Jerry F. London, MD, FACP, FACG
Gastroenterology Associates
1
2

1.6% of general adult population (3.3 M)


6.8% of persons over age 40 (8.7 M)


Ronkainen J, et al. Prevalence of BE… Gastroenterology 2005;129:1825-31.
Rex DK, et al. Screening for Barrett’s... Gastroenterology 2003; 125:1670-77.
25% of persons without GERD > age 50 (20
M)

Gerson LB, et al. Prevalence of Barrett’s…Gastroenterology 2002;123:461-7.
3
Evolution of Barrett’s and Cancer
Injury
Acid & bile reflux
nitrous oxide
Genetics
Gender, race,
? other factors (cox-2)
Accumulate
Genetic
Changes
4
Esophagus
Melanoma
Prostate
Lung/Breast
Colorectal
From: Pohl H, Welch HG. Natl Cancer Inst 2005
5
6
Esophageal
cancer
Colorectal
cancer
General Population
Cancer Incidence
ND-IM Cohort
Cancer Incidence
Multiple
3.0 per 100,000
(0.003%)
600 per 100,000
(0.6%)
200X
General Population
Cancer Incidence
Polyp Cohort
Cancer Incidence
Multiple
47 per 100,000
(0.047%)
580 per 100,000
(0.58%)
12X
http://www.seer.cancer.gov/ (accessed Jun 8, 2011)
Surveillance, Epidemiology and End Results (SEER)
Wani S, et al. Am J Gastroenterol 2009
Winawer SJ, et al. N Engl J Med 1993
Risk multiple for developing
cancer conferred by NDBE or polyp
versus risk of that cancer in
the general U.S. population
7
Barrett’s Esophagus
Colon Polyp
0.5%/patient/year cancer
0.5%/patient/year cancer
0.9%/patient/year HGD
7.5M colonoscopies/year
8
Esophageal
cancer
Colorectal
cancer
General Population
Cancer Incidence
LGD Cohort
Cancer Incidence
Multiple
3.0 per 100,000
(0.003%)
1,700 per 100,000
(1.7%)
560x
General Population
Cancer Incidence
Polyp Cohort
Cancer Incidence
Multiple
47 per 100,000
(0.047%)
580 per 100,000
(0.58%)
12X
http://www.seer.cancer.gov/ (accessed Jun 8, 2011)
Surveillance, Epidemiology and End Results (SEER)
Wani S, et al. Am J Gastroenterol 2009
Winawer SJ, et al. N Engl J Med 1993
Risk multiple for developing
cancer conferred by LGD or polyp
versus risk of that cancer in
the general U.S. population
9
Esophageal
cancer
Colorectal
cancer
General Population
Cancer Incidence
HGD Cohort
Cancer Incidence
Multiple
3.0 per 100,000
(0.003%)
6,600 per 100,000
(6.6%)
2,200X
General Population
Cancer Incidence
Polyp Cohort
Cancer Incidence
Multiple
47 per 100,000
(0.047%)
580 per 100,000
(0.58%)
12X
http://www.seer.cancer.gov/ (accessed Jun 8, 2011)
Surveillance, Epidemiology and End Results (SEER)
Wani S, et al. Am J Gastroenterol 2009
Winawer SJ, et al. N Engl J Med 1993
Risk multiple for developing
cancer conferred by HGD or polyp
versus risk of that cancer in
the general U.S. population
10
TREATMENT
11
Esophagectomy
 Photodynamic Therapy
 Cryotherapy
 Radiofrequency Ablation

