Barrett's Esophagus and Adenocarcinoma

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  • Study Details
    Design: controlled trial of 70 patients to determine the role of duodeno-gastroesophageal reflux in producing mucosal injury across the spectrum of GERD
    Population: 20 controls, 30 patients with GERD, and 20 patients with BE
    24-Hour ambulatory pH and bilirubin measurements were obtained using a glass pH electrode and fiberoptic sensor
    Key Point
    Both acid and duodenogastroesophageal reflux show a graded increase in severity across the GERD spectrum, and both occur simultaneously in most reflux episodes
  • Screening & Surveillance: A Cost-Utility Analysis
    The costs and benefits of screening and different surveillance intervals compared to no screening or surveillance are demonstrated by cost per quality-adjusted life years. The incremental cost-effectiveness ratio for surveillance intervals more often than every 5 years was consistently greater than $380,000 per quality life year saved.
    Inadomi, Ann Intern Med 2003; 138:181
  • Interpretation of Barrett’s Esophagus in Community Practice
    These data summarize the study of Montgomery et al. Although there was no significant improvement between sets 1 and 2 in the diagnostic categories of indefinite for dysplasia, low-grade dysplasia and high-grade dysplasia/cancer, there was a significant improvement between sets 1 and 2 in recognizing negative for dysplasia. Thus, this study concluded that pathologists could improve on agreeing on criteria for negative for dysplasia.
    Alikhan M, et al. Gastrointest Endosc 1999; 50:23
  • Barrett's Esophagus and Adenocarcinoma

    1. 1. Barrett’s Esophagus &Barrett’s Esophagus & AdenocarcinomaAdenocarcinoma Professor of MedicineProfessor of Medicine Cleveland Clinic Lerner College of Medicine ofCleveland Clinic Lerner College of Medicine of Case Western Reserve UniversityCase Western Reserve University Department of Gastroenterology & HepatologyDepartment of Gastroenterology & Hepatology Taussig Cancer CenterTaussig Cancer Center USAUSA Gary W. Falk, M.D., M.S.Gary W. Falk, M.D., M.S.
    2. 2. Barrett’s Esophagus &Barrett’s Esophagus & AdenocarcinomaAdenocarcinoma • 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’sWhy should I care about Barrett’s esophagus?esophagus?
    3. 3. Barrett’s Esophagus &Barrett’s Esophagus & AdenocarcinomaAdenocarcinoma • 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?
    4. 4. Barrett’s Esophagus &Barrett’s Esophagus & AdenocarcinomaAdenocarcinoma • 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’sWhy should I care about Barrett’s esophagus?esophagus?
    5. 5. Barrett’s EsophagusBarrett’s Esophagus Intestinal MetaplasiaIntestinal MetaplasiaColumnar distalColumnar distal esophagusesophagus
    6. 6. Barrett’s Esophagus &Barrett’s Esophagus & AdenocarcinomaAdenocarcinoma • 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’sWhy should I care about Barrett’s esophagus?esophagus?
    7. 7. Prevalence of Barrett’sPrevalence of Barrett’s Esophagus at EndoscopyEsophagus at Endoscopy • 6-12% of symptomatic GERD6-12% of symptomatic GERD patientspatients • << 1% of patients without1% of patients without GERD symptomsGERD symptoms
    8. 8. From Van Soest E M et al. Gut 2005;54:1062-1066. Incidence of Barrett's Esophagus Over TimeIncidence of Barrett's Esophagus Over Time In The NetherlandsIn The Netherlands
    9. 9. Prevalence of Barrett’s EsophagusPrevalence 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 (%)(%) 1616 (1.6%)(1.6%) 55 (0.5%)(0.5%) 1111 (1.1%)(1.1%) 984984 (98.4%)(98.4%) % with% with GERDGERD 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%
    10. 10. Barrett’s Esophagus &Barrett’s Esophagus & AdenocarcinomaAdenocarcinoma • 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’sWhy should I care about Barrett’s esophagus?esophagus?
