Barrett's Esophagus and Adenocarcinoma

Barrett’s Esophagus & Barrett’s Esophagus & AdenocarcinomaAdenocarcinoma


Professor of MedicineProfessor of MedicineCleveland Clinic Lerner College of Medicine of Cleveland Clinic Lerner College of Medicine of

Case Western Reserve UniversityCase Western Reserve UniversityDepartment of Gastroenterology & HepatologyDepartment of Gastroenterology & Hepatology

Taussig Cancer CenterTaussig Cancer CenterUSAUSA

Gary W. Falk, M.D., M.S.Gary W. Falk, M.D., M.S.


• What is the definition? What is the definition?

• What is the epidemiology? What is the epidemiology?

• How does it develop?How does it develop?

• How do I make the diagnosis?How do I make the diagnosis?

• Why should I care about Barrett’s Why should I care about Barrett’s esophagus?esophagus?


• What is the rationale for screening & What is the rationale for screening & surveillance strategies?surveillance strategies?

• How do I treat Barrett’s esophagus?How do I treat Barrett’s esophagus?







Barrett’s EsophagusBarrett’s Esophagus

Intestinal MetaplasiaIntestinal MetaplasiaColumnar distal Columnar distal esophagusesophagus







Prevalence of Barrett’s Prevalence of Barrett’s Esophagus at EndoscopyEsophagus at Endoscopy

• 6-12% of symptomatic GERD 6-12% of symptomatic GERD patientspatients

• << 1% of patients without 1% of patients without GERD symptomsGERD symptoms

From Van Soest E M et al. Gut 2005;54:1062-1066.

Incidence of Barrett's Esophagus Over Time Incidence of Barrett's Esophagus Over Time In The Netherlands In The Netherlands

Prevalence of Barrett’s Esophagus Prevalence of Barrett’s Esophagus in General Population of Swedenin General Population of Sweden

From Ronikainen J et al. Gastroenterology 2005;129:1825-31From Ronikainen J et al. Gastroenterology 2005;129:1825-31..

BEBE LSBELSBE

((>> 2cm) 2cm)

SSBESSBE

(< 2cm)(< 2cm)

No BENo BE

CasesCases

(%)(%)

16 16

(1.6%)(1.6%)

5 5

(0.5%)(0.5%)

1111

(1.1%)(1.1%)

984984

(98.4%)(98.4%)

% with % with GERD GERD symptomssymptoms

56.3%56.3% 80.0%80.0% 45.5%45.5% 39.7%39.7%

% with % with esophagitisesophagitis

25.0%25.0% 60.0%60.0% 9.1%9.1% 15.4%15.4%







Relationship of Esophageal Acid and Bile Relationship of Esophageal Acid and Bile Exposure to Barrett’s EsophagusExposure to Barrett’s Esophagus

1.57

15.4 14.7

22.8

0.43.2

14.6

23.0

46.0

0

10

20

30

40

50

60

70

Controls No Esophagitis Esophagitis UncomplicatedBarrett's

ComplicatedBarrett's

To

tal T

ime

pH

<4

an

d B

ilir

ub

in

0.1

4 (

%)

AcidBilirubin

Vaezi and Richter. Vaezi and Richter. GastroenterologyGastroenterology 1996;111:1192-9. 1996;111:1192-9.

Abdominal Obesity As A Risk Factors Abdominal Obesity As A Risk Factors For Barrett’s Esophagus vs. GERD For Barrett’s Esophagus vs. GERD

ControlsControls

From Corley DA et al. Gastroenterology 2007;133:34-41.From Corley DA et al. Gastroenterology 2007;133:34-41.







1. Locate gastro-esophagealjunction

1. Locate gastro-esophagealjunction

3. Describe extent of metaplasia consistently

3. Describe extent of metaplasia consistently

2. Recognize the squamocolumnar junction

2. Recognize the squamocolumnar junction

Three Essential Steps for Endoscopic Diagnosis and Description

Barrett’s Esophagus: Barrett’s Esophagus: The Prague ClassificationThe Prague Classification

From Sharma P et al. Gastroenterology 2006;131:1392-9.From Sharma P et al. Gastroenterology 2006;131:1392-9.







Barrett’s Esophagus & Barrett’s Esophagus & Adenocarcinoma:Adenocarcinoma:

• What is Barrett’s esophagus? What is Barrett’s esophagus?

• How common is it? How common is it?




GI Motility online (May 2006) | doi:10.1038/gimo45GI Motility online (May 2006) | doi:10.1038/gimo45

Adenocarcinoma in Barrett’s Adenocarcinoma in Barrett’s EsophagusEsophagus

Relative Change in Incidence of Esophageal Relative Change in Incidence of Esophageal Adenocarcinoma & Other Malignancies 1975-2001Adenocarcinoma & Other Malignancies 1975-2001

From Pohl H & Welch G. JNCI 2005;97:142-6.From Pohl H & Welch G. JNCI 2005;97:142-6.

Esophageal AdenocaEsophageal Adenoca

MelanomaMelanomaProstateProstate

BreastBreastLungLungColorectalColorectal

Disease Specific Mortality & Incidence Disease Specific Mortality & Incidence of Esophageal Adenocarcinomaof Esophageal Adenocarcinoma

From Pohl H & Welch G. JNCI 2005;97:142-6.From Pohl H & Welch G. JNCI 2005;97:142-6.

