the nondysplastic
and LGD Barretts esophagus epithelium have
been evaluated as alternative strategies [813].
In a multicenter study, the AIM-II Trial, we have
evaluated endoscopic radiofrequency ablation
Background and study aims: The AIM-II Trial in-
cluded patients with nondysplastic Barretts
esophagus (NDBE) treated with radiofrequency
ablation (RFA). Complete eradication of NDBE
(complete response-intestinal metaplasia [CR-
IM]) was achieved in 98.4% of patients at 2.5
years. We report the proportion of patients de-
monstrating CR-IM at 5-year follow-up.
Patients and methods: Prospective, multicenter
US trial (NCT00489268). After endoscopic RFA of
NDBE up to 6 cm, patients with CR-IM at 2.5 years
were eligible for longer-term follow-up. At 5
years, we obtained four-quadrant biopsies from
every 1 cm of the original extent of Barretts
esophagus. All specimens were reviewed by one
expert gastrointestinal pathologist, followed by
focal RFA and repeat biopsy if NDBE was identi-
fied. Primary outcomes were (i) proportion of pa-
tients demonstrating CR-IM at 5-year biopsy, and
(ii) proportion of patients demonstrating CR-IM at
5-year biopsy or after the single-session focal RFA.
Results: Of 60 eligible patients, 50 consented to
participate. Of 1473 esophageal specimens ob-
tained at 5 years 85% contained lamina propria
or deeper tissue (per patient, mean 30 [13],
standard deviation [SD] 13). CR-IM was demon-
strated in 92% (46/ 50) of patients, while 8 % (4/
50) had focal NDBE; focal RFA converted all these
to CR-IM. There were no buried glands, dysplasia,
strictures, or serious adverse events. Kaplan-Mei-
er CR-IM survival analysis showed probability of
maintaining CR-IM for at least 4 years after first
durable CR-IM was 0.91 (95% confidence interval
[CI] 0.770.97) and mean duration of CR-IM was
4.22 years (standard error [SE] 0.12).
Conclusions: In patients with NDBE treated with
RFA, CR-IM was demonstrated in the majority of
patients (92%) at 5-year follow-up, biopsy depth
was adequate to detect recurrence, and all failures
(4 /4, 100 %) were converted to CR-IM with single-
session focal RFA.
* An oral presentation of this work was given at the Amer-
ican Society for Gastrointestinal Endoscopy (ASGE) Presi-
dential Plenary Session at Digestive Diseases Week
(DDW) 2010.
Fleischer D E. et al. Endoscopic RFA for Barretts esophagus: 5-year outcomesEndoscopy 2010; 42: 781 789
(RFA) for patients with nondysplastic Barretts esophagus
(NDBE), and have previously reported complete eradication of
NDBE (all esophageal biopsies negative for intestinal metaplasia,
termed complete response-intestinal metaplasia [CR-IM]) in
98.4% of patients at 2.5-year follow-up [14]. To assess the long-
er-term durability of complete reversion to a squamous epithe-
lium after ablation, we performed endoscopy and biopsy at 5-
year follow-up in patients from the trial who had shown CR-IM
at 2.5 years.
Patients and methods
!
This is a report of the 5-year outcomes of a prospective cohort
study (ClinicalTrials.gov identifier NCT00489268) conducted at
eight US centers between May 2004 and November 2009. Five of
the study centers were tertiary referral academic teaching hospi-
tals, while three were large community practices with the ex-
perience and staffing for conducting clinical trials. The institu-
tional review board at each site approved the study protocol and
the form provided for informed consent from patients. All the
study participants gave their informed consent.
Patients
In Phase I of this study (from study entry to 2.5-year follow-up),
eligibility criteria included age 18 75 years and presence of
NDBE (26 cm). All patients underwent confirmatory endoscopy
with biopsies from the esophageal body within 6 months of en-
rollment for corroboration that the morphological grade of Bar-
retts esophagus was not worse than nondysplastic. Exclusion
criteria were: esophageal stricture or varices, active esophagitis,
previous ablation, previous endoscopic resection, previous radia-
tion therapy to the esophagus, any history of esophageal dyspla-
sia or malignancy, or presence of an implanted electrical device.
Patients were provided with antisecretory medication; oral
esomeprazole (AstraZeneca LP, Wilmington, Delaware, USA) was
used during the first 2.5 years of the study, at 40 mg per day with
dose escalation to 40 mg twice a day for 1 month after ablation.
In Phase II of this study (2.5 years to 5 years), attempts were
made to contact all 60 patients who met eligibility criteria for
the 5-year biopsy. Antisecretory medication type and dosage
were decided at the discretion of the investigator. Patients were
provided with oral esomeprazole 40 mg twice per day for 2
months prior to the 5-year visit to minimize inflammation at
the time of endoscopy with biopsy.
Study devices
In Phase I of the study, endoscopic circumferential RFA was per-
formed with the HALO360 system (BÂRRX Medical, Inc., Sunny-
vale, California, USA) comprising a sizing balloon, a balloon-based
ablation catheter and an energy generator. Endoscopic focal RFA
was done using the HALO90 system, comprising an electrode ar-
ray fitted to the distal end of an endoscope.
Patient flow
At the beginning of the study (Phase I), we enrolled 70 patients
who met all the inclusion criteria for the study and to whom
none of the exclusion criteria applied (
"Fig. 1).
After circumferential RFA, a complete response for intestinal me-
taplasia (CR-IM), defined as all esophageal biopsies being nega-
tive for intestinal metaplasia, was seen in 48 of 69 patients
(70%) at 1-year follow-up. After 1-year follow-up, patients with
persistent Barretts esophagus or an irregular squamocolumnar
junction received focal RFA. As a result, CR-IM was found in 60
of 61 patients (98 %) at 2.5-year follow-up. In the present trial
(phase II), patients with CR-IM at the 2.5-year follow-up were eli-
gible for 5-year endoscopic biopsy to assess the durability of re-
version to a squamous epithelium.
"Fig. 2 shows a series of en-
doscopic images from representative patients at various time
points in the study.
5-year endoscopy with biopsy visit
Radial Jaw-4 2.8-mm forceps (Boston Scientific Corp, Natick,
Massachusetts, USA) were provided at each site for obtaining
biopsies at the 5-year visit. Investigators were permitted, at their
discretion, to use other large-jaw forceps including the Olympus
Endojaw 220 FE 2.8-mm forceps and the Olympus FB-13K 3.7-
mm forceps (Olympus America, Center Valley, Pennsylvania,
USA). Biopsy specimens were obtained using these types of biop-
sy forceps, with tissue samples taken from four quadrants per
Fig. 1 AIM-II Trial: enrollment and follow-up of all patients from inception
of trial. Among the 60 patients eligible for the 5-year follow-up phase based
on complete response of intestinal metaplasia (CR-IM) status at 2.5 years,
50 (83 %) patients elected to participate. RFA, radiofrequency ablation.
Original article782
Fleischer D E. et al. Endoscopic RFA for Barretts esophagus: 5-year outcomesEndoscopy 2010; 42: 781 789
level, beginning at the top of the gastric folds and moving proxi-
mally in 1-cm increments to encompass the entire baseline ex-
tent of Barretts esophagus. Additionally, directed biopsy speci-
mens were obtained from any areas that appeared abnormal.
Biopsies distal to the top of the gastric folds were not mandated
in this trial nor were they included in the analysis if obtained. All
biopsy specimens from one level or one focal area were submit-
ted in one jar containing formalin and labelled with the location
of the biopsy as well as study subject identifier codes.