    11. 11. Relationship of Esophageal Acid and BileRelationship of Esophageal Acid and Bile Exposure to Barrett’s EsophagusExposure to Barrett’s Esophagus 1.5 7 15.4 14.7 22.8 0.4 3.2 14.6 23.0 46.0 0 10 20 30 40 50 60 70 Controls No Esophagitis Esophagitis Uncomplicated Barrett's Complicated Barrett's TotalTimepH<4andBilirubin≥0.14(%) Acid Bilirubin Vaezi and Richter.Vaezi and Richter. GastroenterologyGastroenterology 1996;111:1192-9.1996;111:1192-9.
    12. 12. Abdominal Obesity As A Risk FactorsAbdominal Obesity As A Risk Factors For Barrett’s Esophagus vs. GERDFor 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.
    13. 13. Barrett’s Esophagus &Barrett’s Esophagus & AdenocarcinomaAdenocarcinoma • 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’sWhy should I care about Barrett’s esophagus?esophagus?
    14. 14. 1. Locate gastro-esophageal junction 3. Describe extent of metaplasia consistently 2. Recognize the squamocolumnar junction Three Essential Steps for Endoscopic Diagnosis and Description
    15. 15. 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.
    16. 16. Barrett’s Esophagus &Barrett’s Esophagus & AdenocarcinomaAdenocarcinoma • 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’sWhy should I care about Barrett’s esophagus?esophagus?
    17. 17. 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? • 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’sWhy should I care about Barrett’s esophagus?esophagus?
    18. 18. GI Motility online (May 2006) | doi:10.1038/gimo45GI Motility online (May 2006) | doi:10.1038/gimo45 Adenocarcinoma in Barrett’sAdenocarcinoma in Barrett’s EsophagusEsophagus
    19. 19. Relative Change in Incidence of EsophagealRelative 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 MelanomaMelanoma ProstateProstate BreastBreast LungLung ColorectalColorectal
    20. 20. Disease Specific Mortality & IncidenceDisease 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(215/million)15/million)
    21. 21. Development of Neoplasia inDevelopment of Neoplasia in Barrett’s EsophagusBarrett’s Esophagus 1 2Gastric acid reflux 2 1Duodenal bile reflux Pro-carcinogenic primary and secondary bile salts 3 pH dependent,bile salt induced chronic esophageal injury 4 Chronic esophageal inflammation and PGE2release 5 Neoplasia in Barrett’s esophagus
    22. 22. Population Attributable Risks* ofPopulation 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 EverEver smokersmoker 39.7%39.7% 25.6-55.825.6-55.8 BMIBMI quartile 2-4quartile 2-4 41.1%41.1% 23.8-60.923.8-60.9 AnyAny GERGER symptomssymptoms 29.7%29.7% 19.5-42.319.5-42.3 Low consumption ofLow 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 RiskProportion of Disease Attributable to Given Risk FactorFactor
    23. 23. Barrett’s Esophagus &Barrett’s Esophagus & AdenocarcinomaAdenocarcinoma • What is the rationale for screeningWhat is the rationale for screening & surveillance strategies?& surveillance strategies? • How do I treat Barrett’sHow do I treat Barrett’s esophagus?esophagus?
    24. 24. Screening for Barrett’sScreening for Barrett’s Esophagus: GuidelinesEsophagus: Guidelines ACGACG 20082008 AGAAGA 20052005 BSGBSG 20052005 GERDGERD symptomssymptoms IndividualizeIndividualize MaybeMaybe NoNo No GERDNo GERD symptomssymptoms NoNo NoNo NoNo
    25. 25. Screening For Barrett’sScreening For Barrett’s Esophagus: Why Bother?Esophagus: Why Bother? • OnlyOnly 5%5% of esophagealof esophageal adenocarcinoma casesadenocarcinoma cases undergoing resection occurundergoing resection occur in patients within 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.
    26. 26. Estimates of New EsophagealEstimates of New Esophageal Cancer Cases and Mortality: 2007Cancer Cases and Mortality: 2007 15,560 13,940 0 5,000 10,000 15,000 20,000 New Cases Deaths From American Cancer Society 2007From American Cancer Society 2007
    27. 27. Screening Of Barrett’sScreening 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?