IncidenceIncidence

MortalityMortality(2(215/million)15/million)

Development of Neoplasia in Development of Neoplasia in Barrett’s EsophagusBarrett’s Esophagus

1 2 Gastric acid reflu x

2 1 Duodenal bile reflux

Pro - carcinogenic primary and

secondary bile salts

3 pH dependent,

bile

salt induced chronic esophageal injury

4 Chronic esophageal inflammation

and

PGE2 release

5 N eoplasia in Barrett’s

esophagus

Population Attributable Risks* of Population Attributable Risks* of Esophageal AdenocarcinomaEsophageal Adenocarcinoma

From Engel LS et al. JNCI 2003;95:1404-13.From Engel LS et al. JNCI 2003;95:1404-13.

Risk FactorRisk Factor PARPAR 95% CI95% CI

Ever Ever smokersmoker 39.7%39.7% 25.6-55.825.6-55.8

BMI BMI quartile 2-4quartile 2-4 41.1%41.1% 23.8-60.923.8-60.9

Any Any GERGER symptoms symptoms 29.7%29.7% 19.5-42.319.5-42.3

Low consumption of Low consumption of fruits/vegetablesfruits/vegetables

15.3%15.3% 5.8-34.65.8-34.6

PAR for all factors combinedPAR for all factors combined 78.7%78.7% 66.5-87.366.5-87.3

**Proportion of Disease Attributable to Given Risk Proportion of Disease Attributable to Given Risk

FactorFactor


• What is the rationale for screening What is the rationale for screening & surveillance strategies?& surveillance strategies?

• How do I treat Barrett’s How do I treat Barrett’s esophagus?esophagus?

Screening for Barrett’s Screening for Barrett’s Esophagus: GuidelinesEsophagus: Guidelines

ACGACG

20082008

AGAAGA

20052005

BSGBSG

20052005

GERD GERD symptomssymptoms

IndividualizeIndividualize MaybeMaybe NoNo

No GERD No GERD symptomssymptoms

NoNo NoNo NoNo

Screening For Barrett’s Screening For Barrett’s Esophagus: Why Bother?Esophagus: Why Bother?

• Only Only 5%5% of esophageal of esophageal adenocarcinoma cases adenocarcinoma cases undergoing resection occur undergoing resection occur in patients with in patients with knownknown Barrett’s esophagusBarrett’s esophagus

From Dulai GS et al. Gastroenterology 2002;122:26-33.From Dulai GS et al. Gastroenterology 2002;122:26-33.

Estimates of New Esophageal Estimates of New Esophageal Cancer Cases and Mortality: 2007Cancer Cases and Mortality: 2007

15,56013,940

0

5,000

10,000

15,000

20,000

New Cases Deaths

From American Cancer Society 2007From American Cancer Society 2007

Screening Of Barrett’s Screening Of Barrett’s EsophagusEsophagus

• Who to screenWho to screen• GERD?GERD?• Age?Age?• Gender?Gender?• General population?General population?

• How to screenHow to screen• EGD?EGD?• Unsedated narrow caliber endoscopy?Unsedated narrow caliber endoscopy?• Capsule endoscopy?Capsule endoscopy?• Other?Other?

Screening & Surveillance For Barrett’s Screening & Surveillance For Barrett’s Esophagus: A Cost-Utility AnalysisEsophagus: A Cost-Utility Analysis

• Decision analysisDecision analysis• Assumptions:Assumptions:

• 50 yr old white male50 yr old white male• Symptoms of GERDSymptoms of GERD• Benchmark for intervention benefit:Benchmark for intervention benefit:

–$50,000/QALY saved$50,000/QALY saved

• One time screening with surveillance if One time screening with surveillance if dysplasia:dysplasia:• $10,440/QALY saved$10,440/QALY saved

From Inadomi J, et al. Ann Intern Med 2003;138:178-From Inadomi J, et al. Ann Intern Med 2003;138:178-86.86.

From Inadomi J et al. Ann Intern Med 2003;138:181.From Inadomi J et al. Ann Intern Med 2003;138:181.From Inadomi J et al. Ann Intern Med 2003;138:181.From Inadomi J et al. Ann Intern Med 2003;138:181.

Cost $Cost $

16.4516.45 16.4716.47 16.4916.49 16.5116.51 16.5316.53 16.5516.55 16.5716.57

500500

15001500

25002500

30003000

20002000

10001000

00

16.5916.59 16.6116.61 16.6316.63

Screening with surveillance every:2 years3 years4 years5 years

Screening with surveillance for dysplasia

Screening with surveillance every:2 years3 years4 years5 years

Screening with surveillance for dysplasia

No screening or surveillanceNo screening or surveillance

Quality Adjusted Life-yearQuality Adjusted Life-year

16.6516.65

Screening & Surveillance: Screening & Surveillance: A Cost-Utility AnalysisA Cost-Utility Analysis

Screening & Surveillance: Screening & Surveillance: A Cost-Utility AnalysisA Cost-Utility Analysis

Prevalence of Barrett’s Esophagus Prevalence of Barrett’s Esophagus in VA GERD Patients at Initial EGDin VA GERD Patients at Initial EGD

• 378 GERD patients378 GERD patients

• Barrett’s esophagus in Barrett’s esophagus in 13.2%13.2%

• LSBE-36%LSBE-36%

• SSBE-64%SSBE-64%

From Westhoff B et al. Gastrointest Endosc 2005;61:226-31.From Westhoff B et al. Gastrointest Endosc 2005;61:226-31.

Detection of Barrett’s Esophagus After Detection of Barrett’s Esophagus After Healing of Erosive EsophagitisHealing of Erosive Esophagitis

• N=172 with erosive GERD in KC VAMCN=172 with erosive GERD in KC VAMC

• After PPI therapy:After PPI therapy:• Confirmed Barrett’s esophagus in 21/172 Confirmed Barrett’s esophagus in 21/172

(12%)(12%)• 19/21 (90%) with short segment 19/21 (90%) with short segment

• Median segment length 1 cm (range 0.5-5 Median segment length 1 cm (range 0.5-5 cm)cm)

From Hanna S et al. Am J Gastroenterol 2006;101:1416-20.From Hanna S et al. Am J Gastroenterol 2006;101:1416-20.