The study protocol did not mandate a specific type of endoscopic
technique or type of endoscopic equipment for the 5-year endos-
copy with biopsy visit. Investigators indicated on each case re-
port form whether or not the following techniques were used:
(i) Lugol chromoendoscopy, (ii) high-definition endoscopy, or
(iii) electronic imaging, such as narrow band imaging (NBI).
Central pathology interpretation and processing
Study specimens were sent in a standardized kit to a central pa-
thology laboratory (Gastrointestinal Pathology, LLC, Memphis,
Tennessee, USA). The formalin-fixed specimens from each con-
tainer were embedded in paraffin (one block per jar), affixed to
slides, and stained with hematoxylin and eosin. One slide repre-
sented each level or focal area sampled.
A board-certified pathologist (P.J.D.) specializing in gastrointesti-
nal pathology evaluated each specimen on each slide and cate-
gorized each according to tissue type (intestinal metaplasia ver-
sus squamous), dysplasia or cancer in intestinal metaplasia if
present, and biopsy depth. Depth was defined as the deepest tis-
sue layer present in each specimen: epithelium, lamina propria,
muscularis mucosae, or submucosa. Biopsy specimens were con-
sidered to contain subepithelial structures if they contained la-
mina propria, muscularis mucosae, or submucosa. Each biopsy
specimen was also evaluated for the presence of buried glandular
mucosa, defined as any specialized columnar epithelium cov-
ered by a layer of squamous epithelium with no communication
with the surface[15]. Finally, each tissue block was evaluated for
the presence of inf lammation. All data were entered into a stand-
ardized pathology case report form.
Salvage focal ablation
Patients in whom intestinal metaplasia was detected at the 5-
year follow-up underwent endoscopy with focal RFA 1 month la-
ter, followed by repeat biopsy 2 months after RFA to assess histo-
logical response. Treatment settings were 12 J/cm2and 40 W/
cm2. Areas positive for intestinal metaplasia at 5-year biopsy
were targeted, along with the region of the top of the gastric
folds. Each location was treated twice successively, followed by
cleaning of the coagulum from the treated area and electrode, fol-
lowed by treatment of each location twice again.
Outcome measures
The primary study outcomes were defined a priori as: (i) the pro-
portion of patients with CR-IM at the 5-year biopsy visit, and (ii)
the proportion of patients demonstrating CR-IM at the 5-year
biopsy visit or at the biopsy visit after single-session salvage focal
RFA.
Secondary outcomes were defined a priori as: (i) proportion of 5-
year failures converted to CR-IM after single-session salvage focal
RFA; (ii) biopsy depth; (iii) prevalence of buried glandular muco-
sa; (iv) prevalence of dysplasia; (v) Kaplan-Meier CR-IM survival
analysis; and (vi) adverse events.
All adverse events and serious adverse events were recorded on a
standardized case report form. Specifically, a stricture in this
study was defined a priori as any narrowing of the esophageal lu-
men in the area of treatment causing symptoms or requiring di-
lation. All case repor t forms at each site were monitored through-
out the study period and queries issued in cases of noncompli-
ance.
Statistical analysis
Data analysis was performed using SAS software, version 9 (SAS
Institute, Cary, North Carolina, USA). The study population for the
primary analysis included all eligible patients who gave their in-
formed consent for the 5-year follow-up. Baseline patient data for
the eligible patient group were assessed to detect differences be-
tween participants and decliners. Biopsy sample characteristics
were compared for patients with CR-IM at 5 years vs. those with
failure at 5 years, as well as for those with failure at 5 years vs.
post-salvage RFA after 5 years. Fishers exact test was used to
compare categorical variables. For continuous variables, a ttest
was used for variables which did not display non-normality for
either treatment group (Shapiro-Wilk Pvalue > 0.05) and the
Mann-Whitney test was used otherwise. All tests were two-sided
and Pvalues less than 0.05 were considered statistically signifi-
cant.
In participants, the durability of CR-IM was assessed using the
Kaplan-Meier survival curve with 95 % confidence intervals (CIs)
generated using Greenwoods formula for computing standard
errors. In this analysis, time-zero(start of CR-IM period for the
survival analysis calculation) was the first durable CR-IM after
enrollment (defined as either the 2.5-year time point or an earli-
er time point at which the first of two consecutive study biopsy
sessions demonstrated CR-IM [6 or 12 months]). Sinceall partici-
pants in this phase of the study had CR-IM at 2.5 years, time-zero
was therefore either the 6-month, 12-month, or 2.5-year follow-
Fig. 2 Endoscopic images from representative study patients. aA 6-cm length of Barretts esophagus without dysplasia at baseline. bAppearance immedi-
ately following circumferential ablation. cFocal radiofrequency device mounted on the tip of the gastroscope, with ablation zone seen distally. Ablation was
done for residual intestinal metaplasia after 1-year follow-up. dEndoscopy demonstrating no Barretts esophagus at 2.5 years with all biopsies negative for
intestinal metaplasia. eRetroflexed view of gastroesophageal junction in patient at 5-year follow-up, showing neosquamous epithelium extending to the car-
dia. The esophagus was normal on endoscopy, with all biopsies negative for intestinal metaplasia.
Original article 783
Fleischer D E. et al. Endoscopic RFA for Barretts esophagus: 5-year outcomesEndoscopy 2010; 42: 781 789
up visit (endoscopy with biopsy) for all patients. For the purpose
of this survival analysis, where patients were found to have re-
current intestinal metaplasia after 2.5 years it was assumed that
for half the elapsed time between endoscopies their status had
been CR-IM and for the other half intestinal metaplasia had
been present.
Results
!
For this 5-year follow-up of the AIM-II trial there were 60 eligible
patients from eight US centers, of whom 50 (83 %) were willing to
participate and gave signed consent for the extended follow-up
described in the approved protocol (
"Fig. 1). The baseline pa-
tient characteristics of the eligible (n = 60), participant (n = 50),
and declining (n = 10) subgroups are shown in
"Table 1. Com-
paring baseline characteristics of participants (n = 50) versus de-
cliners (n = 10), only entr y age was different between the groups,
with participants being younger than decliners (P< 0.05).
At the 5-year biopsy visit, the mean (SD) number of biopsies ob-
tained per patient was 30 (13) comprising a total of 1473 biopsies
(
"Table 2).
Regarding the first primary outcome, 92% (46 / 50) of patients
showed CR-IM at the 5-year biopsy visit. Four patients (8%) had
intestinal metaplasia at 5 years (
"Fig. 3).
In these four patients, a mean (SD) of 32 (17) esophageal speci-
mens were obtained from each patient; one patient had three
specimens positive for intestinal metaplasia and three patients
each had one such specimen. Five of the 6 specimens positive for
intestinal metaplasia were located within 1 cm of the squamoco-
lumnar junction near the top of the gastric folds. These four pa-
tients received a single session of focal RFA 1 month after biopsy
and all (4/ 4, 100%) were found to have CR-IM status upon subse-
quent biopsy at 2 months after RFA. Therefore, regarding the sec-
Table 1 Radiofrequency ablation of nondysplastic Barretts esophagus. Patient demographic data at 5-year follow-up.
