Barrett’s surveillance: zinvol of niet

Barrett’s surveillance: zinvol of niet

Dr. M.E.CraanenAfdeling Maag-Darm-Leverziekten

Flevo Zieknhuis, Almere

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


“ 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


General principles of surveillance

Data on Barrett’s oesophagus

Summary/conclusions

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 DATA BEFORE ROUTINE IMPLEMENTATION !!!!!

Hospital management of the additional clinical burden

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

Cancer risk in Barrett’s oesophagus

1/52 patient years 1/55 1/56 1/96 1/115 1/208

1/104

30-100 fold increasedcancer risk, (1% follow-up)

Hameeteman, 1989 Bonelli, 1993 Robertson, 1988 Miros, 1991 Ifthikhar,1992 Drewitz,1992

Overall estimate

General increase

Assessment of publication bias

Funnel diagram Graphic

representation of study size vs risk estimate

No publication bias

0102030405060708090

100

0 1 2 3 4 5 6 7 8 910

risk estimate

No. pts.

Publication bias in Barrett’s literature

Funnel diagram Graphic

representation of study size vs risk estimate

Publication bias likely

0102030405060708090

100

0 1 2 3 4 5 6 7 8 910

risk estimate

No. pts

Shaheen et al. Gastroenterology 2000;119:333





Patient compliance

RANDOMISED DATA BEFORE ROUTINE IMPLEMENTATION !!!!!


The natural history of disease

Biological onset

Early diagnosis possible

Usual clinical diagnosis

Outcome - recovery disability death

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

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

Natural history of Barrett’s carcinoma

intestinal type epithelium

low-grade dysplasia

high-grade dysplasia

adenocarcinoma

Critical point

Problems with dysplasia as a marker for surveillance

Sampling error

Intra- and interobserver variabilityreported concordance of 60% for LGD and 77% for HGD in expert hands !

Natural history not fully understoodSmall studies, selection bias, retrospectiveFocal versus diffuse dysplasiaTemporal progression Which patients progress at what rate ?

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

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 !!

Lead-time bias

0

20

40

60

80

100

0 1 2 3 4 5

Nat Hist Screening

Years of follow-up

Lenght time bias

b.o e.d.p. u.c.d. outcome

b.o e.d.p. u.c.d. outcome

asymptomatic symptomatic

Lead time and lenght time bias in Barrett’s oesophagus

???

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

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-compliancefrequency of testing, test burden, severity of disease, implications for relatives

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

Incremental cost-analysis

0

5000

10000

15000

20000

25000

11.80 11.85 11.90 11.95 12.00 12.05 12.10 12.15

QALY (years)

Cost

s in

US $

a

b

c

d

5-yearinterval

4-yearinterval

No surveillance

Incremental cost-analysis in Barrett’s esophagus

0

5000

10000

15000

20000

25000

11.80 11.85 11.90 11.95 12.00 12.05 12.10 12.15

QALY (years)

Cost

s in

US $

a

b

c

d

5-year$27400

4-year$ 276000

No surveillance$ 5250

Provenzale et al Annual of GI Endoscopy 1995





Patient compliance

RANDOMISED DATA BEFORE ROUTINE CLINICAL IMPLEMENTATION


Impact of surveillance on clinical outcome

Absence of large-scale randomised, prospective trials showing survival benefit!

Computer models

Retrospective small studies

Computer-assisted decision analysis in Barrett’s oesophagus

Hypothetical 55-year male patient

Without surveillanceestimated life expectancy 20.6 years

Yearly interval with oesophagectomy for HGDestimated life expectancy 20.6 + 2.4 years

Yearly interval with oesophagectomy for cancerestimated life expectancy 20.6 + 1.4 years

Provenzale: Ann GI Endosc 1995;p1-7


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

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





Patient compliance

RANDOMISED DATA BEFORE ROUTINE CLINICAL IMPLEMENTATION


““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

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 DATA BEFORE ROUTINE CLINICAL IMPLEMENTATION Sofar, non-existent

Hospital management of the additional clinical burden ?

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)

How to improve ?

Better patient selection for surveillance

- Refinements in diagnostic tools (e.g.HDE)

- New imaging techniques

- Molecular progression markers

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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Barrett’s surveillance: zinvol of niet