Barrett’s Esophagus On Repeat Barrett’s Esophagus On Repeat Endoscopy Within 5 Years According Endoscopy Within 5 Years According To Finding At Baseline: CORI ProjectTo Finding At Baseline: CORI Project

From Rodriguez S et al. Am J Gastroenterol 2008;103:1892-7.From Rodriguez S et al. Am J Gastroenterol 2008;103:1892-7.

High Definition White Light High Definition White Light EndoscopyEndoscopy

Symptomatic GERD As A Risk Factor For Esophageal Adenocarcinoma

0

20

40

60

80

100

Controls EsophagealAdenoca

Cardia Ca EsophagealSquamous

Cell Ca

From Lagergren J et al. NEJM 1999;340:825-31. From Lagergren J et al. NEJM 1999;340:825-31.

AbsenceAbsence of heartburn, regurgitation or both of heartburn, regurgitation or both >> once weekly once weekly

%%

Screening Of Barrett’s Screening Of Barrett’s Esophagus: DilemmasEsophagus: Dilemmas

• Risks of screening:Risks of screening:

• False positivesFalse positives

• Patient anxietyPatient anxiety

• Unnecessary follow-up examsUnnecessary follow-up exams

• Life insurance premiumsLife insurance premiums

Screening for Barrett’s Esophagus: Screening for Barrett’s Esophagus: DilemmasDilemmas

• Large poolLarge pool of patients with chronic GERD of patients with chronic GERD symptomssymptoms• > 10 million!> 10 million!

• Few casesFew cases of adenocarcinoma of adenocarcinoma•

~~7,000 annually7,000 annually

• No prior GERD symptomsNo prior GERD symptoms in 40% of in 40% of adenocarcinoma patients adenocarcinoma patients

• No dataNo data prove effectiveness of screening prove effectiveness of screening programprogram

From Eisen GM et al. Clin Gastro Hepatol 2004;2:861-4.From Eisen GM et al. Clin Gastro Hepatol 2004;2:861-4.

Screening for Barrett’s Screening for Barrett’s Esophagus: ProblemsEsophagus: Problems

• Cost/risk of endoscopy

• Lack of noninvasive alternatives

• Lack of predictors to increase

yield of screening

From Sharma P et al. Am J Gastroenterol 2008;103:525-32.From Sharma P et al. Am J Gastroenterol 2008;103:525-32.

Esophageal Capsule Endoscopy for The Esophageal Capsule Endoscopy for The Diagnosis of Barrett’s EsophagusDiagnosis of Barrett’s Esophagus

Esophageal Capsule Endoscopy for Esophageal Capsule Endoscopy for The Diagnosis of Barrett’s EsophagusThe Diagnosis of Barrett’s Esophagus

From Sharma P et al. Am J Gastroenterol 2008;103:525-32From Sharma P et al. Am J Gastroenterol 2008;103:525-32..

Unsedated Small Caliber Endoscopy Unsedated Small Caliber Endoscopy For Detection of Barrett’s EsophagusFor Detection of Barrett’s Esophagus

• N=121 with GERD or known BEN=121 with GERD or known BE• RCT (crossover) of conventional or unsedated RCT (crossover) of conventional or unsedated

small caliber EGDsmall caliber EGD• Detection rates no different (endo + histo):Detection rates no different (endo + histo):

• Conventional EGD: 26%Conventional EGD: 26%• Small caliber EGD: 30%Small caliber EGD: 30%

• Note:Note:• 45%45% eligible subjects refused to participate eligible subjects refused to participate• 71%71% prefer unsedated scope for future prefer unsedated scope for future

From Jobe B et al. Am J Gastroenterol 2006;101:2693-2703.From Jobe B et al. Am J Gastroenterol 2006;101:2693-2703.

Screening for Barrett’s Esophagus: Screening for Barrett’s Esophagus: 2008 ACG Guidelines2008 ACG Guidelines

• Screening in the general population Screening in the general population cannot be recommendedcannot be recommended

• Screening in selective populations at Screening in selective populations at higher risk remains to be established higher risk remains to be established and should be individualizedand should be individualized

From Wang KK & Sampliner RE. Am J Gastroenterol 2008;103:788-97.From Wang KK & Sampliner RE. Am J Gastroenterol 2008;103:788-97.

AGA Technical Review on Esophageal AGA Technical Review on Esophageal Carcinoma: Summary of EvidenceCarcinoma: Summary of Evidence

• Surveillance supportedSurveillance supported by Level II by Level II evidenceevidence• Cohort studiesCohort studies

• Most cost-effective approach:Most cost-effective approach:• Target patients @ high riskTarget patients @ high risk

From Wang KK et al. Gastroenterology 2005;128:1471-1505.From Wang KK et al. Gastroenterology 2005;128:1471-1505.

Surveillance & Survival in Barrett’s Surveillance & Survival in Barrett’s Adenocarcinoma: A Population Based StudyAdenocarcinoma: A Population Based Study


Surveillance & Cancer Stage in Barrett’s Surveillance & Cancer Stage in Barrett’s Adenocarcinoma: A Population Based Adenocarcinoma: A Population Based

StudyStudy


Surveillance detectedSurveillance detected Not detected in surveillanceNot detected in surveillance

Surveillance of Barrett’s Esophagus: Surveillance of Barrett’s Esophagus: 2008 ACG Guidelines2008 ACG Guidelines

• Assess candidacy for Assess candidacy for surveillancesurveillance• Age < 80 yrsAge < 80 yrs

• Likelihood of survival for 5 yearsLikelihood of survival for 5 years

• Patient understanding of risks & Patient understanding of risks & benefitsbenefits

From Wang KK & Sampliner R. Am J Gastroenterol 2008;103:788-97.From Wang KK & Sampliner R. Am J Gastroenterol 2008;103:788-97.