Parameter All those eligible
for 5-year follow-up
Participating patients Patients declining
participation
Number of patients 60 50 10
Gender, male/female 44 / 16 37 / 13 7 / 3
Ethnicity
White
Black
Hispanic/Latino
42 (70%)
2(3%)
16 (27%)
36 (72 %)
1(2%)
13 (26 %)
6 (60.0 %)
1 (10.0 %)
3 (30.0 %)
Baseline data
Age, years
Mean (SD)
Range
Bodyweight,mean(SD),lbs
History of GERD, n (%)
Barrett esophagus length, mean (SD), cm
Hiatal hernia
Present/Absent, n/n
Length,mean(SD),cm
55.8 (11.1)
2679
177.8 (38.8)
60 (100%)
3.2 (1.3)
50/10
2.5 (1.1)
54.3 (10.8)*
26 72
177.6 (38.0)
50 (100 %)
3.1 (1.3)
43 / 7
2.6 (1.2)
63.6 (9.8)*
48 79
179.0 (44.8)
10 (100.0 %)
3.7 (1.4)
7/3
1.9 (0.7)
RFA treatments in prior study phase, mean (SD), n
Tot al
Circumferential
Focal
3.4 (1.0)
1.6 (0.5)
1.8 (0.7)
3.4 (0.9)
1.5 (0.5)
1.9 (0.7)
3.3 (1.1)
1.6 (0.5)
1.7 (0.7)
SD, standard deviation; GERD, gastroesophageal reflux disease
*P< 0.05, patients who participated vs. those who declined participation
Table 2 Biopsy characteristics at 5-year follow -up after radiofrequency ablation (RFA) of nondysplastic Barretts esophagus. Data are shown for all par ticipants, for
those with persisting complete response of intestinal metaplasia (CR-IM), for those with treatment failure, and following salvage RFA for those with treatment
failure.
Parameter 5-year biopsy Following salvage RFA
All participants CR-IM Treatment failures
Number of patients 50 46 4 4
Total biopsy specimens, n 1473 1347 126 112
Specimens per patient, mean (SD), n 30 (13) 29 (13) 32 (17) 28 (17)
Specimens with lamina propria or deeper
Tot al , n
Proportion, %
Number per patient, mean (SD), n
Proportion per patient, mean (SD), %
1255
85 %
25 (10)
87 % (11 %)
1145
85 %
25 (10)
87 % (11 %)
110
87 %
28 (15)
88 % (5 %)
99
88%
24 (11)
94 % (13%)
Specimens containingburied glandular mucosa, n 0 0 0 0
Specimens with dysplasia or cancer 0 0 0 0
No significant differences for any variables
Original article784
Fleischer D E. et al. Endoscopic RFA for Barretts esophagus: 5-year outcomesEndoscopy 2010; 42: 781 789
ond primary outcome, all patients (50 /50, 100 %) were in CR-IM
at either the 5-year biopsy visit or after a single salvage focal ab-
lation after the 5-year biopsy visit.
In the biopsies obtained at the 5-year visit, subepithelial struc-
tures were present in 85 % of the specimens (
"Fig. 4).
In the four patients with intestinal metaplasia at 5-year biopsy,
the mean (SD) number of biopsies per patient obtained 2 months
after salvage RFA was 28 (17) (total 112 biopsies), with subepi-
thelium present in 88 % of these specimens. No evidence of bur-
ied glandular mucosa or dysplasia was detected on any 5-year
biopsy or post-salvage biopsy.
At the 5-year visit, the Radial Jaw-4 2.8-mm biopsy forceps was
used in 72% of patients (36 / 50), the Olympus Endojaw 220-FE
2.8-mm forceps in 26% (13/ 50), and the Olympus FB-13K 3.7-
mm device in 2% (1 /50). There was no difference in biopsy speci-
men depth according to type of biopsy forceps used.
At the 5-year follow-up biopsies investigators used high-defini-
tion endoscopy in 35/50 of patients (70 %) and electronic ima-
ging (such as NBI) in 17 / 50 (34 %). None used Lugol chromoen-
doscopy. High-definition endoscopy was used in 32 / 46 (70 %) of
the CR-IM patients and 3 / 4 (75%) of those with intestinal meta-
plasia. Corresponding values for electronic imaging were 16 / 46
(35%) and 1 /4 (25 %).
The Kaplan-Meier survival curve for the secondary outcome of
CR-IM survival is shown in
"Fig. 5.
All par ticipants (n = 50) are represented in this analysis. The
probability of maintaining CR-IM for at least 4 years after the f irst
durable CR-IM was 0.91 (95 % confidence interval [CI] 0.77 0.97).
The mean (standard error [SE]) duration of CR-IM in participants
was 4.22 (0.12) years. Included in this survival analysis is one pa-
tient with CR-IM status at 5 years, but who had an off-protocol
biopsy between the 2.5- and 5-year study visits that detected
nondysplastic intestinal metaplasia in one specimen; this was
followed by focal ablation. Although the biopsy was obtained out-
side of the study protocol and the histological findings were not
reviewed by the study pathologist, treatment is considered to
have failed in the survival analysis. However it is not considered
to have failed with regard to the studys primary end point (CR-
IM at 5 years). Of note, amongst the remaining 49 patients, 33
also had a nonprotocol endoscopy with biopsy procedures as
part of standard care during the interval between 2.5 and 5 years
with none having intestinal metaplasia in esophageal biopsies
and none undergoing ablation in the esophagus.
At the 5-year biopsy visit, 45 patients reported taking oral
esomeprazole 40 mg twice per day, 3 patients oral omeprazole
40 mg twice per day, 1 patient oral lansoprazole 30 mg per day,
and 1 patient no antisecretory medication. Of the 50 patients,
three (6 %) had either grade A (n = 1) or grade B (n = 2) erosive
esophagitis (Los Angeles Classification) at the 5-year visit, while
the remainder had no signs of erosive esophagitis. All three pa-
tients with erosive esophagitis were taking oral esomeprazole
40 mg twice per day. None of the four patients subsequently no-
ted to have intestinal metaplasia at 5-year biopsy had erosive
esophagitis during that visit.
There were no differences in baseline demographic data or Bar-
retts esophagus characteristics between patients with CR-IM
status or treatment failure at 5 years. In addition, there was no
difference between these groups in the mean (SD) number of
biopsies collected (29 [13] vs. 32 [17]) or in the percentage per
patient of biopsy specimens containing subepithelium (87 % vs.
88%). Similarly in the treatment failure group, comparing the 5-
year biopsy visit with the follow-up biopsy visit 2 months after
salvage focal RFA, there was no difference between the mean
number of biopsies per patient (32 [17] vs. 28 [17]) or the propor-
tion per patient of biopsies containing subepithelium (88 % vs.
94%) (
"Table 2).
No strictures were noted at any follow-up endoscopy. One pa-
tient reported a globus sensation 1 week after salvage focal abla-
tion, which resolved without intervention. There were no other
adverse events.
Discussion
!
Esophageal mucosa demonstrating glandular epithelium with
goblet cells defines the entity Barretts esophagus [3]. The mor-
phological categories in Barretts esophagus of nondysplastic tis-
sue, LGD, and HGD are surrogate markers of increasing risk for in-
cident EAC, although genetic alterations enabling neoplastic
behavior and progression are present in NDBE prior to develop-
ment of a dysplasia phenotype [16 20]. While nondysplastic tis-
sue is associated with the lowest risk for EAC of the nondysplas-
tic/LGD/HGD categories (0.5 %0.6 % incidence per patient year of
follow-up; 5% 8% lifetime risk), its detection prompts the initia-
tion of a surveillance endoscopy and biopsy regimen intended to
detect neoplastic progression [2124]. Recognized limitations of
Fig. 3 Photomicrographs of esophageal biopsy specimens obtained from a patient with intestinal metaplasia at 5-year follow-up af ter radiofrequency ablation
(RFA), i. e. treatment failure with regard to primary outcome (both images hematoxylin and eosin [H&E]; original magnification × 200). aIntestinal metaplasia
seen in a biopsy obtained in the distal esophagus at the top of the gastric folds. Biopsy depth extends to the muscularis mucosae and intestinal metaplasia is
present at the sur face layer. bEsophageal biopsy 2 months after single-session focal RFA at 5 years for the residual intestinal metaplasia. Neosquamous epi-
thelium is completely re-established and there was no evidence of intestinal metaplasia in any of 30 biopsies. The biopsy depth extends to the muscularis
mucosae and shows completely squamous epithelium.