    28. 28. Screening & Surveillance For Barrett’sScreening & 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 surveillanceOne time screening with surveillance if dysplasia:if 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-
    29. 29. From Inadomi J et al. Ann Intern Med 2003;138:181.From Inadomi J et al. Ann Intern Med 2003;138:181. Cost $ 16.45 16.47 16.49 16.51 16.53 16.55 16.57 500 1500 2500 3000 2000 1000 0 16.59 16.61 16.63 Screening with surveillance every: 2 years 3 years 4 years 5 years Screening with surveillance for dysplasia No screening or surveillance Quality Adjusted Life-year 16.65 Screening & Surveillance:Screening & Surveillance: A Cost-Utility AnalysisA Cost-Utility Analysis
    30. 30. Prevalence of Barrett’s EsophagusPrevalence 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 inBarrett’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.
    31. 31. Detection of Barrett’s Esophagus AfterDetection 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 21/172Confirmed Barrett’s esophagus in 21/172 (12%)(12%) • 19/21 (90%) with short segment19/21 (90%) with short segment • Median segment length 1 cm (range 0.5-5Median 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.
    32. 32. Barrett’s Esophagus On RepeatBarrett’s Esophagus On Repeat Endoscopy Within 5 Years AccordingEndoscopy 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.
    33. 33. High Definition White LightHigh Definition White Light EndoscopyEndoscopy
    34. 34. Symptomatic GERD As A Risk Factor For Esophageal Adenocarcinoma 0 20 40 60 80 100 Controls Esophageal Adenoca Cardia Ca Esophageal Squamous 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 bothof heartburn, regurgitation or both >> once weeklyonce weekly %%
    35. 35. Screening Of Barrett’sScreening 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
    36. 36. Screening for Barrett’s Esophagus:Screening for Barrett’s Esophagus: DilemmasDilemmas • Large poolLarge pool of patients with chronic GERDof patients with chronic GERD symptomssymptoms • > 10 million!> 10 million! • Few casesFew cases of adenocarcinomaof adenocarcinoma • ~~ 7,000 annually7,000 annually • No prior GERD symptomsNo prior GERD symptoms in 40% ofin 40% of adenocarcinoma patientsadenocarcinoma patients • No dataNo data prove effectiveness of screeningprove 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.
    37. 37. Screening for Barrett’sScreening for Barrett’s Esophagus: ProblemsEsophagus: Problems • Cost/risk of endoscopy • Lack of noninvasive alternatives • Lack of predictors to increase yield of screening
    38. 38. 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 TheEsophageal Capsule Endoscopy for The Diagnosis of Barrett’s EsophagusDiagnosis of Barrett’s Esophagus
    39. 39. Esophageal Capsule Endoscopy for TheEsophageal Capsule Endoscopy for The Diagnosis of Barrett’s EsophagusDiagnosis 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..
    40. 40. Unsedated Small Caliber EndoscopyUnsedated 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 unsedatedRCT (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 participateeligible subjects refused to participate • 71%71% prefer unsedated scope for futureprefer 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.
    41. 41. Screening for Barrett’s Esophagus:Screening for Barrett’s Esophagus: 2008 ACG Guidelines2008 ACG Guidelines • Screening in the general populationScreening in the general population cannot be recommendedcannot be recommended • Screening in selective populations atScreening in selective populations at higher risk remains to be establishedhigher 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.
    42. 42. AGA Technical Review on EsophagealAGA Technical Review on Esophageal Carcinoma: Summary of EvidenceCarcinoma: Summary of Evidence • Surveillance supportedSurveillance supported by Level IIby 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.
    43. 43. Surveillance & Survival in Barrett’sSurveillance & Survival in Barrett’s Adenocarcinoma: A Population Based StudyAdenocarcinoma: A Population Based Study From Corley DA et al. Gastroenterology 2002;122:633-40.From Corley DA et al. Gastroenterology 2002;122:633-40.