Surveillance of Nondysplastic Barrett’s Surveillance of Nondysplastic Barrett’s Esophagus: 2008 ACG GuidelinesEsophagus: 2008 ACG Guidelines

• 4 quadrant biopsies Q 2 cm while on 4 quadrant biopsies Q 2 cm while on PPI therapyPPI therapy

• After 2 EGDs negative for dysplasia, After 2 EGDs negative for dysplasia, EGD Q 3 yearsEGD Q 3 years

• Any grade of dysplasia warrants Any grade of dysplasia warrants confirmation by expert pathologistconfirmation by expert pathologist


Management of Low-Grade Dysplasia: Management of Low-Grade Dysplasia:

2008 ACG Guidelines2008 ACG Guidelines

• Confirm diagnosis by expert Confirm diagnosis by expert pathologistpathologist

• Repeat EGD within Repeat EGD within 6 months6 months

• Annual EGD until 2 consecutive Annual EGD until 2 consecutive negative for dysplasianegative for dysplasia


Importance of Expert Importance of Expert Confirmation of DysplasiaConfirmation of Dysplasia

Community DiagnosisCommunity Diagnosis Downgraded Diagnosis Downgraded Diagnosis By Expert PathologistsBy Expert Pathologists

Indefinite for dysplasiaIndefinite for dysplasia 16/22 (73%)16/22 (73%)

Low-grade dysplasiaLow-grade dysplasia 64/71 (90%)64/71 (90%)

High-grade dysplasiaHigh-grade dysplasia 11/23 (48%)11/23 (48%)

From Baak JP et al. J Clin Pathol 2002;55:910-6.From Baak JP et al. J Clin Pathol 2002;55:910-6.

Reasons for downgrading:Reasons for downgrading:-Ulcer-Ulcer-Tangential cutting-Tangential cutting-Severe inflammation-Severe inflammation

Updated 2008 ACG Guidelines: High- Updated 2008 ACG Guidelines: High- Grade Dysplasia ManagementGrade Dysplasia Management

• Confirm diagnosis by expert GI Confirm diagnosis by expert GI pathologistpathologist

• Repeat EGD within Repeat EGD within 3 mos3 mos• More intensive biopsy protocolMore intensive biopsy protocol• If any mucosal nodularityIf any mucosal nodularityEMREMR

• HGD is a threshold for interventionHGD is a threshold for intervention• Review management options with Review management options with

patientpatientFrom Wang KK & Sampliner R. Am J Gastroenterol 2008;103:788-97.From Wang KK & Sampliner R. Am J Gastroenterol 2008;103:788-97.

Updated 2008 ACG Guidelines: High Updated 2008 ACG Guidelines: High Grade Dysplasia Management Grade Dysplasia Management

• Local expertiseLocal expertise• SurgicalSurgical• EndoscopicEndoscopic

• PatientPatient• AgeAge• ComorbidityComorbidity• PreferencePreference

• Esophagectomy no longer necessary Esophagectomy no longer necessary treatment responsetreatment response


Preoperative Prevalence of Barrett’s Esophagus in Preoperative Prevalence of Barrett’s Esophagus in Patients Undergoing Resection for Incident Esophageal Patients Undergoing Resection for Incident Esophageal

Adenocarcinoma: A Systematic ReviewAdenocarcinoma: A Systematic Review

From Dulai GS et al. Gastroenterology 2002;122:26-33.From Dulai GS et al. Gastroenterology 2002;122:26-33.

Summary estimate of Summary estimate of prior prevalence = prior prevalence = 4.7%4.7%

Endoscopic Surveillance: Endoscopic Surveillance: Where Is The Dysplasia?Where Is The Dysplasia?

Distribution of Dysplasia and Cancer in Distribution of Dysplasia and Cancer in Resection SpecimensResection Specimens

Barrett’s, no dysplasiaBarrett’s, no dysplasiaLow - grade dysplasiaLow - grade dysplasiaHigh - grade dysplasiaHigh - grade dysplasiaCancerCancer

SCJSCJ

SCJSCJ

From Cameron AJ et al. Am J Gastroenterol 1997;92:586-91.From Cameron AJ et al. Am J Gastroenterol 1997;92:586-91.

Interpretation of Barrett’s Interpretation of Barrett’s Esophagus in Community PracticeEsophagus in Community Practice

Interpretation of Barrett’s Interpretation of Barrett’s Esophagus in Community PracticeEsophagus in Community Practice

From Alikhan M et al. Gastrointest Endosc 1999;50:23-6.From Alikhan M et al. Gastrointest Endosc 1999;50:23-6.From Alikhan M et al. Gastrointest Endosc 1999;50:23-6.From Alikhan M et al. Gastrointest Endosc 1999;50:23-6.

Gastric metaplasiaGastric metaplasia

IM without dysplasiaIM without dysplasia

Low-grade dysplasiaLow-grade dysplasia

High-grade dysplasiaHigh-grade dysplasia

100100

8080

6060

4040

2020

00

%Agreement

%Agreement

Pathologists’ ReadingPathologists’ Reading

Death Rate of Barrett’s Esophagus Vs. Death Rate of Barrett’s Esophagus Vs. General Population in UKGeneral Population in UK

From Moayyedi P et al. Aliment Pharmacol Ther 2008;27:316-20.From Moayyedi P et al. Aliment Pharmacol Ther 2008;27:316-20.

