BARRETT’S ESOPHAGUS
| BARRETT’S ESOPHAGUS: STATE OF THE ART —Richard E. Sampliner, MD, Professor of Medicine, University of Arizona
College of Medicine, Tucson
|
| Barrett’s esophagus: controversy attached to all aspects of condition; little data; review of randomized trials found
only 8 published
|
| Key issues: screening, surveillance, medical therapy, management of high-grade dysplasia (HGD), and cancer prevention
(big ‘scare’ issue)
|
| Screening: defined as identification of premalignant lesion; in Barrett’s, usual practice to screen people with reflux symptoms,
but practice now evolving
|
| Definition of Barrett’s: change in lining of esophagus so as to resemble intestinal cells; definition does not enjoy full
consensus; Scandinavian study (1999) highlighted question of whether Barrett’s constitutes preceding lesion; speaker acknowledges
he presents selective evidence
|
| Surveillance: defined as ongoing evaluation of patients with premalignant disease (ie, Barrett’s); goal early detection of
HGD or early cancer to improve outcome; endoscope shows section of esophagus with columnar-lined appearance reaching
above esophagogastric junction; goblet cells (distended barrel-shaped blue-staining cells) hallmark of intestinal metaplasia
|
| Data from United Kingdom: data from large number of patients with Barrett’s esophagus, esophagitis, or reflux, and
from reference control cohort; looked at standardized incidence ratio of development of adenocarcinoma of esophagus in
this population; ratio 30, similar to number in many cohort studies of Barrett’s; esophagitis significant but reflux alone not
significant (compared to reference cohort), suggesting Barrett’s is precursor lesion; compares to early arguments (1970s) on
polyps and origin of colon cancer, when cancer could be seen but not polyp; early realization that cancer would overgrow
polyp; same for Barrett’s, especially short-segment Barrett’s
|
| German study: highlights problems of accuracy of endoscopy; of patients who underwent endoscopy but biopsy showed no
intestinal metaplasia (49 patients), 10 showed intestinal metaplasia on repeat endoscopy; another group showed no apparent columnar
cells but on biopsy, showed intestinal metaplasia (on repeat endoscopy only 17 had Barrett’s); those positive for both
columnar lining and intestinal metaplasia all positive on next endoscopy
|
| Incidence: latest data from Surveillance, Epidemiology, and End Results (SEER) database; 10% random sample of US
population; shows incidence of adenocarcinoma of esophagus in white men continues to rise, while incidence of other
cancers remains relatively flat
|
| American College of Gastroenterology: screening guidelines; try to identify patients likely to give highest yield of
finding Barrett’s, ie, those with chronic symptoms of gastroesophageal reflux disease (GERD); men, especially white
men, and those in older age group; data suggest adenocarcinoma now occurring in younger men
|
| Data on esophagectomy: of patients who underwent esophagectomy for esophageal adenocarcinoma, <5% had preoperative
diagnosis of Barrett’s
|
| Mortality rates: new population-based study from Northern Ireland; of >2000 patients with Barrett’s esophagus and
mean follow-up of 3 yr, only 4.7% died of cancer; in decade-old cohort study of 155 patients not undergoing surveillance
endoscopy and followed for almost 9 yr, 2.5% died from cancer
|
| Likelihood of cancer: since no studies have follow-up >7 yr, and likely outcome for man 30 yr of age does not compare
to that of older man, speaker believes accurate to say Barrett’s probably carries <5% lifetime risk for adenocarcinoma
|
| Surveillance: controversial; no evidence-based stratification criteria; no randomized trials looking at efficacy of surveillance;
basic concept if no dysplasia on 2 consecutive endoscopies with systematic biopsies, endoscopic interval extended
to 3 to 5 yr; if low-grade dysplasia found, repeat endoscopy; dysplasia often adjacent to cancer or even overlying (annual
endoscopy)
|
| High-grade dysplasia: controversial; need repeat endoscopy with biopsy; need expert gastrointestinal pathologist to
confirm and document; endoscopic mucosal resection (EMR) important staging technique; intervention on individual basis
|
| Medical therapy: establish goal of symptom relief or normalization of pH in esophagus
|
| Normalization of pH: randomized trial from Netherlands in which 24 patients on omeprazole 40 mg bid had exquisite
pH control; pH abnormal for 1.4 min in 24-hr period; <1% showed pH <4, but these were not “free-range Barrett’s”; to
get into trial, needed to have reflux symptoms controlled on ranitidine 150 mg tid with or without cisapride 10 mg tid;
many people clinically recognized with Barrett’s not controlled with H2 -receptor antagonists, explaining degree of control
not seen in most patients with Barrett’s
|
| Effect of proton pump inhibitor (PPI) therapy: Arizona study looked at length of newly diagnosed Barrett’s in relation