    44. 44. Surveillance & Cancer Stage in Barrett’sSurveillance & Cancer Stage in Barrett’s Adenocarcinoma: A Population BasedAdenocarcinoma: A Population Based StudyStudy From Corley DA et al. Gastroenterology 2002;122:633-40.From Corley DA et al. Gastroenterology 2002;122:633-40.  Surveillance detectedSurveillance detected  Not detected in surveillanceNot detected in surveillance
    45. 45. Surveillance of Barrett’s Esophagus:Surveillance of Barrett’s Esophagus: 2008 ACG Guidelines2008 ACG Guidelines • Assess candidacy forAssess 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.
    46. 46. Surveillance of Nondysplastic Barrett’sSurveillance of Nondysplastic Barrett’s Esophagus: 2008 ACG GuidelinesEsophagus: 2008 ACG Guidelines • 4 quadrant biopsies Q 2 cm while on4 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 warrantsAny grade of dysplasia warrants confirmation by expert pathologistconfirmation by expert pathologist From Wang KK & Sampliner R. Am J Gastroenterol 2008;103:788-97.From Wang KK & Sampliner R. Am J Gastroenterol 2008;103:788-97.
    47. 47. Management of Low-Grade Dysplasia:Management of Low-Grade Dysplasia: 2008 ACG Guidelines2008 ACG Guidelines • Confirm diagnosis by expertConfirm diagnosis by expert pathologistpathologist • Repeat EGD withinRepeat EGD within 6 months6 months • Annual EGD until 2 consecutiveAnnual EGD until 2 consecutive negative for dysplasianegative for dysplasia From Wang KK & Sampliner R. Am J Gastroenterol 2008;103:788-97.From Wang KK & Sampliner R. Am J Gastroenterol 2008;103:788-97.
    48. 48. Importance of ExpertImportance of Expert Confirmation of DysplasiaConfirmation of Dysplasia Community DiagnosisCommunity Diagnosis Downgraded DiagnosisDowngraded 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
    49. 49. Updated 2008 ACG Guidelines: High-Updated 2008 ACG Guidelines: High- Grade Dysplasia ManagementGrade Dysplasia Management • Confirm diagnosis by expert GIConfirm diagnosis by expert GI pathologistpathologist • Repeat EGD withinRepeat EGD within 3 mos3 mos • More intensive biopsy protocolMore intensive biopsy protocol • If any mucosal nodularityIf any mucosal nodularityEMREMR • HGD is a threshold for interventionHGD is a threshold for intervention • Review management options withReview management options with patientpatient From Wang KK & Sampliner R. Am J Gastroenterol 2008;103:788-97.From Wang KK & Sampliner R. Am J Gastroenterol 2008;103:788-97.
    50. 50. Updated 2008 ACG Guidelines: HighUpdated 2008 ACG Guidelines: High Grade Dysplasia ManagementGrade Dysplasia Management • Local expertiseLocal expertise • SurgicalSurgical • EndoscopicEndoscopic • PatientPatient • AgeAge • ComorbidityComorbidity • PreferencePreference • Esophagectomy no longer necessaryEsophagectomy no longer necessary treatment responsetreatment response From Wang KK & Sampliner R. Am J Gastroenterol 2008;103:788-97.From Wang KK & Sampliner R. Am J Gastroenterol 2008;103:788-97.
    51. 51. Preoperative Prevalence of Barrett’s Esophagus inPreoperative Prevalence of Barrett’s Esophagus in Patients Undergoing Resection for Incident EsophagealPatients 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 ofSummary estimate of prior prevalence =prior prevalence = 4.7%4.7%
    52. 52. Endoscopic Surveillance:Endoscopic Surveillance: Where Is The Dysplasia?Where Is The Dysplasia?
    53. 53. Distribution of Dysplasia and Cancer inDistribution of Dysplasia and Cancer in Resection SpecimensResection Specimens Barrett’s, no dysplasiaBarrett’s, no dysplasia Low - grade dysplasiaLow - grade dysplasia High - grade dysplasiaHigh - grade dysplasia CancerCancer 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.
