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GASTROENTEROLOGY 2005;128:1471–1505

merican Gastroenterological Association Technical Review onhe Role of the Gastroenterologist in the Management ofsophageal Carcinoma

ENNETH K. WANG, MICHEL WONGKEESONG, and NAVTEJ S. BUTTAR
arrett’s Esophagus Unit, St. Mary’s Hospital, Mayo Clinic, Rochester, Minnesota
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he goal of this evidence-based review was to examinethe clinical practice of the gastroenterologist in the

anagement of patients with esophageal carcinoma. Theethods for this review were to search and review the

iterature available on MEDLINE and PREMEDLINE onhe topics of esophageal neoplasm, esophageal cancer,nd Barrett’s esophagus from 1968 to 2004. Bibliogra-hies of significant reports were also reviewed to ensurehat the pertinent literature was reviewed. Recommen-ations are graded as to the level of evidence available onscale of I–V. Level I evidence is the presence of at leastne prospective, randomized, controlled trial, level IIvidence is based on well-designed cohort or case-con-rolled studies, level III evidence is based on case series orawed clinical trials, level IV evidence is based on opin-ons of respected authorities or expert committees, andevel V evidence is insufficient evidence to form anypinions.

Significance of Esophageal Cancer

Esophageal cancer is associated with one of theighest cancer mortality rates in the United States. In000, the last year of complete data available from theational cancer Surveillance, Epidemiology, and End Re-ults database, the 5-year relative survival rates fromsophageal cancer were the fifth lowest at 15.4%. Inddition, the incidence of esophageal cancer is still sig-ificantly trending upward in white men with a 0.4%nnual percentage increase from 1992 to 2000. This cane compared with colon cancer, which has actually had aignificant decrease of 0.9% annual percentage changever the same period. Esophageal cancer is a predomi-antly male condition with a male/female incidence of.6:1. Esophageal cancers affect older patients, with theeak incidence in those 65–74 years old. It is estimatedhat, in 2003, there were 13,900 new cases of esophagealancer and 13,000 deaths due to esophageal cancer. Theortality rate of esophageal cancer is significantly higher

n minority populations than in white people.

There are 2 major types of esophageal cancer: adeno-arcinoma and squamous cell cancer. The primary knownisk factors for adenocarcinoma of the esophagus aremoking, chronic gastroesophageal reflux disease, andarrett’s esophagus. Known risk factors for squamousell cancer of the esophagus include smoking, alcoholse, exposure to nitrosamines, ingestion of lye, Fanconi’snemia, achalasia, Plummer–Vincent webs, and tylosis.

Screening and Surveillance forEsophageal Cancer

Screening for Esophageal Cancer

Adenocarcinoma. Screening for esophageal can-er depends on the determination of the patient’s risk forancer, the cost and efficacy of the screening procedure,he stage at which the cancer can be diagnosed, and thereatment options available. At the current time, there iso direct evidence that has validated the use of screeningor esophageal cancer in the United States. Screening forsophageal adenocarcinoma has been primarily focusedn the detection of Barrett’s esophagus with subsequenturveillance. Although screening for Barrett’s esophagusas not been proven to decrease the risk of cancer, it hasecome accepted that surveillance for Barrett’s esophagusan detect disease at earlier stages.1–3 Barrett’s esophagusas traditionally been found to be associated with chronicastroesophageal reflux disease, and case series haveound increasing incidences of Barrett’s esophagus de-ending on the number of years of reflux symptoms.4

owever, a single-center study of 110 subjects foundhat 7% of asymptomatic individuals had long-segment

Abbreviations used in this paper: CI, confidence interval; CT, com-uted tomography; EUS, endoscopic ultrasonography; FDA, Food andrug Administration; Nd:YAG, neodymium:yttrium-aluminum-garnet;CT, optical coherence tomography; PAR, population attributable risk;DT, photodynamic therapy; PET, positron emission tomography;ALY, quality-adjusted life year; SEMS, self-expanding metal stents.

© 2005 by the American Gastroenterological Association0016-5085/05/$30.00

doi:10.1053/j.gastro.2005.03.077

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1472 WANG ET AL GASTROENTEROLOGY Vol. 128, No. 5

�3 cm) Barrett’s esophagus.5 A multicenter study of36 subjects found that long-segment Barrett’s esopha-us was only present in 0.36% of subjects, althoughhort-segment Barrett’s esophagus was found in 5.6%.6

his study did find that patients with heartburn had aignificantly higher prevalence of long-segment Barrett’ssophagus than those who did not. This is significantecause past studies have shown that the degree of neo-lasia found in Barrett’s esophagus appears to be corre-ated with the length of Barrett’s esophagus.7 Otherroups that may be at risk would include those withamilial occurrence of adenocarcinoma, but this hasnly been described in a limited number of families.he cost-efficacy of screening family members becausef a history of Barrett’s esophagus has not beenemonstrated.8 –12

Screening methods for detection of Barrett’s esophagusave included standard endoscopy, unsedated endoscopyith ultrathin endoscopes, catheter-based cytology, andalloon cytology.13–16 Although preliminary studies in-icate some promise with these technologies in terms ofcreening for adenocarcinoma, there have not been anyefinitive trials to allow recommendation of theseechniques.