to prior therapy; in patients treated with PPI only, mean length 3.4 cm; in patients on no therapy, mean length 4.8 cm;
not intuitive, but patients treated with PPI prior to endoscopic diagnosis of Barrett’s had shorter Barrett’s; this finding still
significant when corrected for year of diagnosis, gender, and ethnicity; another study looked only at patients who got care at
Southern Arizona Veterans’ Affairs Hospital; none had baseline dysplasia or cancer; Cox multiple regression analysis of
risk factors for development of dysplasia showed use of PPI after diagnosis associated with 75% reduction in development
of dysplasia; nonwhite ethnicity associated independently with major reduction (88%); length of Barrett’s significant, ie,
longer the Barrett’s, more likely the development of dysplasia; Kaplan-Meier curve showed PPI-treated patients had lower
incidence of dysplasia and delayed development of dysplasia; similar-sized data set from Australia with similar mean follow-up
showed patients with no PPI therapy for first 2 yr after diagnosis had 5 times development of dysplasia seen in those
treated with PPI from onset of diagnosis; results suggest chemopreventive role for PPIs
|
| Biomarker stratification: looking for better marker than dysplasia for prediction of cancer; ≈85 markers identified;
best documented markers from Reid’s large cohort of prospectively followed patients with markers determined at baseline;
perhaps strongest data from group of patients with no dysplasia, indefinite, or low-grade dysplasia; by flow cytometry
|
| Molecular risk stratification: looking at p53 change molecularly, not by immunohistochemistry; Reid argues 30%
inaccuracy with immunohistochemistry, ie, not as sensitive as looking for specific loss of heterozygosity (significant risk
of developing cancer across all grades of dysplasia); promising markers but no multicenter trial yet
|
| Therapy for HGD: try to treat nonsurgically; many patients elderly or refuse surgery (even good surgical candidates);
aware now of operative morbidity and mortality of esophagectomy; operative mortality related to number of procedures performed
annually at center; photodynamic therapy (PDT)—Food and Drug Administration (FDA)-approved endoscopic
therapy; uses intravenous (IV) photosensitizer (porfimer sodium); in University of Washington study, patients with HGD
randomized to PDT plus PPI or PPI only; systematic biopsies performed every 3 mo; 77% of patients given PDT had no
HGD at 2 yr, compared to 39% of those not given PDT; shows variable natural history of HGD; cancer developed in 13% of
patients who got PDT, 28% of those in non-PDT arm of study; Overholt found underlying intestinal metaplasia after PDT
<5% of time; however, Massachussetts General Hospital study found 27% of patients post-PDT had buried HGD or intramucosal
cancer (attributed to systematic posttreatment biopsy of area treated)
|
| Endoscopic ablation: decision-making complex; look at—lesion (nodularity?); patient’s comorbidities; patient’s
wishes (cancer-free survival or just survival?); local expertise
|
| Staging: staging HGD with no lymph node involvement; regional lymph node involvement uncommon above muscularis
mucosae, but common in submucosa, so these patients not candidates for endoscopic therapy; EMR important staging
procedure rather than therapy; Weisbaden results—used high-resolution endoscopy (not yet available in United States)
for optimal detection of dysplasia and mucosal abnormalities; treated with oral photosensitizer; had no tumor-related
deaths
|
| Agenda for future: identify which patients with Barrett’s will progress to cancer; treat HGD nonsurgically after identifying
those who already harbor cancer; develop strategy for prevention of adenocarcinoma
|
| ENDOSCOPIC TREATMENT OF ESOPHAGEAL/GASTRIC CANCER —Michael Kochman, MD, Professor of Medicine
and Surgery, University of Pennsylvania School of Medicine, Philadelphia
|
| Endoscopic therapeutics: evolving convergence and combination of techniques for different purposes; endoscopic ultrasonography
(EUS), vital stains, saline-assisted polypectomy, band ligation techniques, EMR; if not possible, can endoscopically
prognosticate, mark lesions, consider dilating and placement of endoprosthetics for palliation
|
| Staging: problems with evidence-based medicine in this area; speaker provides category III and IV information (case series,
nonrandomized noncontrolled trials, and opinion); clear stage difference in survival basis for therapy stratification, but cannot
accurately predict survival before therapy applied; need multidisciplinary, objective approach based on goal (cure or palliaton)
|
| Neoadjuvant therapy: way of risk-stratifying patients; patient who survives neoadjuvant therapy will probably do better
overall and benefit from surgery
|
| Nodal status: speaker’s study (2001)—≈200 patients with adenocarcinoma and squamous cell carcinoma of esophagus;