    54. 54. Interpretation of Barrett’sInterpretation 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. Gastric metaplasia IM without dysplasia Low-grade dysplasia High-grade dysplasia 100 80 60 40 20 0 % Agreement Pathologists’ Reading
    55. 55. 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.
    56. 56. 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’sCauses of Death of Barrett’s Esophagus Patients in the UKEsophagus Patients in the UK
    57. 57. Limitations of Endoscopic BiopsyLimitations of Endoscopic Biopsy Surveillance of Barrett’s EsophagusSurveillance of Barrett’s Esophagus • Dysplasia/early cancerDysplasia/early cancer • IndistinguishableIndistinguishable • Patchy distributionPatchy distribution • Interobserver variability in dysplasiaInterobserver variability in dysplasia interpretationinterpretation • Most patients never develop cancerMost patients never develop cancer • Incidence 0.5%/yearIncidence 0.5%/year
    58. 58. Future Strategies for SurveillanceFuture 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 focusIdentify patients @ increased risk and focus efforts on themefforts on them
    59. 59. Enhancements to EndoscopicEnhancements 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
    60. 60. Tandem NBI + HD WLE Vs. StandardTandem NBI + HD WLE Vs. Standard WLE For Dysplasia Detection inWLE 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.
    61. 61. Tandem NBI + HD WLE Vs. Standard WLETandem NBI + HD WLE Vs. Standard WLE For Dysplasia Detection in Barrett’sFor Dysplasia Detection in Barrett’s EsophagusEsophagus NBI/HDNBI/HD WLEWLE StandardStandard WLEWLE P-valueP-value Higher gradeHigher grade of histologyof histology 12 (18%)12 (18%) 00 <.001<.001 DysplasiaDysplasia 37 (57%)37 (57%) 28 (43%)28 (43%) Mean biopsyMean biopsy numbernumber 4.74.7 ++ 2.72.7 8.58.5 ++ 5.15.1 <.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
    62. 62. Conventional Indigo carmine AFI φ10mm LST (NG) Tubular adenoma with severe atypia Provided by Juntendo UniversityProvided by Juntendo University
    63. 63. 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.
    64. 64. ETMI False PositiveETMI False Positive From Curvers W et al. Gut 2008;57:167-72.From Curvers W et al. Gut 2008;57:167-72.
    65. 65. ETMI for Detection of EarlyETMI 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 • DetectedDetected 1111 additional patients normal by HREadditional patients normal by HRE • MissedMissed 33 patients detected by random biopsies andpatients 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 From Curvers W et al. Gut 2008;57:167-72.From Curvers W et al. Gut 2008;57:167-72.
    66. 66. Field of view: 500x500Field of view: 500x500µmµm Range: 0-250Range: 0-250µmµm Lateral resolution: <1µmLateral resolution: <1µm Technique of EndomicroscopyTechnique of Endomicroscopy
    67. 67. Confocal Laser Endomicroscopy in Barrett’sConfocal 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.
    68. 68. Confocal Laser EndomicroscopyConfocal 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.
    69. 69. Chromoendoscopy Guided EndomicroscopyChromoendoscopy Guided Endomicroscopy Chromo +Chromo + EndomicroscopyEndomicroscopy ConventionalConventional 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 withTargeted biopsies with chromoendoscopychromoendoscopy 312312 227227 <.0001<.0001 Targeted biopsies withTargeted biopsies with endomicroscopyendomicroscopy 6262 -- -- No of targeted biopsies withNo of targeted biopsies with intraepithelial neoplasiaintraepithelial neoplasia 5757 1313 <.0001<.0001 No of biopsy specimens withNo 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.
    70. 70. Molecular ImagingMolecular Imaging From Mahmood U & Wallace MB. Gastroenterology 2007;132:11-14.From Mahmood U & Wallace MB. Gastroenterology 2007;132:11-14.