From Moayyedi P et al. Aliment Pharmacol Ther 2008;27:316-20.From Moayyedi P et al. Aliment Pharmacol Ther 2008;27:316-20.

Causes of Death of Barrett’s Causes of Death of Barrett’s Esophagus Patients in the UKEsophagus Patients in the UK

Limitations of Endoscopic Biopsy Limitations of Endoscopic Biopsy Surveillance of Barrett’s EsophagusSurveillance of Barrett’s Esophagus

• Dysplasia/early cancerDysplasia/early cancer• IndistinguishableIndistinguishable

• Patchy distributionPatchy distribution

• Interobserver variability in dysplasia Interobserver variability in dysplasia interpretationinterpretation

• Most patients never develop cancerMost patients never develop cancer • Incidence 0.5%/yearIncidence 0.5%/year

Future Strategies for Surveillance Future Strategies for Surveillance of Barrett’s Esophagusof Barrett’s Esophagus

• More efficientMore efficient • Target biopsiesTarget biopsies

• Sample larger area of mucosaSample larger area of mucosa

• Less frequentLess frequent• Risk stratify patientsRisk stratify patients

• Identify patients @ increased risk and focus Identify patients @ increased risk and focus efforts on themefforts on them

Enhancements to Endoscopic Enhancements to Endoscopic SurveillanceSurveillance

• ChromoendoscopyChromoendoscopy• Magnification endoscopyMagnification endoscopy• Autofluorescence endoscopyAutofluorescence endoscopy• Narrow band imagingNarrow band imaging• Photodynamic diagnosisPhotodynamic diagnosis• Optical coherence tomographyOptical coherence tomography• SpectroscopySpectroscopy• Confocal microscopyConfocal microscopy• Molecular imagingMolecular imaging

Tandem NBI + HD WLE Vs. Standard Tandem NBI + HD WLE Vs. Standard WLE For Dysplasia Detection in WLE For Dysplasia Detection in

Barrett’s EsophagusBarrett’s Esophagus

From Wolfsen HC et al. Gastroenterology 2008;135:24-31.From Wolfsen HC et al. Gastroenterology 2008;135:24-31.

Tandem NBI + HD WLE Vs. Standard WLE Tandem NBI + HD WLE Vs. Standard WLE For Dysplasia Detection in Barrett’s For Dysplasia Detection in Barrett’s

EsophagusEsophagus

NBI/HD NBI/HD WLEWLE

Standard Standard WLEWLE

P-valueP-value

Higher grade Higher grade of histologyof histology

12 (18%)12 (18%) 00 <.001<.001

DysplasiaDysplasia 37 (57%)37 (57%) 28 (43%)28 (43%)

Mean biopsy Mean biopsy numbernumber

4.7 4.7 ++ 2.7 2.7 8.5 8.5 ++ 5.1 5.1 <.001<.001

From Wolfsen HC et al. Gastroenterology 2008;135:24-31.From Wolfsen HC et al. Gastroenterology 2008;135:24-31.

3/5 cases of HGD detected by NBI detected by HD WLE3/5 cases of HGD detected by NBI detected by HD WLE

Conventional Indigo carmine

AFI

φ10mm LST (NG)Tubular adenoma with severe

atypia

Provided by Juntendo UniversityProvided by Juntendo University

ETMI True PositiveETMI True Positive

From Curvers W et al. Gut 2008;57:167-72.From Curvers W et al. Gut 2008;57:167-72.

http://0-gut.bmj.com.library.ccf.org/content/vol57/issue2/images/large/GUT-57-02-0167-f03.jpeg

ETMI False PositiveETMI False Positive


http://0-gut.bmj.com.library.ccf.org/content/vol57/issue2/images/large/GUT-57-02-0167-f04.jpeg

ETMI for Detection of Early ETMI for Detection of Early Neoplasia in Barrett’s EsophagusNeoplasia in Barrett’s Esophagus

• 84 BE patients underwent ETMI84 BE patients underwent ETMI• AFI per patient diagnosisAFI per patient diagnosis

• Detected all 16 patients abnormal by HREDetected all 16 patients abnormal by HRE• Detected Detected 1111 additional patients normal by HRE additional patients normal by HRE• Missed Missed 3 3 patients detected by random biopsies and patients detected by random biopsies and

normal HREnormal HRE

• AFI per lesion diagnosisAFI per lesion diagnosis• 102 lesions-19 with early neoplasia102 lesions-19 with early neoplasia• False + 81%False + 81%26% after NBI26% after NBI


Field of view: 500x500Field of view: 500x500µmµmRange: 0-250Range: 0-250µmµmLateral resolution: <1µmLateral resolution: <1µm

Technique of EndomicroscopyTechnique of Endomicroscopy

Confocal Laser Endomicroscopy in Barrett’s Confocal Laser Endomicroscopy in Barrett’s Esophagus Intestinal MetaplasiaEsophagus Intestinal Metaplasia

From Kiesslich R et al. Clin Gastroenterol Hepatol 2006;4:979-87.From Kiesslich R et al. Clin Gastroenterol Hepatol 2006;4:979-87.

Confocal Laser Endomicroscopy Confocal Laser Endomicroscopy of Barrett’s Associated Neoplasia

From Kiesslich R et al. Clin Gastroenterol Hepatol 2006;4:979-87.From Kiesslich R et al. Clin Gastroenterol Hepatol 2006;4:979-87.