found that as T-stage increases, survival decreases; nodal status key issue that drives survival, regardless of T-stage or type
of therapy; speaker’s study (2001)—used standard EUS scopes; found that suspicion of submucosal involvement usually
correct; better to operate than leave one positive node behind
|
| Endoscopic mucosal resection: performed to obtain tissue from histologically unknown or suspicious lesions; to remove
known neoplastic lesions; to aid in staging; potentially definitive treatment in patients with malignancy; need to
know nodal status, muscularis propria involvement, and submucosal involvement; randomized prospective studies not
available; May et al study (2002)—investigated EMR in 70 patients; PDT in 32; argon plasma coagulation (APC) in 3;
combined modalities in 10; showed after lesions resected (endoscopically and biopsy-proven; multiple sessions), at 6 mo
98% had no lesion; key issue at 3 yr, 88% maintained remission
|
| Multifocal and unifocal dysplasia in Barrett’s: biopsy pathology findings not always confirmed by surgery;
question of multifocal or unifocal HGD drives treatment decisions (EMR vs PDT vs surgery)
|
| Treatment studies: must know whether lesion mucosal or submucosal; other data suggest combinations of chemoradiation
therapy and EMR valid alternative to esophagectomy in selected patients; speaker chooses EMR and reserves ablative
therapies for nonsurgical candidates; study—ablation of Barrett’s and dysplasia with PDT plus omeprazole vs
omeprazole; high numbers to support ablation reduction in dysplasia with omeprazole not reproducible in other studies;
secondary end point showed 25% to 30% reduction in progression to cancer in Barrett’s with HGD when ablated with
PDT and subsequent treatment with omeprazole; solid data
|
| Summary of new modalities: optimal endoscopic therapy not available; palliation in evolution; need multidisciplinary
approach; need to look at reproducibility of endoscopic therapies; comparative trials against surgery needed
|
| BARRETT’S ESOPHAGUS AND CANCER: OVERVIEW OR OVERDONE? —Brennan M.R. Spiegel, MD, Assistant Professor
of Medicine, Greater Los Angeles Veterans Affairs Healthcare System and David Geffen School of Medicine at the
University of California, Los Angeles
|
| Esophageal adenocarcinoma: incidence increasing faster than any other in Western world; spreading all over United
States (supported by SEER database); almost quintupled since 1995; 5-yr survival abysmal (4% to 10%); white men supposedly
more susceptible, but anyone can get Barrett’s
|
| Data reassessment: need to ask—how common is esophageal cancer? does having Barrett’s shorten survival? how often
does Barrett’s lead to cancer? does screening for Barrett’s prolong survival? is screening for Barrett’s worth cost? annual
data—150,000 cases of colorectal cancer, ≈50,000 cases of melanoma, ≈7000 cases of esophageal adenocarcinoma
|
| Survival: European data compared 6-yr all-cause mortality in Barrett’s and non-Barrett’s patients; no difference in survival;
suggests comorbidities; data do not support shortened survival
|
| Incidence: increasing but small; 3.3 million Americans with Barrett’s; 7000 esophageal adenocarcinomas per year;
chance of developing adenocarcinoma 0.2% per year; published data suggest chance of developing adenocarcinoma 0.5%
per year, not 10% risk of some Internet claims; assuming “pill” available that reduces risk by 50%, need to treat 400 people
with Barrett’s to prevent 1 cancer
|
| Dysplasia in Barrett’s: greater Los Angeles Veterans Affairs system data; Barrett’s patients with low-grade dysplasia
at baseline more likely to develop cancer over 10 yr than those with no dysplasia (0.35% chance per year vs 0.09%
chance per year); would have to treat 570 people with low-grade dysplasia for 1 yr to prevent 1 cancer or (57 people for
10 yr)
|
| Screening and surveillance: no large prospective randomized trial; study showed cancer patients not part of Barrett’s
surveillance program more likely to have nodal involvement at surgery than those in program; 2-yr survival data favor
patients whose cancers detected in surveillance program; projected lifespan differences—based on white men ≥50 yr of
age with GERD; those who undergo no screening projected to live additional 16.47 yr; those in surveillance due to dysplasia
found at screening live 1.9 mo longer; surveillance of everyone with Barrett’s (with or without dysplasia) provides
additional 0.4 days of life; projected managed care budget impact of screening—white men >50 yr of age with
GERD; no screening costs $100 per patient; screening for Barrett’s and surveillance of those with dysplasia costs $1700
per patient
|
| Summary: esophageal cancer not public health hazard; Barrett’s does not appear to shorten survival; Barrett’s rarely
leads to cancer unless dysplasia present, and even with dysplasia, <1% per year develop cancer; screening for Barrett’s
may prolong survival but is it worth cost?