    71. 71. 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
    72. 72. Barrett’s Esophagus &Barrett’s Esophagus & AdenocarcinomaAdenocarcinoma • What is the rationale forWhat is the rationale for screening & surveillancescreening & surveillance strategies?strategies? • How do I treat Barrett’sHow do I treat Barrett’s esophagus?esophagus?
    73. 73. Points of Disruption in Barrett’sPoints of Disruption in Barrett’s Esophagus Dysplasia-CarcinomaEsophagus Dysplasia-Carcinoma SequenceSequence MetaplasiaMetaplasia DysplasiaDysplasia CarcinomaCarcinoma AblationAblationChemopreventionChemoprevention ?? ??
    74. 74. Therapy of Barrett’s EsophagusTherapy of Barrett’s Esophagus • Antisecretory therapyAntisecretory therapy • SurgerySurgery • AblationAblation • ChemopreventionChemoprevention
    75. 75. Management/Surveillance of Barrett’sManagement/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 generalSurvival 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.
    76. 76. PPIs Associated with Reduced Incidence ofPPIs 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
    77. 77. 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 refluxDecreases acid & bile reflux • Squamous islands commonSquamous islands common • Insignificant regression of Barrett’sInsignificant regression of Barrett’s epitheliumepithelium
    78. 78. PPIs In Barrett’s Esophagus:PPIs In Barrett’s Esophagus: What Do We Know?What Do We Know? • Persistent acid exposure despitePersistent 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 forNo particular expertise required for prescribing PPIsprescribing PPIs
    79. 79. Systematic Review of Surgical Vs.Systematic Review of Surgical Vs. Medical Therapy of Barrett’sMedical Therapy of Barrett’s Esophagus: Cancer IncidenceEsophagus: Cancer Incidence From Chang EY et al. Ann Surg 2007;246:11-21.From Chang EY et al. Ann Surg 2007;246:11-21.
    80. 80. Antireflux Surgery As AnAntireflux 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 beLaparoscopic 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 surgeryNo convincing data that antireflux surgery decreases cancer risk in Barrett’sdecreases cancer risk in Barrett’s esophagusesophagus From Shaheen N. Am J Gastroenterol 2005;100:1009-11.From Shaheen N. Am J Gastroenterol 2005;100:1009-11.
    81. 81. ChemopreventionChemoprevention DefinitionDefinition • To prevent halt or reverseTo prevent halt or reverse cancer process in one orcancer 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.
    82. 82. PGEPGE22 in Carcinogenesisin Carcinogenesis From Wang D, Dubois RN. Gut 2006;55:115-122.From Wang D, Dubois RN. Gut 2006;55:115-122.
    83. 83. Protective Association of ASA & NSAIDSProtective Association of ASA & NSAIDS With Esophageal Cancer: A SystematicWith 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. ThunThun FunkhouserFunkhouser FarrowFarrow FarrowFarrow CooganCoogan LangmanLangman CombinedCombined .01.01 .1.1 .25.25 .5.5 .75.75 .75.75 1.51.5 2.02.0
    84. 84. ASA/NSAIDs & Risk of NeoplasticASA/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.
    85. 85. 2008 ACG Barrett’s Esophagus2008 ACG Barrett’s Esophagus Guidelines: ChemopreventionGuidelines: Chemoprevention • Sufficient evidence that anySufficient evidence that any treatment prevents cancer ortreatment prevents cancer or cancer-related deaths is lackingcancer-related deaths is lacking • Chemoprevention represents aChemoprevention represents a promisingpromising futurefuture 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.