Original article 785
Fleischer D E. et al. Endoscopic RFA for Barretts esophagus: 5-year outcomesEndoscopy 2010; 42: 781 789
a surveillance strategy include biopsy sampling error, lack of
compliance with surveillance protocols, cost, cost-utility issues,
and failure to avert EAC in many cases [813]. An ideal manage-
ment paradigm for an nondysplastic population in the future
might be to risk-stratify patients by assaying for a genotype asso-
ciated with propensity for neoplastic progression, and then to
eradicate the NDBE in those patients at highest risk, with surveil-
lance or no action in those patients at lower or zero risk. The abil-
ity to risk-stratify a Barretts esophagus population according to
genotype has proven elusive, and is not yet possible.
More, however, is now known regarding the safety and short- to
intermediate-term efficacy of a number of endoscopic techniques
used to eradicate the Barretts esophagus epithelium. We pre-
viously reported the 1- and 2.5-year safety and efficacy outcomes
of the AIM-II trial, which applied endoscopic RFA in patients with
up to 6 cm of NDBE. Circumferential ablation achieved CR-IM in
70% of patients at 1-year follow-up [25]. Thereafter, focal abla-
tion of residual intestinal metaplasia achieved CR-IM in 98% of
these patients at 2.5-year follow-up [14]. There were no stric-
tures, neoplastic progression, buried glands, or serious adverse
events. Others studies of RFA applied in nondysplastic, LGD, and
HGD Barretts esophagus populations, including a randomized,
sham-controlled multicenter trial, report similarly high rates of
CR-IM (or complete response for dysplasia) with acceptable safe-
ty profiles [26 40].
Since Barretts esophagus is a chronic disease state with long-
term implications for neoplastic progression, information on
longer-term outcomes regarding the durability of CR-IM after
RFA are essential to assess the utility of this strategy. In this
long-term follow-up of patients from the AIM-II trial, we con-
ducted endoscopy and biopsy at 5-year follow-up and found
that in 92% of patients (46 / 50) CR-IM was maintained. We uti-
lized the more objective measurement of histological findings
rather than endoscopic observation. A Kaplan-Meier survival
curve showed the probability of maintaining CR-IM for at least 4
years after first durable CR-IM was 0.91 (95 %CI 0.77 0.97), while
the mean (SE) duration of CR-IM was 4.22 (0.12) years. Recurrent
NDBE was identified in four patients at 5 years (8%) in 6/128
esophageal specimens, most of which were located within 1 cm
of the top of the gastric folds. These patients underwent single-
session focal RFA and all showed CR-IM thereafter. No dysplasia,
stricture, serious adverse event, or buried glandular mucosa was
noted. Assessment of the depth of esophageal biopsy specimens
showed that 85% of the 1473 esophageal biopsy specimens con-
tained lamina propria or deeper structures, a depth considered
adequate for detection of buried glandular mucosa. Our 5-year
data with RFA can be compared with long-term outcomes of
other ablative modalities. A technical review by Wani et al. re-
ported recurrence rates of up to 68 % in patients with NDBE treat-
ed with argon plasma coagulation (APC) [41,42] . While long-
term data for multipolar electrocoagulation (MPEC) are limited,
one case series described recurrence at 2-year follow-up in 27 %
Fig. 4 Photomicro-
graphs of esophageal
biopsy specimens
obtained from a patient
deemed to have com-
plete response-intes-
tinal metaplasia (CR-IM)
at 5 years (hematoxylin
and eosin [H&E]; origi-
nal magnification
× 200). Depth of speci-
men categorized as:
afull epithelium;
blamina propria;
cmuscularis mucosae;
dsubmucosa.
Fig. 5 Kaplan-Meier survival curve for duration of complete response of
intestinal metaplasia (CR-IM). All par ticipants (n = 50) are represented in
this analysis. The probability of maintaining CR-IM for at least 4 years after
first durable CR-IM is 0.91 (95 %CI 0.77 0.97). The mean duration of CR-IM
in participants was 4.22 years (standard error [SE] 012).
Original article786
Fleischer D E. et al. Endoscopic RFA for Barretts esophagus: 5-year outcomesEndoscopy 2010; 42: 781 789
of patients with baseline nondysplastic or LGD Barretts esopha-
gus [43]. In the PHOBAR trial, which evaluated the safety, efficacy
and durability of photodynamic therapy in patients with HGD in
Barretts esophagus, there was a 48 % probability of maintaining
complete eradication of HGD at 5 years [44].
Several cost-utility models indicate that endoscopic ablation is a
cost-effective strategy for Barretts esophagus with nondysplastic
tissue, LGD, and HGD. The cost-utility evidence is strongest for
the highest risk lesions, i. e., LGD/HGD, with ablation being pre-
ferred or dominant to other strategies. Specifically regarding no
dysplasia, however, Inadomi et al. reported that ablation is the
preferred strategy for Barretts with no dysplasia if a permanent
CR-IM is achieved in 40% of patients and surveillance discontin-
ued after CR-IM. This models threshold for costeffectiveness re-
presents a lower CR-IM (40%) than reported in published trials of
RFA, yet sets a high threshold for the durability of CR-IM and re-
quires cessation of surveillance in CR-IM patients, a step that may
not be acceptable to patients or physicians. However, the next
most preferred strategy from this model (over that of surveil-
lance) is ablation in which CR-IM is achieved in 40 % and surveil-
lance is, in fact, continued in all patients [45]. In a separate model,
Das et al. found that, if CR-IM was achieved in 50% of patients,
RFA yielded the most quality-adjusted life-years (QALYs) when
compared with strategies of no intervention (natural history)
and management following current American College of Gastro-
enterology surveillance guidelines [46]. Both of these models in-
dicate that durability of CR-IM after ablation of NDBE has an im-
portant influence on the cost-utility of the strategy. The persist-
ence of CR-IM in 92% of NDBE patients at 5-year follow-up in the
present study, as well as the successful re-establishment of CR-IM
in all patients with treatment failure by single-session focal RFA
after 5 years, is promising in that it permits us to apply these
models for the first time in clinical practice and to consider RFA
as a viable alternative to surveillance alone for NDBE.
As Barretts esophagus is a surrogate marker identifying risk for
neoplasia progression and EAC incidence, therapeutic manage-
ment strategies should be designed to avert these outcomes. In a
meta-analysis, Wani et al. reported that the incidence of EAC in
an observed NDBE population was 0.598 % per patient per year
of follow-up, while the incidence of EAC in ablated NDBE popula-
tions (regardless of CR-IM outcome) was 0.163% [21]. In this a-
nalysis, ablation affords an absolute risk reduction (ARR) of
0.435% per patient per year of follow-up in patients with NDBE,
demonstrating that ablation does avert EAC for this population.