Squamous cell cancer. Screening for squamousell cancer in the general population of the United Statesannot be justified because of the low incidence of thisorm of cancer. However, specific subgroups may bedentified that warrant screening endoscopy for squa-ous cell cancer. The most likely to benefit from screen-

ng would be those who have tylosis, which is a geneticefect in the 17q25 region that is found in patients withhickened palms and soles.17,18 This group is likely toevelop cancer by the age of 65 years and should undergocreening for squamous cell cancer. Patients with lye-nduced or caustic strictures develop cancers approxi-ately 46 years after ingestion and have been described

o have an 8% incidence of cancer.19,20 The developmentf cancer in patients with long-standing achalasia isnfrequent, especially in women, and it is unclear ifurveillance is warranted in these patients.21 Most pa-ients with achalasia are found to have prevalent cancersecause they are usually diagnosed when obstruction andsophageal dilation are found.22 Fanconi’s anemia haslso been associated with the development of esophagealancer and may become more common as patients surviveonger after bone marrow transplantation.23 Patientsith existing aerodigestive tumors, especially those of

he oral cavity, who have had long-term extensive expo-ure to alcohol and tobacco might benefit from screeningor cancers of the esophagus, although the rationale for
his is based on case series.24 Screening for esophageal i
ancer should be performed at the time of diagnosis ofhe head-and-neck cancer. Extensive alcohol consump-ion alone has been found to be an important criterion forcreening in Asian patient populations.25 Partial gastrec-omies have been associated with an increased incidencef squamous cell cancers of the esophagus; these reportstem from areas of the world where squamous cell cancers commonly found, and there is no convincing evidenceo support the screening of patients in the Unitedtates.26 The occurrence of squamous cell cancer is notecreasing in minority populations in the United Statesnd remains the most frequent form of esophageal cancern black and Hispanic populations.27,28 Other conditionsuch as Plummer–Vinson webs have also been identifieds being associated with an increased risk for squamousell cancers, but the decreasing frequency of these websakes this almost a historical footnote in Western

ountries.29

Screening methods such as cytologic balloons orponges for screening for squamous cell cancers have beenxtensively tested in Asia. Balloons appear to be betterhan sponges, with an increased sensitivity of 44% com-ared with 18% for sponges.30 This technology has beensed as the primary screening tool in high-risk areas ofhina.31

Summary of Evidence—There is level III evidence thatndoscopic screening of male white patients older than0 years of age with symptoms of gastroesophageal refluxay be cost-effective. Patients with tylosis, lye-induced

trictures, or Fanconi’s anemia would benefit fromcreening endoscopy for squamous cell cancers (level IIIvidence). In addition, patients with long-term tobaccond alcohol use, achalasia, or prior head-and-neck cancersould be considered for screening, depending on theirther risk factors (level III evidence). The interval forurveillance of these patients has not been established,ut yearly investigations would seem to be reasonablelevel IV evidence).

Surveillance for Esophageal Cancer

Significance of surveillance. The importance ofarrett’s esophagus derives from its association with esoph-geal adenocarcinoma.32,33 Approximately 5%–10% of pa-ients diagnosed with Barrett’s esophagus may developsophageal adenocarcinoma based on older studies.32,34,35

he incidence of cancer will most likely decrease withhe increasing detection of Barrett’s esophagus throughcreening programs. Surveillance of Barrett’s esophagusan detect dysplasia in Barrett’s esophagus, which canredict the risk of future diagnosis of esophageal cancer
n these patients.36,37

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May 2005 AMERICAN GASTROENTEROLOGICAL ASSOCIATION 1473

The incidence of cancer in patients with Barrett’ssophagus is low in general, which makes surveillanceost-ineffective unless at-risk populations can be identi-ed.38,39 At the current time, dysplasia is used as therimary means to discriminate at-risk patients. A sys-ematic endoscopic biopsy protocol, generally acceptedo be 4 quadrant biopsy specimens taken every 2 cm ofarrett’s mucosa, can provide tissue for histologic diag-osis of dysplasia. The grading system used to classifyysplasia in Barrett’s esophagus is based on the systemeveloped for ulcerative colitis.40–42 Although moleculararkers have shown promise, dysplasia is currently the

est indicator for the risk of cancer. Increasing grade andxtent of dysplasia are associated with increasing risk ofancer.37,43–48 Information from several prospective stud-es and a Barrett’s esophagus registry provide a totalf 783 patients with a follow-up of 2.7–7.3ears.37,43,45,47,49,50 These combined series indicate that% of patients without dysplasia progressed to cancer.rogression from low-grade dysplasia to cancer was noted

n 7% of patients and from high-grade dysplasia toancer in 22% of patients. Unfortunately, it is difficult tobtain true cancer incidence per year of observation basedn the data provided in these series. It is also apparenthat low-grade dysplasia had a wide range of rates ofrogression between the series. This may be because ofhe variability in interpretation of low-grade dysplasia.46

