Nicholas Shaheen, MD, MPH, FACG
Barrett’s Esophagus:Ablate Everyone?
Nicholas Shaheen, MD, MPH, FACGCenter for Esophageal Diseases and Swallowing
University of North Carolina
Greetings from UNC, the University of National Champions!
• Men’s Basketball: ’24, ’57, ’82, ’93, ’05, ‘09
• Women’s Soccer: ’82, ‘83, ’84, ’86, ‘87, ‘88, ‘89, ‘90, ‘91, ‘92, ‘93. ’94, ’96, ’97, ’99, ’00, ’03, ‘06, ’08, ’09,’12
• Men’s Soccer: ’01, ‘11• Women’s Basketball: ’94• Men’s Lacrosse: ’81, ’82, ’86, ’91, ‘16• Field Hockey: ’89, ’95, ’96, ’97, ’07, ’09• Women’s Lacrosse: ’13, ‘16
ACG 2016 Annual Postgraduate Course Copyright 2016 American College of Gastroenterology
Page 1 of 19
Nicholas Shaheen, MD, MPH, FACG
The Conceptual Underpinnings for
Endoscopic Therapy in Barrett’s Esophagus
Adenocarcinoma – A Disease with a Rapidly Increasing Incidence
S Kroep et al. Am J Gastroenterol 2014.
ACG 2016 Annual Postgraduate Course Copyright 2016 American College of Gastroenterology
Page 2 of 19
Nicholas Shaheen, MD, MPH, FACG
It is not going to change any time soon…
Kong CY et al, CEBP, 2014.
It is clear that the status quo is failing.
ACG 2016 Annual Postgraduate Course Copyright 2016 American College of Gastroenterology
Page 3 of 19
Nicholas Shaheen, MD, MPH, FACG
The Case for Ablation in HGD
• The risk of progression of the lesion is high• The risk of a metachronous cancer is substantial• The competing strategy (surgery) is morbid• Patients are often more comfortable with a
proactive strategy• Data suggest a decreased cancer risk
RFA
RCT of 127 Subjects with LGD & HGD• Intervention: RFA+PPI or Sham+PPI (2:1)• Follow-up: 12 mos• Assessment: Bx’s q3 mos (HGD)/ 6 mos
(LGD)• 1° Outcomes:
• Ablation of all dysplasia:• 81% of HGD• 91% of LGD• app 20% of controls
• Complete eradication of IM (77% of Rx, 2% Sham)
• SE’s: Strictures in 6% of subjects
05
1015202530
CancerIncidence (%)
Sham+PPIRFA +PPI
Shaheen NJ et al. N Engl J Med, 2009.
The AIM-D Trial
19%
2%
ACG 2016 Annual Postgraduate Course Copyright 2016 American College of Gastroenterology
Page 4 of 19
Nicholas Shaheen, MD, MPH, FACG
Complete Eradication, US RFA Registry
AIM-D at 5 Years
0.0
00
.25
0.5
00
.75
1.0
0IM
-fre
e p
rop
ortio
n
0 500 1000 1500 2000Days since first CEIM at 12 months or after
LGD HGD
Kaplan-Meier analysis of the durability of CEIM
0.0
00
.25
0.5
00
.75
1.0
0D
ysp
lasi
a-fr
ee p
rop
ortio
n
0 500 1000 1500 2000Days since first CED at 12 months or after
LGD HGD
Kaplan-Meier analysis of the durability of CED
Shaheen et al. DDW 2015
ACG 2016 Annual Postgraduate Course Copyright 2016 American College of Gastroenterology
Page 5 of 19
Nicholas Shaheen, MD, MPH, FACG
Recurrence Rates by Baseline Histology, U.S. RFA Registry
0.00
0.25
0.50
0.75
1.00
0 1 2 3Time after CEIM (years)
Nondysplastic BE Indefinite dysplasiaLGD HGDIMC
If Someone Recurs, What Do They “Come Back” As?
Pre
-T
reat
men
t H
isto
logy
IM Recurrence Histology
Recurrencen (%)
NDBEn (%)
INDn (%)
LGDn (%)
HGDn (%)
IMCn (%)
EACn (%)
All Patients (N=1634) 334(20) 269 (81) 18 (5) 19 (6) 15 (4) 13 (4) 0
NDBE (N=668) 119 (18) 110 (92) 4 (3) 3 (3) 2 (2) -- --
Indefinite Dysplasia (N=114) 25 (22) 21 (84) 2 (8) 1 (4) 1 (4) -- --
LGD(N=323) 70 (22) 57 (81) 6 (9) 4 (6) 1 (1) 2 (3) --
HGD(N=416) 93 (22) 64 (69) 4 (4) 10 (11) 9 (10) 6 (6) --
IMC(N=92) 21 (23) 16 (76) -- -- 1 (5) 4 (19) --
EAC(N=21) 6 (29) 1 (17) 2 (33) 1 (17) 1 (17) 1 (17) --
ACG 2016 Annual Postgraduate Course Copyright 2016 American College of Gastroenterology
Page 6 of 19
Nicholas Shaheen, MD, MPH, FACG
Most Recurrences Are Handled Endoscopically
Phoa KN et al. Gastroenterology 2013.