Chromoendoscopy Guided EndomicroscopyChromoendoscopy Guided Endomicroscopy

Chromo + Chromo + EndomicroscopyEndomicroscopy

Conventional Conventional Colonoscopy + Colonoscopy + Random BiopsiesRandom Biopsies

P-valueP-value

NN 8080 7373

No. of intraepithelial neoplasiaNo. of intraepithelial neoplasia 1919 44 .005.005

Total biopsiesTotal biopsies 16881688 30813081 .008.008

Targeted biopsies with Targeted biopsies with chromoendoscopychromoendoscopy

312312 227227 <.0001<.0001

Targeted biopsies with Targeted biopsies with endomicroscopyendomicroscopy

6262 -- --

No of targeted biopsies with No of targeted biopsies with intraepithelial neoplasiaintraepithelial neoplasia

5757 1313 <.0001<.0001

No of biopsy specimens with No of biopsy specimens with intraepithelial neoplasiaintraepithelial neoplasia

5757 77 <.0001<.0001

From Kiesslich R et al. Gastroenterology 2007;132:874-82.From Kiesslich R et al. Gastroenterology 2007;132:874-82.

Molecular ImagingMolecular Imaging

From Mahmood U & Wallace MB. Gastroenterology 2007;132:11-14.From Mahmood U & Wallace MB. Gastroenterology 2007;132:11-14.

Adenocarcinoma Risk & Biomarker PanelsAdenocarcinoma Risk & Biomarker Panels

From Galipeau PC et al. PLOS Medicine 2007;4:342-54.From Galipeau PC et al. PLOS Medicine 2007;4:342-54.

Biomarkers:Biomarkers:-17pLOH-17pLOH-DNA content-DNA content-9pLOH-9pLOH


• What is the rationale for screening What is the rationale for screening & surveillance strategies?& surveillance strategies?

• How do I treat Barrett’s How do I treat Barrett’s esophagus?esophagus?

Points of Disruption in Barrett’s Points of Disruption in Barrett’s Esophagus Dysplasia-Carcinoma Esophagus Dysplasia-Carcinoma

SequenceSequence

MetaplasiaMetaplasia

DysplasiaDysplasia

CarcinomaCarcinoma

AblationAblationChemopreventionChemoprevention

??

??

Therapy of Barrett’s EsophagusTherapy of Barrett’s Esophagus

• Antisecretory therapyAntisecretory therapy

• SurgerySurgery

• AblationAblation

• ChemopreventionChemoprevention

Management/Surveillance of Barrett’s Management/Surveillance of Barrett’s Esophagus Without DysplasiaEsophagus Without Dysplasia

• Education about cancer riskEducation about cancer risk• 0.5%/year0.5%/year• *Lifetime risk estimate:*Lifetime risk estimate:

–RRkk = 1-e = 1-e(-Ik(-Ik∆tk)∆tk)

• Most patients die of other causesMost patients die of other causes• Survival no different than general Survival no different than general

populationpopulation

• Control reflux symptomsControl reflux symptoms

*From Shaheen N et al. Gastroenterology 2005;129:429-436.From Shaheen N et al. Gastroenterology 2005;129:429-436.

PPIs Associated with Reduced Incidence of PPIs Associated with Reduced Incidence of Dysplasia in Barrett’s EsophagusDysplasia in Barrett’s Esophagus

From El-Serag H et al. Am J Gastroenterol 2004;99:1877-83.From El-Serag H et al. Am J Gastroenterol 2004;99:1877-83.

P < 0.001P < 0.001

PPIs In Barrett’s Esophagus: PPIs In Barrett’s Esophagus: What Do We Know?What Do We Know?

• Consistent symptom controlConsistent symptom control

• Heals concomitant esophagitisHeals concomitant esophagitis

• Decreases acid & bile reflux Decreases acid & bile reflux

• Squamous islands commonSquamous islands common

• Insignificant regression of Barrett’s Insignificant regression of Barrett’s epitheliumepithelium

PPIs In Barrett’s Esophagus: PPIs In Barrett’s Esophagus: What Do We Know?What Do We Know?

• Persistent acid exposure despite Persistent acid exposure despite symptom control in 25% to 40%symptom control in 25% to 40%

• No change in cancer riskNo change in cancer risk

• May decrease dysplasia riskMay decrease dysplasia risk

• No particular expertise required for No particular expertise required for prescribing PPIsprescribing PPIs

Systematic Review of Surgical Vs. Systematic Review of Surgical Vs. Medical Therapy of Barrett’s Medical Therapy of Barrett’s

Esophagus: Cancer Incidence Esophagus: Cancer Incidence

From Chang EY et al. Ann Surg 2007;246:11-21.From Chang EY et al. Ann Surg 2007;246:11-21.

Antireflux Surgery As An Antireflux Surgery As An Antineoplastic MeasureAntineoplastic Measure

• Cancer risk in GERD population lowCancer risk in GERD population low

• Cancer risk in Barrett’s population lowCancer risk in Barrett’s population low

• Laparoscopic antireflux surgery can be Laparoscopic antireflux surgery can be done safelydone safely

• Complications/risks of antireflux surgery > Complications/risks of antireflux surgery > cancer risk!cancer risk!

• No convincing data that antireflux surgery No convincing data that antireflux surgery decreases cancer risk in Barrett’s decreases cancer risk in Barrett’s esophagusesophagusFrom Shaheen N. Am J Gastroenterol 2005;100:1009-11.From Shaheen N. Am J Gastroenterol 2005;100:1009-11.

ChemopreventionChemopreventionDefinitionDefinition

• To prevent halt or reverse To prevent halt or reverse cancer process in one or cancer process in one or several organs using:several organs using:• Dietary agentsDietary agents• Herbal agentsHerbal agents• Pharmacologic agentsPharmacologic agents

From Jankowski J & Hawk ET. Nat Clin Pract Gastroenterol Hepatol 2006;3:101-11. From Jankowski J & Hawk ET. Nat Clin Pract Gastroenterol Hepatol 2006;3:101-11.

