Best Treatment for Barrett's esophagus is Medical

George Triadafilopoulos, MDClinical Professor of Medicine

Stanford University School of Medicine

M.I.S.S., Salt Lake City, UT, 2.23.2011

Outline

• Why acid control is important

• What can we do

• How good are we

Effects of acid: In vitro studies

Acid pulses increase proliferation in Barrett’s esophagus

cpm/mg protein

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Esophagus

6 18 24

Time (hrs)

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*P<0.001;**P<0.05.

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Barrett’s Esophagus

6 18 24

Time (hrs)

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1

Duodenum

6 18 24

Time (hrs)

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+ Acid – Acid

**

**

*

Fitzgerald, RC, et al, JCI 1996

PCNA expression before and after acid suppression+ in Barrett’s esophagus

Ouatu-Lascar et al. Gastro 1999

PCNA units

+Complete: %pH<4%

*

COX-2 expression in Barrett’s esophagus explants and the effect of acid and/or bile salt

exposure

Shirvani V, et al. Gastroenterol. 118: 487-496, 2000

COX-2 inhibition plus PPI decreases PCNA Expression in Barrett’s esophagus

**

*

E40 BID + ASA325

(n = 31)

E40 BID + R25

(n = 34)

E40 BID

(n = 30)

R25

(n = 36)

*P < .05 versus baseline.

*

*

*

Triadafilopoulos G et al. APT 2006

Acid

NOX5-S

ROS

p16 gene hypermethylation

Down-regulation of P16 mRNA

Increase in cell proliferation

Esophageal carcinogenesisHong et al. AJP, 2010

Hong et al. AJP, 2010

Acid-Induced P16 hypermethylation contributes to development of esophageal adenocarcinoma

via activation of NADPH oxidase NOX5-S

Ratioof p16to 18S

Hong et al. AJP, 2010

Acid increases methylation levels of p16 gene promoter in BAR-T cells and OE33 cells

Ratioand % control

2

Smith, et al. Annals of Surgery. 252(1):63-69, 2010.

Number of methylated genes in biopsies of squamous and columnar mucosa from pH normal and pH abnormal fundoplication subjects and no surgery subjects.

Effect of GERD control by fundoplication on aberrant DNA methylation in Barrett Esophagus.

PPI Therapy and Dysplasia

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0.1

0.2

0.3

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0 1000 2000 3000 4000 5000 6000 7000

Days of Follow-Up

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plas

ia R

ate

5 year 10 year H2RA/No Therapy

PPI Therapy

El-Serag, Am J Gastroenterol. 2004;99:1877.

Kaplan–Meier curves of the cumulative proportion of patients who were free of low-grade dysplasia (n = 299*)

Hillman L, et al. MJA 2004; 180 (8): 387-391

Conclusions

• In vitro and ex vivo data in cultured cells and Barrett’s esophagus explants suggest that acid exposure is important in Barrett’s carcinogenesis

• Normalization of intra-esophageal acid exposure -albeit not formally proven in RCT studies- should be beneficial and diminish the likelihood of neoplastic progression of Barrett’s esophagus

Treatment options for Barrett’s esophagus

•Control of GERD symtoms

•Healing of co-existing esophagitis

•Prevention of recurrent esophagitis

•Control of bile reflux

•Prevention of stricture formation

•Regression/elimination of Barrett’s surface

•Regression/elimination of dysplasia •Chemoprevention of dysplasia & adenocarcinoma

PPI Rx bid

PPI Rx bid

PPI Rx bid

Fundoplication

PPI/Fundoplication

Ablation + PPI

Ablation + PPI

PPI bid + ASA/COX-2

RFA+PPI versus surgery: Not directly comparable

• Symptoms

• Disease progression

• Disease regression

Time

Distinction• Where PPIs are only able to decrease acid content

in the stomach (and thus change the pH of the refluxate), surgery has the ability to prevent any type of reflux (i.e. bile).

• Fundoplication does not alter the length of Barrett’s esophagus

• In contrast, RFA ablates Barrett’s metaplasia, and, used together with PPI therapy that suppresses acid reflux, leads to squamous re-epitheliazation

Definitions• Progression: A change from either intestinal

metaplasia to any form of dysplasia or an increase in grade of dysplasia or development of adenocarcinoma

• Regression: A change from high-grade dysplasia (HGD) to low-grade dysplasia (LGD) or no dysplasia, change from LGD to metaplasia or loss of metaplasia, and change from IM to squamous epithelium

• Shortening of the segment or development of squamous cell islands, although considered by some as regression, usually is not accurately measured and reported

How good is fundoplication in patients with Barrett’s

esophagus? The LOTUS trial• 554 patients with GERD • 60 had Barrett’s esophagus: 28 randomized to

esomeprazole and 32 to LARS. • 4 of 60 BE patients on either treatment strategy

experienced treatment failure during the 3-year follow-up. • Esophageal pH in BE patients was significantly

better controlled after surgical treatment than after esomeprazole (p = 0.002)

• QoL scores were similar for the two therapies at baseline and at 3 years. Operative difficulty was slightly greater in patients with BE than those without

• There was no difference in postoperative complications or level of symptomatic reflux control

Atwood, SJ. J. Gastrointestinal Surg. 2008; 12:1646-54

Long-term outcomes of fundoplication in Barrett’s esophagus cohorts

%

Wassenaar EB et al WJG 2010

11 studies; N=551; f/u 3.4 years

Antireflux surgery (ARS) does not decrease cancer risk

SIR Lagergren; Gastro. 2010;138:1297–130115 year-long population study

Medical therapy vs surgery for Barrett’s esophagus

3 studies: PPI:708; Nissen 115

%

Wassenaar EB et al WJG 2010

Radiofrequency Ablation for Barrett’s Esophagus

Multi-center, randomized, sham-controlled study of radiofrequency ablation in patients with dysplastic Barrett’s esophagus

2:1 RFA versus shamStratified by:

- degree of dysplasia (LGD vs. HGD)- length of segment (1-4 cm vs 4-8 cm)

Maximum of 4 RFA sessionsIdentical biopsy protocols, equal samplingEsomeprazole 40 mg orallytwice daily 12 month cross-over

Shaheen N, et al. NEJM 2009

RCT of Barrett’s dysplasia: Complete Eradication (ITT)

RCT of Barrett’s dysplasia: Disease Progression

HALO: Long-term dataFleischer D et al. DDW 2010

• 50 patients followed for 5 years• No strictures or mucosal lesions.• Mean per pt # of biopsies: 31• In 46 of 50 patients (92%) had CR-IM, while 4 (8%)

had IM (6 out of 126 specimens).• Single-session focal RFA cleared residual IM

RFA is durable and effective at 5 years

Conclusions

• Although both regression and progression have been noted after ARS, surgery does not completely or substantially eliminate metaplasia

• Esophago-gastric cancer still develops after 15 years of ARS

• Medical therapy (RFA+PPI) is effective and durable but no data on cancer incidence are (yet) available.