|
Educational Objectives
| The goal of this program is to educate the listener about Barrett’s esophagus. After hearing and assimilating this program,
the clinician will be better able to:
|
 | 1. Name major issues in Barrett’s esophagus.
|
| 2. Discuss alternatives to esophagectomy in treatment of Barrett’s.
|
| 3. List techniques used in endoscopic treatment of esophageal cancer.
|
| 4. Discuss incidence and survival in Barrett’s esophagus.
|
| 5. Describe the target population for screening for Barrett’s esophagus.
|
Discussed on This Program
Cisapride [Propulsid]
Omeprazole [Prilosec, Prilosec OTC, Rapinex]
Ranitidine HCl [Zantac, Zantac 75, Zantac EFFERdose]
Suggested Reading
Ciovica R et al: Quality of Life in GERD Patients: Medical Treatment Versus Antireflux Surgery. J Gastrointest Surg
10:934, 2006; DeMeester SR et al: Columnar mucosa and intestinal metaplasia of the esophagus: fifty years of controversy.
Ann Surg 231:303, 2000; DeMeester SR: Endoscopic mucosal resection and vagal-sparing esophagectomy for
high-grade dysplasia and adenocarcinoma of the esophagus. Semin Thorac Cardiovasc Surg 17:320, 2005; Edwards
MJ et al: The rationale for esophagectomy as the optimal therapy for Barrett’s esophagus with high-grade dysplasia. Ann
Surg 223:585, 1996; Hammoud ZT et al: Survival outcomes of resected patients who demonstrate a pathologic complete
response after neoadjuvant chemoradiation therapy for locally advanced esophageal cancer. Dis Esophagus19:69,
2006; Hunt RH: Controversial issues in gastroesophageal reflux disease. Can J Gastroenterol 11 Suppl B:87B, 1997;
Katz PO: Management of the patient with Barrett’s esophagus: a continuing dilemma for the clinician. Rev Gastroenterol
Disord 4:49, 2004; Keswani RN et al: Clinical use of p53 in Barrett’s esophagus. Cancer Epidemiol Biomarkers
Prev 15:1243, 2006; Kinoshita Y et al: The pharmacodynamic effect of omeprazole 10 mg and 20 mg once daily in patients
with nonerosive reflux disease in Japan. J Gastroenterol 41:554, 2006; Layke JC et al: Esophageal cancer: a review
and update. Am Fam Physician 73:2187, 2006; May A et al: Intraepithelial high-grade neoplasia and early
adenocarcinoma in short-segment Barrett’s esophagus (SSBE): curative treatment using local endoscopic treatment techniques.
Endoscopy 34:604, 2002; Morales TG et al: Barrett’s esophagus: update on screening, surveillance, and treatment.
Arch Intern Med 159:1411, 1999; Pultrum BB et al: Outcome of palliative care regimens in patients with
advanced oesophageal cancer detected during explorative surgery. Anticancer Res 26:2289, 2006; Robb-Nicholson C:
By the way, doctor. I’ve been taking Prilosec for over a year for GERD. Recently, I read that long-term use of proton pump
inhibitors increases the risk of certain gastric cancers. Your opinion? Harv Womens Health Watch 13:8, 2006; Roberts
KE et al: Controversies in the treatment of gastroesophageal reflux and achalasia. World J Gastroenterol 12:3155, 2006;
Sampliner RE et al: Association of ablation of Barrett's esophagus with high grade dysplasia and adenocarcinoma of
the gastric cardia. Dis Esophagus 19:277, 2006; Schrager JJ et al: Endoscopic ultrasound: impact on survival in patients
with esophageal cancer. Am J Surg 190:682, 2005; Sujendran V et al: Oesophagectomy remains the gold standard
for treatment of high-grade dysplasia in Barrett’s oesophagus. Eur J Cardiothorac Surg 28:763, 2005; Wijnhoven
BP et al: Reduced p120ctn expression correlates with poor survival in patients with adenocarcinoma of the gastroesophageal
junction. J Surg Oncol 92:116, 2005.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial relationship
with the manufacturer or provider of any commercial product or service discussed. For this issue, the speakers reported
nothing to disclose.
Dr. Sampliner spoke at the 30th Annual Texas Program held in Houston, TX, September 17, 2005, and sponsored by the
Texas Society for Gastroenterology and Endoscopy, the American College of Gastroenterology, and the Texas Regional
Societies. Drs. Kochman and Spiegel spoke at the 3rd Annual UCLA Gastroenterology Symposium held in Beverly Hills,
CA, February 18 and 19, 2006, and sponsored by the Division of Digestive Diseases and the Office of Continuing Medical
Education, David Geffen School of Medicine at the University of California, Los Angeles. The Audio-Digest Foundation
thanks the speakers and the sponsors for their cooperation in the production of this program.
|