PGEPGE22 in Carcinogenesis in Carcinogenesis

From Wang D, Dubois RN. Gut 2006;55:115-122.From Wang D, Dubois RN. Gut 2006;55:115-122.

http://gut.bmjjournals.com/content/vol55/issue1/images/large/gt47100.f2.jpeg

Protective Association of ASA & NSAIDS Protective Association of ASA & NSAIDS With Esophageal Cancer: A Systematic With Esophageal Cancer: A Systematic

ReviewReview

From Corley DA et al. Gastroenterology 2003;124:47-56.From Corley DA et al. Gastroenterology 2003;124:47-56.From Corley DA et al. Gastroenterology 2003;124:47-56.From Corley DA et al. Gastroenterology 2003;124:47-56.

ThunThunThunThun

FunkhouserFunkhouserFunkhouserFunkhouser

Farrow Farrow Farrow Farrow

Farrow Farrow Farrow Farrow

CooganCooganCooganCoogan

LangmanLangmanLangmanLangman

CombinedCombinedCombinedCombined

.01.01.01.01 .1.1.1.1 .25.25.25.25 .5.5.5.5 .75.75.75.75.75.75.75.75

1.51.51.51.52.02.02.02.0

ASA/NSAIDs & Risk of Neoplastic ASA/NSAIDs & Risk of Neoplastic Progression in Barrett’s EsophagusProgression in Barrett’s Esophagus

From Vaughan TL et al. Lancet Oncol 2005;6:945-52.From Vaughan TL et al. Lancet Oncol 2005;6:945-52.

2008 ACG Barrett’s Esophagus 2008 ACG Barrett’s Esophagus Guidelines: ChemopreventionGuidelines: Chemoprevention

• Sufficient evidence that any Sufficient evidence that any treatment prevents cancer or treatment prevents cancer or cancer-related deaths is lackingcancer-related deaths is lacking

• Chemoprevention represents a Chemoprevention represents a promising promising future future strategystrategy

From Wang KK and Sampliner RE. Am J Gastroenterol 2008;103:788-97.From Wang KK and Sampliner RE. Am J Gastroenterol 2008;103:788-97.

Ablation Therapy: The OptionsAblation Therapy: The Options

• ThermalThermal• MPECMPEC• HeaterHeater• APCAPC• LaserLaser• RadiofrequencyRadiofrequency• CryotherapyCryotherapy

• PhotodynamicPhotodynamic• 5-ALA5-ALA• Porfimer sodiumPorfimer sodium• Hematoporphyrin Hematoporphyrin

derivativederivative

• MechanicalMechanical• Endoscopic Endoscopic

mucosal resectionmucosal resection

89

Radiofrequency AblationRadiofrequency Ablation

Radiofrequency AblationRadiofrequency Ablation

90

Radiofrequency Ablation of Nondysplastic Radiofrequency Ablation of Nondysplastic Barrett’s Epithelium: 30 Month Follow UpBarrett’s Epithelium: 30 Month Follow Up

Per Protocol Per Protocol (N=61)(N=61)

ITT ITT (N=62)(N=62)

Complete Complete ResponseResponse

98%98% 97%97%

From Fleischer D et al. Gastrointest Endosc 2008;68:867-876.2008;68:867-876.

No buried IM noted in any biopsiesNo buried IM noted in any biopsies

Ablation of Ablation of NondysplasticNondysplastic Barrett’s Barrett’s Esophagus: An EBM PerspectiveEsophagus: An EBM Perspective

• Assume 50% reduction in Ca risk:Assume 50% reduction in Ca risk:

• 0.5% 0.5% →→ 0.25% 0.25%

• Absolute risk reduction:Absolute risk reduction:• 0.005 - 0.0025 = 0.00250.005 - 0.0025 = 0.0025

• Number needed to treat to prevent 1 CaNumber needed to treat to prevent 1 Ca• 1/absolute risk reduction1/absolute risk reduction

• 1/0.0025 = 1/0.0025 = 400400From Spechler SJ et al. Gastroenterology 2000;119:587-9.From Spechler SJ et al. Gastroenterology 2000;119:587-9.

From Shaheen N et al. Gastroenterology 2008;134:A37.

AIM Dysplasia TrialAIM Dysplasia Trial

• RCT of RFA vs. shamRCT of RFA vs. sham

• N=127N=127• HGDHGD

• LGDLGD

• Primary end pointsPrimary end points• Clearance of dysplasia @ Clearance of dysplasia @ 12 mos12 mos

• Clearance of IM @ Clearance of IM @ 12 mos12 mos

80%

91%

11% 12%

0%

20%

40%

60%

80%

100%

Intention to Treat Per Protocol

RFASham

* p<0.001

*

*

Complete Response Dysplasia HGD Complete Response Dysplasia HGD Cohort (n=43)Cohort (n=43)

From Shaheen N et al. Gastroenterology 2008;134:A37.From Shaheen N et al. Gastroenterology 2008;134:A37.