    86. 86. Ablation Therapy: The OptionsAblation Therapy: The Options • ThermalThermal • MPECMPEC • HeaterHeater • APCAPC • LaserLaser • RadiofrequencyRadiofrequency • CryotherapyCryotherapy • PhotodynamicPhotodynamic • 5-ALA5-ALA • Porfimer sodiumPorfimer sodium • HematoporphyrinHematoporphyrin derivativederivative • MechanicalMechanical • EndoscopicEndoscopic mucosal resectionmucosal resection
    87. 87. 89 Radiofrequency AblationRadiofrequency Ablation
    88. 88. Radiofrequency AblationRadiofrequency Ablation 90
    89. 89. Radiofrequency Ablation of NondysplasticRadiofrequency Ablation of Nondysplastic Barrett’s Epithelium: 30 Month Follow UpBarrett’s Epithelium: 30 Month Follow Up Per ProtocolPer Protocol (N=61)(N=61) ITTITT (N=62)(N=62) CompleteComplete 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
    90. 90. Ablation ofAblation of NondysplasticNondysplastic Barrett’sBarrett’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 = 400400 From Spechler SJ et al. Gastroenterology 2000;119:587-9.From Spechler SJ et al. Gastroenterology 2000;119:587-9.
    91. 91. 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
    92. 92. 80% 91% 11% 12% 0% 20% 40% 60% 80% 100% Intention to Treat Per Protocol RFA Sham * p<0.001 * * Complete Response Dysplasia HGDComplete 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.
    93. 93. 90% 95% 37% 41% 0% 20% 40% 60% 80% 100% Intention to Treat Per Protocol RFA Sham * p<0.001 * * Complete Response Dysplasia LGDComplete 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
    94. 94. 77% 83% 0% 0% 0% 20% 40% 60% 80% 100% Intention to Treat Per Protocol RFA Sham * p<0.001 * * Complete Response Intestinal MetaplasiaComplete Response Intestinal Metaplasia All Patients (n=101)All Patients (n=101) From Shaheen N et al. Gastroenterology 2008;134:A37From Shaheen N et al. Gastroenterology 2008;134:A37
    95. 95. 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 * From Shaheen N et al. Gastroenterology 2008;134:A37From Shaheen N et al. Gastroenterology 2008;134:A37
    96. 96. Histology: Sub-squamous IntestinalHistology: Sub-squamous Intestinal MetaplasiaMetaplasia • 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
    97. 97. Endoscopic Mucosal ResectionEndoscopic Mucosal Resection • Focal EMRFocal EMR • Stepwise radical (circumferential)Stepwise radical (circumferential) EMREMR • EMR + thermal therapyEMR + thermal therapy
    98. 98. 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.
    99. 99. EMR of Early Cancer: Long-TermEMR of Early Cancer: Long-Term Wiesbaden ResultsWiesbaden Results • RecurrentRecurrent carcinoma in 11%carcinoma in 11% • All successfullyAll successfully removedremoved • 2 deaths were2 deaths were unrelated tounrelated to cancercancer From Ell C et al. Gastrointest Endosc 2007;65:3-10.From Ell C et al. Gastrointest Endosc 2007;65:3-10.
    100. 100. Combined EMR + RFA ofCombined EMR + RFA of Intraepithelial NeoplasiaIntraepithelial Neoplasia • N=12 with HGD or intramucosal CaN=12 with HGD or intramucosal Ca • All visible lesions removed by EMRAll visible lesions removed by EMR (N=7)(N=7) • Residual flat diseaseResidual flat disease • HGD-11HGD-11 • LGD-1LGD-1 • Circumferential + focal RFACircumferential + focal RFA From Gondrie JJ et al. Endoscopy 2008;40:370-9From Gondrie JJ et al. Endoscopy 2008;40:370-9
    101. 101. Combined EMR + RFA ofCombined EMR + RFA of Intraepithelial NeoplasiaIntraepithelial Neoplasia • Median fu 9 mosMedian fu 9 mos • 12/12 patients12/12 patients • No dysplasiaNo dysplasia • Complete endoscopic + histologicComplete 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
    102. 102. Long Term Survival After TreatmentLong 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 yrsthen q 6 mosthen q 6 mos if HGD eliminated for 1-2 yrsif HGD 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.
    103. 103. Long Term Survival AfterLong 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.
    104. 104. Long Term Cancer Free SurvivalLong 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.
    105. 105. Cancer Free Survival: EndoscopicCancer Free Survival: Endoscopic Therapy Vs Surgery for Early EsophagealTherapy 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

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