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Barrett’s surveillance: zinvol of niet

Barrett’s surveillance: zinvol of niet. Dr. M.E.Craanen Afdeling Maag-Darm-Leverziekten Flevo Zieknhuis, Almere. Barrett’s surveillance.

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Barrett’s surveillance: zinvol of niet

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  1. Barrett’s surveillance: zinvol of niet Dr. M.E.Craanen Afdeling Maag-Darm-Leverziekten Flevo Zieknhuis, Almere

  2. Barrett’s surveillance The constellation of a cancer (albeit a rare one) with an increasing incidence, a premalignant precursor lesion, a readily available diagnostic test (upper GI endoscopy), and a large at-risk population (patients with GERD), combined wiith a physicians’ good intentions, creates a ” perfect storm” environment for Barrett’s esophagus GIE 2007;65:31-5

  3. Barrett’s surveillance “ Routine clinical implementation of protocols without data from properly conducted randomised clinical trials should be avoided as much as possible. Once such strategies have become routine, their rigorous evaluation is exceedingly difficult, if not impossible “ Sackett et al. Clinical Epidemiology 1985

  4. Barrett’s surveillance • General principles of surveillance • Data on Barrett’s oesophagus • Summary/conclusions

  5. To survey or not to survey In Barrett’s oesophagus ? • Underlying cancer incidence/risk • Protocol feasibility (costs, accuracy, acceptability) • Impact on clinical outcome parameters ( survival, QALY) • Patient compliance • RANDOMISED DATABEFORE ROUTINE IMPLEMENTATION !!!!! • Hospital management of the additional clinical burden

  6. Prevalence of Barrett’s oesophagus • autopsy series 0.4% • GERD 10-20% • M:F ratio 3:1 • Barrett’s oesophagus estimated to occur in 1/700,000 U.S. adults • Rare in Afro-American adults

  7. 1/52 patient years 1/55 1/56 1/96 1/115 1/208 1/104 30-100 fold increased cancer risk, (1% follow-up) Hameeteman, 1989 Bonelli, 1993 Robertson, 1988 Miros, 1991 Ifthikhar,1992 Drewitz,1992 Overall estimate General increase Cancer risk in Barrett’s oesophagus

  8. Assessment of publication bias • Funnel diagram • Graphic representation of study size vs risk estimate • No publication bias

  9. Publication bias in Barrett’s literature • Funnel diagram • Graphic representation of study size vs risk estimate • Publication bias likely Shaheen et al. Gastroenterology 2000;119:333

  10. To survey or not to survey In Barrett’s oesophagus ? • Underlying cancer incidence/risk • Protocol feasibility (costs, accuracy, acceptability) • Impact on clinical outcome parameters ( survival, QALY) • Patient compliance • RANDOMISED DATABEFORE ROUTINE IMPLEMENTATION !!!!! • Hospital management of the additional clinical burden

  11. The natural history of disease Biological onset Early diagnosis possible Usual clinical diagnosis Outcome - recovery disability death

  12. Critical points along the natural history of disease (1) Definition A critical point is that point during disease progression before which treatment is either more effective or easier to apply than afterward Sackett et al. Clinical Epidemiology 1985

  13. Critical points along the natural history of disease (2) Biological onset Early diagnosis possible Usual clinical diagnosis Outcome - recovery disability death CP 1 CP 2 CP 3

  14. Natural history of Barrett’s carcinoma intestinal type epithelium low-grade dysplasia high-grade dysplasia adenocarcinoma Critical point

  15. Problems with dysplasia as a marker forsurveillance • Sampling error • Intra- and interobserver variability reported concordance of 60% for LGD and 77% for HGD in expert hands ! • Natural history not fully understood Small studies, selection bias, retrospective Focal versus diffuse dysplasia Temporal progression Which patients progress at what rate ?

  16. Dysplasia; follow-up N=618, 2546 patient’s years of F.U, Mean 4.12 years Cancer incidence: 0.5% 18/34 patients with HGD; at least two previously consecutive normal endoscopic-bioptic results Incidence LGD 4.3%/year LGD N=156 - 66% regression to normal, 21% stable, 13% HGD/Ca - cancer risk 0.6% Sharma P et al: Clin Gastroenterol Hepatol 2006;4:566-72

  17. Biomarkers • dysplasia ( “ gold standard “ ) • oncogenes: H-ras, cyclin D1 • tumor suppressor genes: p53 • growth factors: EGF, EGF-r, TGFalpha • proliferation markers: Ki-67, PCNA • chromosomal abnormalities, cell kinetics • except for dysplasia no clinical use yet !!