Using these data for NDBE, the number needed to treat (NNT) to
avoid one EAC over a 1-year period is 230 (1/ARR), while the NNT
to avoid one EAC over 5 years is 46. Sharma et al. found that non-
dysplastic tissue progresses to HGD at a rate of 0.9 % per patient
per year of follow-up [22]. Using the natural history progression
rates from Wani et al. and Sharma et al. for NDBE to EAC (0.6%)
and HGD (0.9%), we might have expected seven cases of EAC or
HGD in this trial over the 5-year study period (if the patients
were observed and not treated), rather than the absence of HGD
or EAC cases that was noted.
Buried glandular mucosa is an important consideration in the
management of Barretts esophagus. This entity is present in a
significant proportion of ablation-naïve Barretts esophagus pa-
tients (25% 39 %), as well as in post-PDT (51%) and post-APC
(44%) patients [26, 42, 47, 48]. In the present study, we collected
1473 esophageal biopsies at 5-year follow-up and 3930 biopsies
at earlier visits and found no evidence of buried glandular muco-
sa. Others have reported similarly low rates of this finding after
RFA. Shaheen et al. found that 25% of LGD and HGD patients had
buried glands prior to RFA, while at 1-year buried glands were
present in 5% of RFA patients and 40% of sham patients [26]. In
our study, and in the randomized controlled trial of Shaheen et
al., post-RFA biopsy specimens contained lamina propria or dee-
per structures in 85 % and 79 % of cases, respectively, suggesting
that biopsy depth after RFA is adequate for detection of buried
glandular mucosa and that occult buried glandular mucosa after
RFA is unlikely [49].
Strengths of this study include the prospective, multicenter de-
sign, long duration of follow-up, large number of biopsy speci-
mens obtained, standardized biopsy sampling protocol, use of
large-jaw biopsy forceps, use of a single expert gastrointestinal
pathologist for histological interpretation, objective histological
outcomes, and use of complete histological response as the pri-
mary outcome.
This study has some possible limitations:
"Regarding patient attrition, the original patient group com-
prised 70 patients, whereas 69 and 61 patients were available
for evaluation at 1 and 2.5 years, respectively. There were 60
eligible patients for the present study (those with CR-IM at 2.5
years), while 50 (83%) provided consent and participated.
Nonparticipants were older than participants. If, because of
age or other unmeasured factors, nonparticipants were three
times more likely to have treatment failure (a very conserva-
tive estimate given that age was not associated with response
to therapy in this study), our 5-year CR-IM outcome would
drop nominally from 92% (46 /50) to 82 % (49/ 60). Therefore,
it is unlikely that attrition significantly impacted our primary
findings.
"One patient with CR-IM at 5 years had an off-protocol biopsy
between the 2.5-year and 5-year study visits that showed
nondysplastic intestinal metaplasia in one specimen obtained
from the region of the gastric folds and the patient was treat-
ed with focal ablation. Although the biopsy was obtained out-
side of the protocol and not reviewed histologically by the
study pathologist, to present the data transparently and as
conservatively as possible, this patient was considered to have
treatment failure in the Kaplan-Meier CR-IM survival analysis.
No other patients underwent ablation between 2.5 and 5
years. If we considered this single patient as having treatment
failure for the primary analysis, the 5-year CR-IM would drop
nominally from 92% (46 / 50) to 90% (45 /50).
"Another possible limitation of this study relates to the Kaplan-
Meier CR-IM durability analysis and our methodology for as-
signment of a time zerofor durable CR-IM for each patient.
After the 1-year follow-up, focal RFA was applied at 2-month
intervals (maximum of 3 sessions) in patients with intestinal
metaplasia (1-year failure) as well as in patients with an ir-
regular squamocolumnar junction (without confirmation of
intestinal metaplasia) with the aim of optimizing efficacy
outcomes at the 2.5-year follow-up. If some of the focal RFA
sessions in patients without confirmation of intestinal meta-
plasia actually ablated minute residual foci of intestinal meta-
plasia, then it is possible that our durability analysis overesti-
mated the true duration of CR-IM in these patients by setting
the time zeropoint too early. While we do not believe that
this would significantly affect the durability curve, an optimal
study design might have required histological confirmation of
intestinal metaplasia prior to any focal ablation after the
1-year follow-up.
Original article 787
Fleischer D E. et al. Endoscopic RFA for Barretts esophagus: 5-year outcomesEndoscopy 2010; 42: 781 789
"The study had no concurrent control arm, although the objec-
tive histological end points mitigate the likelihood of bias due
to lack of controls at 5 years.
"There was no standardized post 2.5-year antisecretory medi-
cation regimen. Up to 2.5 years, all patients were provided
with oral esomeprazole 40 mg per day (with escalation to
twice per day for 1 month post-RFA). The inability to assess
adequacy of acid suppression and compliance with medica-
tion during the post 2.5-year period, however, limits our abil-
ity to draw conclusions about the role of these factors in dis-
ease recurrence or persistent cure. However, given the high
degree of maintenance of CR-IM at 5 years, despite the het-
erogeneity of antisecretory regimens in the post 2.5-year fol-
low-up period, it is unlikely that the composition of the anti-
secretory regimen is an important predictor of CR-IM dur-
ability.
"There is an inherent lack of precision in identifying the precise
location of the distal terminus of the esophagus and in accu-
rately distinguishing this from the proximal extent of the
stomach. This may be important regarding accurate assess-
ment of the presence or absence of intestinal metaplasia in
the esophagus after ablative therapy. Our biopsy methodology
in this trial used the top of the gastric folds as the landmark for
the distal terminus of the esophagus, and we obtained biop-
sies from this location (and proximally at 1-cm inter vals) in all
patients at all follow-up visits. It is possible that this metho-
dology could: (i) overestimate the presence of intestinal me-
taplasia if these distal biopsies were actually from the un-
treated gastric cardia and if they contained intestinal meta-
plasia (a common finding); or (ii) underestimate the presence
of intestinal metaplasia if the location of the gastric folds was
located too proximally, as we would miss sampling a portion
of the distal, previously treated esophagus. The importance of
thoroughly assessing the distal esophagus is emphasized by
our finding that 5 /6 biopsy specimens positive for intestinal
metaplasia in the patients with treatment failure were located
within 1 cm of the top of the gastric folds.
"The interval of 2 months from salvage RFA to subsequent
biopsy to assess CR-IM after salvage was short. It is possible
that after salvage RFA occult intestinal metaplasia was present
that would have been detected after additional time or with
further biopsy sessions. However, this only affected four pa-
tients (8 %) and the salvage outcome was not used for calcula-
tion of the main study end point, that of CR-IM at 5 years.
"A final possible limitation is that biopsy forceps were not
standardized for all cases, with the Radial Jaw-4 2.8-mm for-
ceps employed in two-thirds of the biopsy visits and the En-
dojaw 220 FE 2.8-mm or Olympus FB-13K 3.7-mm forceps
used in one-third. However biopsy depth did not differ ac-
cording to forceps type, so this is unlikely to be a confounding
variable.
In summary, this is the first report of 5-year CR-IM outcomes
related to RFA for Barretts esophagus. In our patients from the
AIM-II Trial who had NDBE treated previously with RFA, CR-IM
persisted in the majority of patients (92 %) at 5-year follow-up,
the biopsy depth was adequate to detect recurrence, and all treat-
ment failures were converted to CR-IM with single-session focal
RFA (4/ 4, 100%). Kaplan-Meier survival analysis of CR-IM dur-
ability demonstrated that the probability of maintaining CR-IM
for at least 4 years is 0.91 (95 %CI 0.77 0.97) and mean (SE) dura-
tion of CR-IM is 4.22 (0.12) years. There were no buried glands,
dysplasia, strictures or serious adverse events. These long-term
data have important implications for the clinical management of
patients with NDBE and perhaps also those with LGD/HGD. If ear-
ly recurrence of Barretts esophagus had been common in these
patients, the value of this therapeutic intervention for Barretts
esophagus (specifically, nondysplastic) would be called into
doubt. Our report of CR-IM at 5 years in the context of the many
other studies reporting favorable outcomes related to the safety,
efficacy, cost-utility, and reduction in neoplastic progression lend
further credence for a role of RFA in the treatment of NDBE.