12
NDBE
LGD
HGD
Natural
History
(53 studies)
0.6%
1.7%
6.6%
After
Ablation
(65 studies)
0.16%
0.16%
1.7%
NNT=45
NNT=13
NNT= 4
Progression risk expressed as “Per-patient-per-year” (%) risk of developing EAC
NNT calculated on 5-year basis (number needed to treat to avoid one cancer over 5 years)
From: Esophageal adenocarcinoma in BE: a meta-analysis. Wani S, et al. Am J Gastro 2009
13
NDBE
LGD
HGD
Polyp
Natural
History
(53 studies)
0.6%
1.7%
6.6%
0.58%
After
Ablation
(65 studies)
0.16%
0.16%
1.7%
0.06%
NNT=45
NNT=13
NNT= 4
NNT= 38
Progression risk expressed as “Per-patient-per-year” (%) risk of developing EAC
NNT calculated on 5-year basis (number needed to treat to avoid one cancer over 5 years)
Esophageal adenocarcinoma in BE: a meta-analysis. Wani S, et al. Am J Gastro 2009
Prevention of colorectal cancer by colonoscopic polypectomy. Winawer SJ, et al. NEJM 1993
14
Technology
15
16
HALO360+
HALO90
17
Baseline, Barrett’s esophagus
Courtesy of Charlie Lightdale, M.D., Columbia Presbyterian, New York
18
Courtesy of Charlie Lightdale, M.D., Columbia Presbyterian, New York
19
20
21
22
23
Courtesy of Charlie Lightdale, M.D., Columbia Presbyterian, New York
24
25
Shaheen, et al. NEJM 2009.
26
Baseline
Post-RFA: 2 years
27
Baseline
Post-RFA: 2 years
28
Micro-array at Tissue Interface
RFA depth
29
30
n
FU
CR-IM
CR-D
CR-HGD
Buried
Glands
Stricture
Rate
61
30 mo
98.4%
--
--
None
0%
50
60 mo
92%
--
--
None
0%
AIM-LGD
10
24 mo
90%
100%
--
None
0%
HGD Registry
92
12 mo
54%
80%
90%
None
0.4%
AMC-I
11
14 mo
100%
100%
--
None
0%
AMC-II
12
14 mo
100%
100%
--
None
0%
AMC Long-term FU
23
52 mo
100%
100%
--
None
--
Comm Registry
429
20 mo
77%
100%
--
None
1.1%
EURO-I
24
15 mo
96%
100%
--
None
4.0%
EURO-II
118
12+ mo
96%
100%
Emory
27
<12 mo
100%
100%
--
None
0%
Dartmouth
25
20 mo
78%
--
Henry Ford
66
varied
93%
--
--
None
6.0%
Mayo
63
24 mo
79%
89%
--
None
0%
LGD
39
24 mo
87%
95%
--
None
0%
HGD
24
23mo
67%
79%
--
None
0%
127 (RFA 84)
12 mo
77% (83%)
86% (92%)
--
5.1%
6.0%
106
24 mo
93%
95%
--
3.8%
7.6%
47
24 mo
--
--
--
RFA/ER
22
22 mo
96%
96%
--
None
14.0%
SRER
25
25 mo
92%
100%
--
8.0%
31
88.0%
AIM-II Trial
AIM RCT (primary)
Long-term FU
RFA/ER vs. SRER RT
32
Study Design
 Randomized, sham-controlled design


2:1 RFA vs. sham
Stratified by:
 degree of dysplasia (LGD vs. HGD)
 length of segment (1-4 cm vs. 4-8 cm)



Maximum of 4 RFA sessions
Identical biopsy protocols, equal sampling
12 month cross-over
33



Primary endpoint: CR-IM and CR-D (12
months)
Central expert pathology lab (Cleveland Clinic)
Secondary endpoints:



Progression (advanced dysplasia and cancer)
Discomfort
Adverse events
34
35
NNT= 8
NNT= 6
NNT= 11
NNT= 12
36

In this multi-center, randomized, shamcontrolled study of radiofrequency ablation in
patients with dysplastic Barrett’s esophagus,
there was a high rate of complete
eradication of dysplasia and intestinal
metaplasia and decreased disease
progression in the ablation group, as
compared with the control group.
37
Nicholas J. Shaheen, MD, MPH, Bergein F. Overholt, MD, Richard E. Sampliner, MD,
Herbert C. Wolfsen, MD, Kenneth K. Wang, MD, David E. Fleischer, MD, VK Sharma,
MD, Glenn M. Eisen, M.D., MD, MPH, M. Brian Fennerty, MD, John G. Hunter, MD,
Mary P. Bronner, MD, John R. Goldblum, MD, Ana E. Bennett, MD, Hiroshi Mashimo,
MD, Richard I. Rothstein, MD, Stuart R. Gordon, MD, Steven A. Edmundowicz, MD,
Ryan D. Madanick, MD, Anne F. Peery, MD, V. Raman Muthasamy, MD, Kenneth J.
Chang, MD, Michael B. Kimmey, MD, Stuart J. Spechler, MD, Ali A. Siddiqui, MD,
Rhonda Souza, MD, Anthony Infantolino, M.D., John Dumot, DO, Gary W. Falk, MD, MS,
Joseph A. Galanko, PhD, Blair A. Jobe, MD, Robert H. Hawes, MD, Brenda J. Hoffman,
MD, Prateek Sharma, MD, Amitabh Chak, MD,and Charles J. Lightdale, MD
ClinicalTrials.gov number NCT00282672. Support from BÂRRX Medical. Study medication was provided by
AstraZeneca. Statistical analysis and data management were supported by a grant (P30 DK034987) from the
National Institutes of Health.
38
Safety

Long-term Durability
119 Post-RFA pts

CE-IM
SAE: 3.4% (n=4)
(Entire
Cohort)
 1 bleed
 3 chest pain (24 hr
admission)

Strictures: 7.6% (n=9)
 1.8% of cases
 All resolved, median 2.8
dilations
Year 2
Year 3
CE-D
CE-D
(HGD
(LGD
Cohort) Cohort)
% (n)
93%
% (n)
95%
% (n)
98%
(99/106)
(50/54)
(51/52)
91%
96%
100%
(51/56)
(23/24)
(32/32)
39



RFA treatment induced high rates of complete
eradication of IM and dysplasia
At 3 years, eradication of IM was maintained in
>90% of subjects allowing for interim therapy,
and >75% not allowing for interim therapy
Longer term safety data yields no new
concerns




40
Stricture rate of 7.6%
No procedure- or cancer-related mortality
Few patients progressed to a worse grade of
dysplasia
AIM Trial: 5-Year Durability
(Fleischer, Endoscopy, 2010)