  18. Lead-time bias Years of follow-up

  19. Lenght time bias b.o e.d.p. u.c.d. outcome b.o e.d.p. u.c.d. outcome asymptomatic symptomatic

  20. Lead time and lenght time bias in Barrett’s oesophagus ???

  21. Patient-related hazards of surveillance • Wrong diagnosis, particularly in case of low prevalence ( PPV , NPV  ) • Physical and/or psychological complications • Non-compliance - frequency of testing test burden severity of disease implications for relatives

  22. Patient-related hazards of Barrett’s surveillance • Wrong diagnosis, particularly in case of low prevalence ( PPV , NPV  ) Dysplasia related problems • Physical and/or psychological complications Oesophagectomy: mortality 3-10%, morbidity up to 45% • Non-compliance frequency of testing, test burden, severity of disease, implications for relatives

  23. Economic aspects • Initial expenditures for screening/surveillance • Additional costs for further evaluation • Costs related to management after a correct final diagnosis, e.g. surgery • Costs related to an inappropriate diagnosis

  24. Incremental cost-analysis 4-year interval 5-year interval d No surveillance c a b

  25. Incremental cost-analysis in Barrett’s esophagus 4-year $ 276000 5-year $27400 d No surveillance $ 5250 c a b Provenzale et al Annual of GI Endoscopy 1995

  26. To survey or not to survey In Barrett’s oesophagus ? • Underlying cancer incidence/risk • Protocol feasibility (costs, accuracy, acceptability) • Impact on clinical outcome parameters ( survival, QALY) • Patient compliance • RANDOMISED DATABEFORE ROUTINE CLINICAL IMPLEMENTATION • Hospital management of the additional clinical burden

  27. Impact of surveillance on clinical outcome • Absence of large-scale randomised, prospective trials showing survival benefit! • Computer models • Retrospective small studies

  28. Computer-assisted decision analysis in Barrett’s oesophagus Hypothetical 55-year male patient • Without surveillance estimated life expectancy 20.6 years • Yearly interval with oesophagectomy for HGD estimated life expectancy 20.6 + 2.4 years • Yearly interval with oesophagectomy for cancer estimated life expectancy 20.6 + 1.4 years Provenzale: Ann GI Endosc 1995;p1-7

  29. Barrett’s surveillance • Sandick et al. Gut 1998;43:216-22 T,N stage in surveillance group lower 2-year’s survival 86% vs 43% BUT….. Retrospective analysis of resected cases using pathological diagnosis as search criterion • Lagergren et al. NEJM 1999;340;825:31 cancer risk in longstanding reflux independent from concomitant Barrett’s esophagus

  30. Cause of death in patients with Barrett’s oesophagus • Cohort study • N=166 • period 1973-1986 • traced number of patients 155 • mean follow-up 9.3 years (1440 pt years) • cancers 8 (symptomatic but 1) • alive 76 (3 E.Res), dead 79 ( 5 cancers, in 2 C.o.D) van der Burgh et al. Gut 1996;39:5-8

  31. To survey or not to survey In Barrett’s oesophagus ? • Underlying cancer incidence/risk • Protocol feasibility (costs, accuracy, acceptability) • Impact on clinical outcome parameters ( survival, QALY) • Patient compliance • RANDOMISED DATABEFORE ROUTINE CLINICAL IMPLEMENTATION • Hospital management of the additional clinical burden

  32. “Definite” surveillance study • Assumption: annual incidence =1.3% • Power analysis; p< 0.05 • Randomized trial would need 5000 patients with a 10-year follow-up to detect a 50% reduction in cancer mortality ! • However, the present estimate of the annual incidence is 0.5% indicating that such study is not going to be performed

  33. To survey or not to survey In Barrett’s esophagus ? - Summary • Underlying cancer incidence/risk 0.5% • Protocol feasibility (costs, accuracy, acceptability) Poor • Impact on clinical outcome parameters ( survival, QALY) Sofar, nil • Patient compliance Likely • RANDOMISED DATABEFORE ROUTINE CLINICAL IMPLEMENTATION Sofar, non-existent • Hospital management of the additional clinical burden ?

  34. To survey or not to survey In Barrett’s esophagus ? – Current status • ACG Practice Parameters Committee: Sampliner RE et al. Am J Gastroenterol 2002;97:1888-95 YES, go ahead • AGA Chicago workshop. Sharma P et al. Gastroenterology 2004;127:310-30 NOT sufficient solid data to endorse large-scale surveillance • New BSG guidelines on Barrett’s esophagus Playford et al. GUT 2006;55:442-3 17 out of 22 recommendations; level C evidence (expert opinion)

  35. How to improve ? • Better patient selection for surveillance - Refinements in diagnostic tools (e.g.HDE) - New imaging techniques - Molecular progression markers

  36. Overall conclusion • To date, the clinician has no other choice than to tailor surveillance towards individual demand, taking into account e.g. family history, medical history, age, and anxiety about potential long-term hazards

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