Acknowledgments
!
This research was supported at each research institution by a
study grant from BÂRRX Medical Inc., Sunnyvale, California,
USA. This research was also supported by the Investigator-Spon-
sored Study Program of AstraZeneca (AstraZeneca LP, Wilming-
ton, Delaware, USA).
Competing interests: D.E.F., B.F.O., V.K.S., R.C., R.M., C.J.L., and D.K.
P. report having received professional lecture fees from BÂRRX
Medical. K.J.C. reports a minor equity ownership in, a royalty
agreement with, and receipt of professional lecture fees from
BÂRRX Medical. A.R., M.B.K., N.S., P.J.D., and K.K.W. report no con-
flict of interest and no disclosures
Institutions
1Mayo Clinic, Scottsdale, Arizona, USA
2Gastrointestinal Associates, Knoxville, Tennessee, USA
3Ponce Gastroenterology, Ponce, Puerto Rico, USA
4Tacoma Digestive Disease Center, Tacoma, Washington, USA
5Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
6University California, Irvine, California, USA
7Columbia Presbyterian Medical Center, New York, USA
8GI Pathology, Memphis, Tennessee, USA
9Mayo Clinic, Rochester, Minnesota, USA
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Fleischer D E. et al. Endoscopic RFA for Barretts esophagus: 5-year outcomesEndoscopy 2010; 42: 781 789
Reprint
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Endoscopic radiofrequency
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Endoscopy_Sonder_silbern_1c_u1u4:Muster_Sonder_silbern_1c_u1u4.qxd 30.09.2010 10:49 Seite 1
... Most studies were performed in Europe (11 studies), followed by the United States (4 studies), South America (2 studies), Australia (2 studies) and China (1 study). Fourteen studies were prospective case series (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34), and 6 were randomized controlled trials (RCTs) (35)(36)(37)(38)(39)(40). EET modalities included APC (12 studies), RFA (3 studies), multipolar electrocoagulation (MPEC) (3 studies), PDT (1 study) and laser therapy (1 study). ...
... Two studies that directly compared EET (using APC) with surveillance-only reported progression from NDBE to HGD/EAC, i.e., 2 patients in the surveillance group progressed to HGD versus 0 in the APC group, while no cases of EAC were reported in these studies (37,38). When including single-arm studies, 17 studies reported progression to EAC after EET (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(34)(35)(36)(37)(38)41). EAC was found in 4 of 928 NDBE patients treated with EET (during 3652 patient-years of follow-up). ...
... In both single-arm studies reporting EAC cases after EET, HGD incidence was not an outcome measure (23,31). Thirteen other studies reported on a combined HGD/EAC incidence (22,(24)(25)(26)(27)(28)(29)(30)(34)(35)(36)(37)(38), but no cases of HGD were reported after EET ( Table 1). ...
... When remaining Barrett's mucosa is left untreated, case series have reported recurrence of neoplasia, with rates varying from 11 % to 30 % [170][171][172]. The multicenter EURO-II study demonstrated that complete eradication of neoplasia and Barrett's mucosa can be achieved with the combination of ER and RFA in 98 % and 93 %, respectively (in a per-protocol analysis). ...
Article
Main recommendations ESGE recommends that the evaluation of superficial gastrointestinal (GI) lesions should be made by an experienced endoscopist, using high definition white-light and chromoendoscopy (virtual or dye-based). ESGE does not recommend routine performance of endoscopic ultrasonography (EUS), computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET)-CT prior to endoscopic resection. ESGE recommends endoscopic submucosal dissection (ESD) as the treatment of choice for most superficial esophageal squamous cell and superficial gastric lesions. For Barrett’s esophagus (BE)-associated lesions, ESGE suggests the use of ESD for lesions suspicious of submucosal invasion (Paris type 0-Is, 0-IIc), for malignant lesions > 20 mm, and for lesions in scarred/fibrotic areas. ESGE does not recommend routine use of ESD for duodenal or small-bowel lesions. ESGE suggests that ESD should be considered for en bloc resection of colorectal (but particularly rectal) lesions with suspicion of limited submucosal invasion (demarcated depressed area with irregular surface pattern or a large protruding or bulky component, particularly if the lesions are larger than 20 mm) or for lesions that otherwise cannot be completely removed by snare-based techniques. ESGE recommends that an en bloc R0 resection of a superficial GI lesion with histology no more advanced than intramucosal cancer (no more than m2 in esophageal squamous cell carcinoma), well to moderately differentiated, with no lymphovascular invasion or ulceration, should be considered a very low risk (curative) resection, and no further staging procedure or treatment is generally recommended. ESGE recommends that the following should be considered to be a low risk (curative) resection and no further treatment is generally recommended: an en bloc R0 resection of a superficial GI lesion with superficial submucosal invasion (sm1), that is well to moderately differentiated, with no lymphovascular invasion, of size ≤ 20 mm for an esophageal squamous cell carcinoma or ≤ 30 mm for a stomach lesion or of any size for a BE-related or colorectal lesion, and with no lymphovascular invasion, and no budding grade 2 or 3 for colorectal lesions. ESGE recommends that, after an endoscopically complete resection, if there is a positive horizontal margin or if resection is piecemeal, but there is no submucosal invasion and no other high risk criteria are met, this should be considered a local-risk resection and endoscopic surveillance or re-treatment is recommended rather than surgery or other additional treatment. ESGE recommends that when there is a diagnosis of lymphovascular invasion, or deeper infiltration than sm1, or positive vertical margins, or undifferentiated tumor, or, for colorectal lesions, budding grade 2 or 3, this should be considered a high risk (noncurative) resection, and complete staging and strong consideration for additional treatments should be considered on an individual basis in a multidisciplinary discussion. ESGE recommends scheduled endoscopic surveillance with high definition white-light and chromoendoscopy (virtual or dye-based) with biopsies of only the suspicious areas after a curative ESD.
... Further, it has not been clearly shown to be superior to EMR for neoplasia remission, recurrence or need for surgery in BE [88]. At present, it is usually reserved for large lesions with endoscopic evidence of submucosal invasion [89]. ...
Article
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Barrett's esophagus (BE) is the precursor to esophageal adenocarcinoma (EAC). Progression to cancer typically occurs in a stepwise fashion through worsening dysplasia and ultimately, invasive neoplasia. Established EAC with deep involvement of the esophageal wall and/or metastatic disease is invariably associated with poor long-term survival rates. This guides the rationale of surveillance of Barrett's in an attempt to treat lesions at an earlier, and potentially curative stage. The last two decades have seen a paradigm shift in management of Barrett's with rapid expansion in the role of endoscopic eradication therapy (EET) for management of dysplastic and early neoplastic BE, and there have been substantial changes to international consensus guidelines for management of early BE based on evolving evidence. This review aims to assist the physician in the therapeutic decision-making process with patients by comprehensive review and summary of literature surrounding natural history of Barrett's by histological stage, and the effectiveness of interventions in attenuating the risk posed by its natural history. Key findings were as follows. Non-dysplastic Barrett's is associated with extremely low risk of progression, and interventions cannot be justified. The annual risk of cancer progression in low grade dysplasia is between 1%-3%; EET can be offered though evidence for its benefit remains confined to highly select settings. High-grade dysplasia progresses to cancer in 5%-10% per year; EET is similarly effective to and less morbid than surgery and should be routinely performed for this indication. Risk of nodal metastases in intramucosal cancer is 2%-4%, which is comparable to operative mortality rate, so EET is usually preferred. Submucosal cancer is associated with nodal metastases in 14%-41% hence surgery remains standard of care, except for select situations.