Complications with RFA
5,516 Patients
15,665 FAs
Complications: 283
Per Patient: 5.4%
Per RFA: 1.8%
Strictures: 233Per Patient: 4.5%
Per RFA: 1.5%
Bleeding: 28Per Patient: 0.5%
Per RFA: 0.2%
Hospitalization: 47Per Patient: 0.9%
Per RFA: 0.3%
Perforation: 2Per Patient: 0.04%
Per RFA: 0.01%
Deaths:0
Wolf A et al. DDW 2014.
ACG 2016 Annual Postgraduate Course Copyright 2016 American College of Gastroenterology
Page 7 of 19
Nicholas Shaheen, MD, MPH, FACG
What are Cancer Rates after RFA?
Baseline Histology
No. of Patients
n (%)
Patient Years of
Follow-up
No. Incident
EAC
EAC Incidence Rate per 1000 person-years
[95% CI]
No. Deaths from EAC
EAC Mortality Rate per 1000 person-years
[95% CI]
NDBE 2,473 (48) 5,691 3 0.5[0.1, 1.4]
0 0
IND 385 (8) 883 2 2.3[0.4, 7.5]
0 0
LGD 1049 (21) 2,563 14 5.5 [3.1, 8.9]
0 0
HGD 972 (19) 2,591 81 31.3[25.0, 38.7]
3 1.15 [0.29, 3.15]
Total, non-malignant
4,879 (95) 11,729 100 8.5 [7.0, 10.3]
3 0.26 [0.07, 0.70]
IMC 178 (4) 459 -- -- 1 2.18 [0.11, 10.7]
IAC 60 (1) 155 -- -- 0 0Total 5,117 (100) 12,343 -- -- 4 0.32
[0.10, 0.78]
Wolf WA et al, Gastroenterology 2015.
So Ablative Therapy WorksBut Does Everyone Need It?
ACG 2016 Annual Postgraduate Course Copyright 2016 American College of Gastroenterology
Page 8 of 19
Nicholas Shaheen, MD, MPH, FACG
The Decision for Endoscopic Therapy – When to Intervene?
Favors Surveillance Favors Endoscopic Therapy
COST
Favors Surveillance Favors Endoscopic Therapy
ACG 2016 Annual Postgraduate Course Copyright 2016 American College of Gastroenterology
Page 9 of 19
Nicholas Shaheen, MD, MPH, FACG
COST
RISK
Favors Surveillance Favors Endoscopic Therapy
COST
RISKCHANCE OF
INTERVENTION LATER
Favors Surveillance Favors Endoscopic Therapy
ACG 2016 Annual Postgraduate Course Copyright 2016 American College of Gastroenterology
Page 10 of 19
Nicholas Shaheen, MD, MPH, FACG
COST
RISKCHANCE OF
INTERVENTION LATER
LEVEL IEVIDENCE
Favors Surveillance Favors Endoscopic Therapy
COST
RISKCHANCE OF
INTERVENTION LATER
LEVEL I EVIDENCE
PEACE OF MIND
Favors Surveillance Favors Endoscopic Therapy
ACG 2016 Annual Postgraduate Course Copyright 2016 American College of Gastroenterology
Page 11 of 19
Nicholas Shaheen, MD, MPH, FACG
What is Rate of Progression of LGD?
Hvid-Jensen F et al. N Engl J Med 2011.
How Benign is Low-Grade Dysplasia?
• 147 subjects with a diagnosis of LGD made in a community practice in the Netherlands
• Path reviewed by 2 expert pathologists• Disagreements resolved by consensus
• 85% of cases were down-graded• In the 15% who were not, the incidence rate of
HGD or EAC was 13.4%/pt-yr (mean f/u: 51 months)
Curvers WL et al. Am J Gastroenterol 2010.
ACG 2016 Annual Postgraduate Course Copyright 2016 American College of Gastroenterology
Page 12 of 19
Nicholas Shaheen, MD, MPH, FACG
Is LGD an Indication for Endoscopic Intervention?SURF study
RCT, n=140, surveillance EGD vs. ablation with RFA• Primary outcome: occurrence of HGD/EAC
Phoa KN et al. JAMA 2014
Is Non-Dysplastic BE an Indication for Ablation?