90%95%

37%41%

0%

20%

40%

60%

80%

100%


RFASham

* p<0.001

**

Complete Response Dysplasia LGD Complete Response Dysplasia LGD Cohort (n=58)Cohort (n=58)

From Shaheen N et al. Gastroenterology 2008;134:A37From Shaheen N et al. Gastroenterology 2008;134:A37

77%83%

0% 0%0%

20%

40%

60%

80%

100%


RFASham

* p<0.001

**

Complete Response Intestinal Metaplasia Complete Response Intestinal Metaplasia All Patients (n=101)All Patients (n=101)


Histological ProgressionHistological Progression

• Sham: 7/37 (18.9%)*Sham: 7/37 (18.9%)*• RFA: 3/64 (4.7%)RFA: 3/64 (4.7%)• CancersCancers

• HGD to CA, Sham: 4/18HGD to CA, Sham: 4/18– 2 IMC (EMR+RFA)2 IMC (EMR+RFA)– 2 T1sm (surgery)2 T1sm (surgery)

• HGD to CA, RFA: 1/25HGD to CA, RFA: 1/25– 1 IMC (EMR+RFA)1 IMC (EMR+RFA)

4.7% 5.1%4.0%

15.8%

22.2%

18.9%

0%

5%

10%

15%

20%

25%

Any progression(n=101)

LGD to HGD(n=58)

HGD to CA(n=43)

RFA Sham * p<0.05

*


Histology: Sub-squamous Intestinal MetaplasiaHistology: Sub-squamous Intestinal Metaplasia

• Baseline incidence of SSIM (25%)Baseline incidence of SSIM (25%)• HGD cohort: 21% of patientsHGD cohort: 21% of patients• LGD cohort: 30% of patientsLGD cohort: 30% of patients

• 12 month incidence of SSIM12 month incidence of SSIM• RFA cohort: RFA cohort: 6.8% of patients6.8% of patients• Sham cohort: Sham cohort: 60% of patients*60% of patients*

ResultsResults

*p<0.05 Fisher’s exact test, RFA vs. Sham

Endoscopic Mucosal ResectionEndoscopic Mucosal Resection

• Focal EMRFocal EMR

• Stepwise radical (circumferential) Stepwise radical (circumferential) EMREMR

• EMR + thermal therapyEMR + thermal therapy

EMR of Early Cancer & HGD: EMR of Early Cancer & HGD: Long-Term Wiesbaden ResultsLong-Term Wiesbaden Results

• N=100 low risk lesionsN=100 low risk lesions

• Median f/u 33 mosMedian f/u 33 mos

• EMR technique:EMR technique:• Macroscopic lesionMacroscopic lesion

• Suck and cutSuck and cut

• Mean of 1.5 resections/patientMean of 1.5 resections/patient

From Ell C et al. Gastrointest Endosc 2007;65:3-10.From Ell C et al. Gastrointest Endosc 2007;65:3-10.

EMR of Early Cancer: Long-Term EMR of Early Cancer: Long-Term Wiesbaden ResultsWiesbaden Results

• Recurrent Recurrent carcinoma in 11% carcinoma in 11% • All successfully All successfully

removedremoved

• 2 deaths were 2 deaths were unrelated to unrelated to cancercancer

From Ell C et al. Gastrointest Endosc 2007;65:3-10.From Ell C et al. Gastrointest Endosc 2007;65:3-10.

Combined EMR + RFA of Combined EMR + RFA of Intraepithelial Neoplasia Intraepithelial Neoplasia

• N=12 with HGD or intramucosal CaN=12 with HGD or intramucosal Ca• All visible lesions removed by EMR All visible lesions removed by EMR

(N=7)(N=7)• Residual flat diseaseResidual flat disease

• HGD-11HGD-11• LGD-1LGD-1

• Circumferential + focal RFACircumferential + focal RFAFrom Gondrie JJ et al. Endoscopy 2008;40:370-9From Gondrie JJ et al. Endoscopy 2008;40:370-9

Combined EMR + RFA of Combined EMR + RFA of Intraepithelial Neoplasia Intraepithelial Neoplasia

• Median fu 9 mosMedian fu 9 mos

• 12/12 patients12/12 patients• No dysplasiaNo dysplasia

• Complete endoscopic + histologic Complete endoscopic + histologic removal of BEremoval of BE

• 0/363 biopsies with buried IM0/363 biopsies with buried IM

From Gondrie JJ et al. Endoscopy 2008;40:370-9From Gondrie JJ et al. Endoscopy 2008;40:370-9

Long Term Survival After Treatment Long Term Survival After Treatment of HGD: PDT + EMR Vs. Surgeryof HGD: PDT + EMR Vs. Surgery

• Retrospective cohort studyRetrospective cohort study• N=199N=199• PDT cohortPDT cohort

• 4 quadrant Q 1cm biopsies4 quadrant Q 1cm biopsies• EMR of mucosal abnormalitiesEMR of mucosal abnormalities• Surveillance Q 3 mos for 2 yrsSurveillance Q 3 mos for 2 yrsthen q 6 mos if then q 6 mos if

HGD eliminated for 1-2 yrsHGD eliminated for 1-2 yrs

• Surgery cohort (N=70)Surgery cohort (N=70)From Prasad GA et al. Gastroenterology 2007;132:1226-33.From Prasad GA et al. Gastroenterology 2007;132:1226-33.

Long Term Survival After Long Term Survival After Treatment of HGDTreatment of HGD

From Prasad GA et al. Gastroenterology 2007;132:1226-33.From Prasad GA et al. Gastroenterology 2007;132:1226-33.

Long Term Cancer Free Survival Long Term Cancer Free Survival After Treatment of HGDAfter Treatment of HGD

From Prasad GA et al. Gastroenterology 2007;132:1226-33.From Prasad GA et al. Gastroenterology 2007;132:1226-33.

Cancer Free Survival: Endoscopic Cancer Free Survival: Endoscopic Therapy Vs Surgery for Early Esophageal Therapy Vs Surgery for Early Esophageal

CancerCancer

From Das A et al. Am J Gastroenterol 2008;103:1340-5From Das A et al. Am J Gastroenterol 2008;103:1340-5

Surgery

Endotherapy

Documents

Barrett's Esophagus and Adenocarcinoma