... Several studies, including well designed randomized studies, found that RFA is safe and effective in BE with an 80-100% complete eradication rate (2,3,5,6,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). One of these studies assessed a 3-year follow-up of 106 patients and found complete eradication of dysplasia at a rate of 95%, and no recurrence in 91% of patients (19). ...
... 24,25 The five-year follow-up data from RFA suggests that eradication of the BE is maintained in roughly 85% to 90% of patients. 7,26 In comparison to RFA, hybrid-APC is possibly less suitable for extremely long BE, although the longest extent of BE in our study was 13 cm (Prague C13M13) and no complications were observed. Submucosal saline injection was feasible in all patients, even those with post EMR scarring. ...
... Published data showed metachronous lesions of up to 30% in 3 years, if the remaining Barrett segment was not removed (19,20). ...
... Furthermore, ablation has also been performed to treat precancerous lesions or oligo-progressive tumors. Numerous clinical trials have demonstrated that RFA is a safe and effective treatment for Barrett's esophagus, with more than 80% of patients achieving complete eradication after approximately two to three treatments (89)(90)(91)(92). In patients with oligometastatic and oligoprogressive NSCLC, which is defined as those with limited metastatic disease, and in selected individuals with resistance to targeted therapies, evidence for the clinical benefit of local ablative therapy is increasing (57,93). ...
Article
Recent progress in immunotherapy provides hope of a complete cure to cancer patients. However, recent studies have reported that only a limited number of cancer patients with a specific immune status, known as "cold tumor", can benefit from a single immune agent. Although the combination of immune agents with different mechanisms can partially increase the low response rate and improve efficacy, it can also result in more side effects. Therefore, discovering therapies that can improve tumors' response rate to immunotherapy without increasing toxicity for patients is urgently needed. Tumor interventional therapy is promising. It mainly includes transcatheter arterial chemoembolization, ablation, radioactive particle internal irradiation, and photodynamic interventional therapy based on a luminal stent. Interventional therapy can directly kill tumor cells by targeted drug delivery in situ, thus reducing drug dosage and systemic toxicity like cytokine release syndrome. More importantly, interventional therapy can regulate the immune system through numerous mechanisms, making it a suitable choice for immunotherapy to combine with. In this review, we provide a brief description of immunotherapies (and their side effects) on tumors of different immune types and preliminarily elaborate on interventional therapy mechanisms to improve immune efficacy. We also discuss the progress and challenges of the combination of interventional therapy and immunotherapy.
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Objective Radiofrequency ablation (RFA)±endoscopic resection (ER) is the preferred treatment for early neoplasia in Barrett’s oesophagus (BE). We aimed to report short-term and long-term outcomes for all 1384 patients treated in the Netherlands (NL) from 2008 to 2018, with uniform treatment and follow-up (FU) in a centralised setting. Design Endoscopic therapy for early BE neoplasia in NL is centralised in nine expert centres with specifically trained endoscopists and pathologists that adhere to a joint protocol. Prospectively collected data are registered in a uniform database. Patients with low/high-grade dysplasia or low-risk cancer, were treated by ER of visible lesions followed by trimonthly RFA sessions of any residual BE until complete eradication of BE (CE-BE). Patients with ER alone were not included. Results After ER (62% of cases; 43% low-risk cancers) and median 1 circumferential and 2 focal RFA (p25-p75 0–1; 1–2) per patient, CE-BE was achieved in 94% (1270/1348). Adverse events occurred in 21% (268/1386), most commonly oesophageal stenosis (15%), all were managed endoscopically. A total of 1154 patients with CE-BE were analysed for long-term outcomes. During median 43 months (22–69) and 4 endoscopies (1–5), 38 patients developed dysplastic recurrence (3%, annual recurrence risk 1%), all were detected as endoscopically visible abnormalities. Random biopsies from a normal appearing cardia showed intestinal metaplasia (IM) in 14% and neoplasia in 0%. A finding of IM in the cardia was reproduced during further FU in only 33%, none progressed to neoplasia. Frequent FU visits in the first year of FU were not associated with recurrence risk. Conclusion In a setting of centralised care, RFA±ER is effective for eradication of Barrett’s related neoplasia and has remarkably low rates of dysplastic recurrence. Our data support more lenient FU intervals, with emphasis on careful endoscopic inspection. Random biopsies from neosquamous epithelium and cardia are of questionable value. Netherlands trial register number NL7039.
The treatment of early Barrett's esophagus (BE) has undergone a paradigm shift from surgical subtotal esophagectomy to organ-saving endoluminal treatment. Over the past 15 years, several high-quality studies were conducted to assess safe oncological outcome of endoscopic resection of mucosal adenocarcinoma and high-grade dysplasia. It became clear that add-on ablative therapy with radiofrequency ablation (RFA) significantly reduces recurrence risk of neoplasia after resection. In this review, we highlight the most essential elements to optimize outcomes of RFA of BE, addressing the correct indication and patient selection in combination with the most efficient and safest treatment protocols to obtain long-term durability.
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The aim of the current study was to evaluate the efficacy and safety of stepwise circumferential and focal ablation using the HALO system for Barrett's esophagus containing flat, high-grade dysplasia (HGD) or residual dysplasia after endoscopic resection for HGD or intramucosal cancer (IMC). Visible abnormalities were removed with endoscopic resection prior to ablation. Persistence of dysplasia and absence of IMC were confirmed with biopsy after endoscopic resection. A balloon-based electrode was used for primary circumferential ablation and an endoscope-mounted electrode was used for secondary focal ablation. Twelve patients (nine men; median age 70 years) were treated (median Barrett's length 7 cm). Visible abnormalities were removed by endoscopic resection in seven patients. The worst pathological grade of residual Barrett's esophagus after resection and prior to ablation was low-grade dysplasia (LGD) (n = 1) and HGD (n = 11). Patients underwent a median of one circumferential and two focal ablation sessions. Complete remission of dysplasia was achieved in 12/12 patients (100%). Complete endoscopic and histological removal of Barrett's esophagus was achieved in 12/12 patients (100%). There were no ablation-related stenoses, and no subsquamous Barrett's esophagus was observed in 363 biopsies obtained from post-ablation neo-squamous mucosa. Protocolized cleaning of the ablation zone and electrode in between ablations resulted in superior regression of Barrett's esophagus compared with previous studies. During a median follow-up of 14 months no recurrence of dysplasia or Barrett's esophagus was observed. Stepwise circumferential and focal ablation for Barrett's esophagus with flat HGD or for Barrett's with residual dysplasia after endoscopic resection for HGD/IMC is a safe and effective treatment modality. Its success rate and safety profile compare favorably with alternatives such as esophagectomy, widespread endoscopic resection or photodynamic therapy.