• Is it effective?• Most studies document high rates of reversion to squamous tissue• Data from U.S. RFA Registry shows a markedly decreased rate of cancer
in NDBE after RFA compared to historical controls (0.5/1000 p-y)
• Can we afford it?• Cost-effectiveness is questionable• Will treat 20 or more for one to benefit• Effective intervention is still available if they progress to dysplasia
• Bottom line: Until better risk stratification is available, highly unlikely we will be recommending RFA for all NDBE
ACG 2016 Annual Postgraduate Course Copyright 2016 American College of Gastroenterology
Page 13 of 19
Nicholas Shaheen, MD, MPH, FACG
An Algorithm for Endoscopic Management of Barrett’s
Neoplasia
Nodular Disease Should Be EMR’ed!
Ell C et al. GIE, 2007
ACG 2016 Annual Postgraduate Course Copyright 2016 American College of Gastroenterology
Page 14 of 19
Nicholas Shaheen, MD, MPH, FACG
Algorithm, cont.
• For subjects with nodular disease, EMR histology decides further management
• No cancer, mucosal cancer, or maybe sm1 cancer -> ablative therapy
• Worse than sm1 -> consideration of multimodality Rx and esophagectomy
• Flat HGD -> ablation• Given current data, RFA seems most appropriate
Algorithm, cont.• LGD
• Unifocal, elderly, and/or wishing conservative Rx -> surveillance endo’s
• Multifocal, previously nodular, young, family hx of cancer, pathologically worried -> consider ablation
• Non-dysplastic• Ablation is an option, but role in average risk patients not
clear
ACG 2016 Annual Postgraduate Course Copyright 2016 American College of Gastroenterology
Page 15 of 19
Nicholas Shaheen, MD, MPH, FACG
Unsettled Questions…
Should I Be Learning ESD?
• ESD is more technically challenging and time-consuming than EMR
• Asian endoscopists learn in the stomach and colon
• The only real data that ESD yields that EMR does not is lateral margin data
• Because depth of invasion is the most clinically actionable data from EMR, the lateral margin data are not essential
• Given the limited availability of training, the low utility of the incremental data, and the potential for greater complications, performing good EMR should be the focus for most Western endoscopists
ACG 2016 Annual Postgraduate Course Copyright 2016 American College of Gastroenterology
Page 16 of 19
Nicholas Shaheen, MD, MPH, FACG
Does Case Volume Matter and How Much Do I Need?
p=0.01
2.1
2.2
2.3
2.4
2.5
2.6
0 50 100 150 200
Patients Previously Treated at CenterPredicted Value 95% CI
RFA
Ses
sions
based upon Center ExperiencePredicted RFA Sessions to Achieve CEIM
Pasricha et al, Gastroenterology 2015.
Rates of Recurrence after CEIM by Volume at USRFA Centers
Pasricha et al, Gastroenterology 2015.
ACG 2016 Annual Postgraduate Course Copyright 2016 American College of Gastroenterology
Page 17 of 19
Nicholas Shaheen, MD, MPH, FACG
When Is Endoscopic Rx Inadequate?• Lesion too deep
• Anything SM1 or deeper deserves consideration of esophagectomy
• SM1 may be managed endoscopically if the patient is a poor surgical cancer
• Lesion too aggressive• Poor differentiation • Lymphovascular invasion
• Lesion not amenable to endoscopic Rx• Won’t raise, too large
Invasion depth and risk of LNM
500µm500µmmm
sm
lpep
m1 m2 m3 sm2 sm3
36 – 54%0-3%
1000µm1000µm
sm10 – 22%
??
ACG 2016 Annual Postgraduate Course Copyright 2016 American College of Gastroenterology
Page 18 of 19
Nicholas Shaheen, MD, MPH, FACG
Conclusions• In 2016, superficial neoplasia, incl. mucosal esophageal
adenocarcinoma, is an endoscopic disease!• Non-dysplastic BE is generally too low risk to warrant ablation
• CAVEATS• Appropriately selected patient• Amenable lesion• Expertise and program in place• Patient appraised of risks and benefits of this approach
• Endoscopist must know when cure becomes less likely• Submucosal invasion is a contra-indication to endoscopic management in a good surgical
candidate
• Results are overall durable, but recurrent intervention is not uncommon
• Close communication, with no recrimination, between surgeon, oncologist and endoscopist is essential
• Endoscopists must learn to think like oncologists
Thanks!
ACG 2016 Annual Postgraduate Course Copyright 2016 American College of Gastroenterology
Page 19 of 19