Extension of AIM II Trial to 5 years
(n=50)
Biopsy surveillance


If BE recurrence:


4Q/1cm; central path lab
focal RFA; biopsy 2 months later
Results:
92% (n=46) CR-IM at 5 yrs
 8% (n=4) with NDBE
(no neoplastic progression)
 All re-established CR-IM after
1 focal RFA
No strictures or perforations
 No buried glands in 1,473 bxs
Conclusion:
 CR-IM after RFA is durable


41
42
EURO-I Trial
(Pouw, Clin Gastro Hep, 2009)
• First multi-center HGD/IMC trial
• 24 pts underwent RFA with 23
receiving pre-RFA EMR for visible
abnormalities
• 2 pts had EMR after RFA
• 100% dysplasia eradication rate
• 96% IM eradication rate
• 22 months median follow-up
• Adverse events:
• melena (n=1)
• dysphagia (n=1)
43
Community Registry
(Lyday, Endoscopy, 2010)



4 community-based GI practices
76% of patients with baseline
NDBE
Safety Cohort (n=429)
1.1% stricture rate
No serious adverse events

Results:

Conclusion: Outcomes are
comparable to published reports
from trials conducted
predominantly at academic
tertiary centers
44
Quality of Life (QoL) after RFA
(Shaheen, Endoscopy 2010)
Evaluate the influence of dysplastic BE
on QoL, and determine whether RFA
improves QoL

10-item questionnaire
Completed at baseline and 12 months
 RFA vs. Sham patients

Results

Baseline, most reported worry
about:

Esophageal cancer (EC) / esophagectomy
12 months, RFA (vs. Sham) had:

Less worry about EC and esophagectomy
 Reduced depression
 Reduced impact on work and family life


Conclusions: RFA is associated with
improved QoL in dysplastic BE pts
45
What is the fate of the genetic
abnormalities of Barrett’s after RFA?
46
Post-RFA Neosquamous
Epithelium Study
(Pouw, Am J Gastro, 2009)
• Evaluation of Barrett’s mucosa prior
to RFA & neo-squamous epithelium
after RFA in 22 pts with LGD (n=3)
& HGD (n=19)
• 100% dysplasia & IM eradication
rate
• No buried glands in NSE using
standard & keyhole bx & EMR
• Genetic abnormalities were
assessed before and after RFA
47
Pre-RFA
Brush
cytology
4Q/1cm
biopsies
Post-RFA
48
Pt. IHC Ki-67
1
+
IHC p53
+
CEP 1 CEP 9
Gain
N
p16
Loss
p53
Loss
2
3
4
+
+
+
+
+
N
Gain
Gain
N
Gain
N
Loss
Loss
Loss
Loss
N
N
5
6
7
8
+
+
+
+
+
+
+
+
N
Gain
Gain
Gain
N
N
N
Gain
N
N
N
Loss
Loss
Loss
N
Loss
9
10
+
+
+
+
N
N
N
N
N
N
Loss
Loss
49
Pt. IHC Ki-67
1
-
IHC p53
-
CEP 1 CEP 9
N
N
p16
N
p53
N
2
3
4
-
-
N
N
N
N
N
N
N
N
N
N
N
N
5
6
7
8
-
-
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
9
10
-
-
N
N
N
N
N
N
N
N
50
RFA for Barrett’s Esophagus
51
Endoscopic Treatment- NDBE+LGD
(Fleischer et al., Dig Dis Sci, 2010)








NDBE displays neoplastic behavior
Molecular aberrations precede
neoplasia phenotype
Morphological neoplasia as a
surrogate for cancer risk is flawed
 Delay vs genetics, sampling
error, observer error
Surveillance is permissive
RFA is effective and safe
RFA removes mutations
Other disease states with similar
behavior are treated with preventive
removal of cancer precursors (colon
polyps for CRC)
RFA (+/- EMR) is appropriate for
ND-BE and LGD (as well as HGD)
52
Routine Colorectal Polypectomy &
BE Ablation: Intellectually the Same
(El-Serag, Graham. Gastroenterology, 2010)
Historical perspective: Current evolution in
BE management parallels colon polyp
paradigm shift of ~25 years ago
BE Management
Past:
Risks of previous endo therapies made
surveillance only viable option for NDBE/LGD
Present: Published literature demonstrates RFA
is safe and effective in NDBE, LGD, HGD
Future: Authors predict ablation will shift the
BE management paradigm from surveillanceonly to cancer prevention via treatment
“In the case of colorectal polyps, the advent
of fiberoptic colonoscopy with polypectomy
has been the turning point in the
management of these lesions. We believe
that the management of BE is likely to
proceed along a similar path .”
Paradigm Shift
53
AGA Medical Position Statement
Gastroenterology 2011;140:1084-1091

HGD: Endotherapy with RFA,
PDT, or EMR is recommended
rather than surveillance

LGD: RFA should be a
therapeutic option for treatment
of patients with confirmed LGD

NDBE: RFA with or without
EMR should be a therapeutic
option for select individuals with
NDBE who are judged to be at
increased risk for progression to
HGD or cancer
54