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Biomarkers are needed to screen multiple stages in the clinical pathway of Barrett's oesophagus patients; from disease diagnosis to risk stratification and predicting response to therapy. Routes to the identification of biomarkers have been recognized by known molecular features of the disease and more recently through transcriptomic, methylation and proteomic screening approaches. The majority of Barrett's oesophagus patients remain undiagnosed in the general population. In order to develop a tool to screen for Barrett's oesophagus in the primary care setting, minimally invasive sampling methods coupled with immunocytology-based biomarkers are currently being assessed. Biomarkers may also have utility in surveillance programmes by allowing endoscopic interval to be adjusted according to individual neoplastic risk. Many individual biomarkers have been proposed in this regard, but have frequently been assessed in studies of limited power, or have lacked sufficient sensitivity or specificity when assessed in wider population-based studies. Biomarker panels may provide a route forward. In this regard, a panel of methylation markers has shown promise in a multicentre, double-blind, validation study. Biomarkers are also being developed to improve detection of high-grade dysplasia and oesophageal adenocarcinoma, utilizing brush cytology combined with FISH (fluorescence in situ hybridization), and to assess therapeutic success and risk of complication during photodynamic therapy. Finally, we outline progress in identifying alternative sources of biomarkers for this condition.
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Gastroesophageal reflux disease, Barrett's esophagus, and esophageal adenocarcinoma are related diseases with environmental and genetic determinants. The genetic changes are relevant in 2 distinct ways. First, there are heritable variations in germline DNA that may influence the individual susceptibility to cancer. Second, there is an accumulation of somatic-cell genetic and epigenetic changes within the epithelium during the metaplasia-dysplasia-carcinoma sequence, which may be an important determinant for the likelihood for cancer progression. Esophageal cancer occurring in the context of a familial syndrome is rare and most cases are sporadic. The sporadic cases still may have heritable germline influences, but these are likely to involve multiple, low-penetrance susceptibility genes. To date, the relative contribution and identity of such genes are unknown. However, in the future the identification of susceptibility genes could have important public health implications for patient management. With regard to the epithelium, a map gradually is being created of the frequently occurring alterations. Some of these changes are critical whereas others are bystanders. As well as the identification of abnormalities in target genes, it also is possible to determine the global gene expression profile of these diseases and to correlate this profile with clinical outcome. It is hoped that these complementary approaches will enable patients to be stratified in terms of their cancer risk so that prevention, surveillance, and treatment strategies can be targeted appropriately. At the current time, genetics does not influence routine clinical management of patients with gastroesophageal reflux disease, Barrett's esophagus, or esophageal adenocarcinoma.
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The guidelines for the diagnosis, surveillance, and therapy of Barrett's esophagus were originally published by the American College of Gastroenterology in 1998 and updated in 2002. These and other guidelines undergo periodic review. Significant advances have occurred in the area of Barrett's esophagus over the past four years leading to another revision of the prior guidelines.
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Squamous islands are frequently visualized at the time of upper endoscopy in patients with Barrett's esophagus, especially those on proton pump inhibitor therapy (PPI). The significance of these islands is not clearly understood. The aim of this study was to systematically biopsy macroscopic squamous islands and to examine their histologic characteristics. Patients with Barrett's esophagus undergoing surveillance had squamous islands documented and biopsied at the time of endoscopy. Barrett's esophagus was defined as the presence of a columnar lined esophagus on endoscopy with intestinal metaplasia on biopsy. All biopsies were obtained by a single senior endoscopist and were stained with alcian blue at pH 2.5. Biopsy samples with inadequate tissue quantity were not included in the study. A total of 39 biopsies were obtained from 22 patients. Twenty of the 22 patients were male, with a mean age of 65.4 yr (range 47-80 yr). The mean length of Barrett's mucosa was 5.6 cm (range 1-11 cm). Eleven of 22 patients were on omeprazole (mean dose 29.1 mg/day), whereas seven patients were on lansoprazole (60 mg/day). The mean duration of PPI therapy was 2.3 yr (range 9-71 months) at the time of biopsy of the squamous islands. Three patients were on H2-blocker therapy whereas the remaining patient had not been started on acid suppression therapy. On histology, 24 biopsy specimens (61.5%) revealed only squamous epithelium, whereas 15 (38.5%) showed the presence of intestinal metaplasia underlying the squamous epithelium. There was no significant difference between the patients with and without underlying intestinal metaplasia in regard to age, Barrett's length, dose, and duration of PPI therapy. In more than one-third of biopsies of macroscopic squamous islands within Barrett's esophagus, microscopic intestinal metaplasia is detected. The presence of squamous islands should not be equated with regression of Barrett's esophagus or with decreased cancer risk.
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The genetic changes that drive metaplastic progression from squamous oesophageal mucosa toward intestinal metaplasia and adenocarcinoma are unclear. The aberrant expression of microRNAs (miRNAs) is involved in the development of cancer. This study examined whether miRNAs play a role in the development of oesophageal adenocarcinoma. RNA was extracted from mucosa of normal oesophageal squamous epithelium, normal gastric epithelium, Barrett's oesophagus with intestinal metaplasia and oesophageal adenocarcinoma obtained from 16 individuals. Expression profiles of 377 human miRNAs were determined by microarray analysis and selected miRNAs were analysed further using real-time reverse transcription-polymerase chain reaction (RT-PCR) in tissues from 32 individuals. Microarray analyses identified 44 miRNAs likely to have altered expression between various mucosal samples. Of these, miR-21, miR-143, miR-145, miR-194, miR-203, miR-205 and miR-215 were chosen for validation by real-time RT-PCR. Tissue-specific expression profiles were observed, with miR-21, miR-143, miR-145, miR-194 and miR-215 significantly upregulated in columnar tissues compared with normal squamous epithelium. Expression of miR-143, miR-145 and miR-215 was lower in oesophageal adenocarcinoma than in Barrett's oesophagus. Levels of miR-203 and miR-205 were high in normal squamous epithelium and low in columnar epithelia. MiR-205 levels were lower in gastric epithelium than in both Barrett's oesophagus and adenocarcinoma. Expression of miRNA might define disease states in oesophageal epithelium. Dysregulation of specific miRNAs could contribute to metaplastic and neoplastic processes in the oesophageal mucosa.
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The use of radiofrequency ablation (RFA) for complete eradication of Barrett's esophagus has shown promise in trials conducted at predominantly tertiary academic centers; however less is known regarding outcomes in the community. We evaluated the safety and efficacy of RFA for Barrett's esophagus delivered in a community practice setting. This was a multicenter registry conducted in community-based gastroenterology practices. Patients had confirmed intestinal metaplasia with or without dysplasia on biopsy of a Barrett's esophagus. Intervention was step-wise RFA with follow-up esophageal biopsies. Endpoints were histology-based; complete response was defined as all biopsies at most recent endoscopy negative for intestinal metaplasia (CR-IM) or dysplasia (CR-D). Three cohorts were reported: 1) safety cohort, all patients; 2) efficacy cohort A, patients with at least one biopsy session after initial treatment; 3) efficacy cohort B, patients with at least one biopsy session > or = 1 year after initial treatment. The safety cohort included 429 patients (71 % men, median age 59 years, median Barrett's segment 3.0 cm). There were no serious adverse events (bleeding, perforation, death), and a stricture occurred after 1.1 % of cases (2.1 % of patients). In efficacy cohort A (n = 338), CR-IM and CR-D were achieved in 72 % and 89 % of patients, respectively (median follow-up 9 months). In efficacy cohort B (n = 137), CR-IM and CR-D were achieved in 77 % and 100 % of patients, respectively (median follow-up 20 months). In this multicenter registry conducted at four community-based practices, the observed safety and efficacy outcomes associated with RFA for Barrett's esophagus are comparable to those previously reported in multicenter trials from predominantly tertiary academic centers.