Other findings on endoscopy that have been shown toredict the development of esophageal cancer include theresence of any mucosal abnormalities noted on endos-opy and the extent of high-grade dysplasia noted onistology.48 The presence of mucosal nodularity has beenssociated with a 2.5-fold increased risk of cancer devel-pment in patients with high-grade dysplasia (P � .01).ocal high-grade dysplasia, defined as involvement of �5rypts in one biopsy specimen from the entire set ofiopsy specimens, has been found to be associated withignificantly less risk of cancer development than thoseith greater amounts of high-grade dysplasia (P �

02).48

Unfortunately, the classification of dysplasia is subjec-ive and does have significant observer variation. Inter-bserver pathologic agreement can improve to 85%–7% when the degree of dysplasia is placed in a 2-tierystem. This is done by combining high-grade dysplasiand intramucosal carcinoma in one category and low-rade dysplasia, indefinite for dysplasia, and no dysplasian another.51 This was substantiated by a recent studysing a group of expert pathologists.52 In this study,hen analysis was performed using 2 broad diagnostic

ategories (Barrett’s esophagus without dysplasia, indef-
nite and low-grade dysplasia vs high-grade dysplasia and H
arcinoma), intraobserver agreement was near perfectmean � � 0.82 and 0.80) and interobserver agreementas substantial (� � 0.66–0.70). When the analysis waserformed using the 4 separate classifiers (Barrett’s with-ut dysplasia, indefinite for dysplasia and low-grade dys-lasia, high-grade dysplasia, and carcinoma), the meanntraobserver � was once again substantial (0.64–0.68)ut the mean interobserver � was only 0.43–0.46 (mod-rate agreement). Because of this difficulty in determin-ng the presence of dysplasia, using recent recommenda-ions to screen and perform surveillance only if dysplasias found may be ineffective if histologic interpretation isot accurate.53

Despite the difficulties with surveillance, the detec-ion of high-grade dysplasia or early cancer has beenhown to have the potential to improve survival inatients with Barrett’s esophagus.54,55 Cancers confinedo the esophagus are associated with a 5-year survival ratef 70% compared with a survival rate of 20% for patientsith more invasive cancers.56 Nodal involvement, whichelps determine prognosis, is far less likely to occur inatients who are found to have cancer on surveillancendoscopies compared with those patients who are notndergoing surveillance.1,3,56,57 This leads to signifi-antly improved survival in surveyed patients comparedith those patients who underwent surgery for symp-

omatic disease. Retrospective studies of patients in sur-eillance programs suggest that the patients with inci-ental cancers detected during surveillance are likely toave earlier staged disease than those who present be-ause of symptoms.58,59 Although these case series seemonvincing, there are several concerns. Many of the ret-ospective studies compared patients in surveillanceroups with historical controls. Patients of advanced ager with significant comorbidity are less likely to benrolled in a surveillance program. On the other hand,ubjects enrolled in surveillance programs might haveealthier lifestyles, might have health-seeking behaviors,r were selected because of overall better health status.urvival differences between these 2 groups may well beue to selection bias. In addition, earlier detection ofancer can lead to a false increase in survival time becausef lead-time bias, which results from an early diagnosis ofreclinical cancer rather than any true effect of detectionn subsequent mortality.

In at least 2 small surveillance cohorts, esophagealancer has been reported to be an uncommon cause ofeath in patients with Barrett’s esophagus.60,61 There-ore, the morbidity and mortality from surveillance andubsequent treatment might overshadow any advantagehat surveillance provides by early detection of cancer.
owever, a retrospective population-based cohort study

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f endoscopic surveillance in 23 patients with Barrett’ssophagus among 589 patients with adenocarcinomaound an improved survival benefit.62 Eleven of 15 pa-ients who were diagnosed with cancer while in surveil-ance programs were alive compared with none of 8atients not under surveillance. None of the deaths in theurveillance group were from cancer compared with 4eaths in the nonsurveillance group that were directlyelated to cancer. Three patients in the surveillanceroup and one patient in the nonsurveillance group dieds a result of complications of surgery.

Allocation of resources based on risk stratification hashe potential to make surveillance more cost-effective. Aecent decision analysis model examined the cost-utilityatio for different surveillance strategies.38 A cohort of0-year-old patients with Barrett’s esophagus withoutysplasia was evaluated for surveillance strategies every–5 years and no surveillance, with esophagectomy per-ormed if high-grade dysplasia was diagnosed. This studyuggested that, with an annual cancer risk of 0.4%,urveillance every 5 years was the only cost-effectivetrategy. More frequent surveillance was associated withore cost and yielded a lower life expectancy. The in-

remental cost-utility ratio for surveillance every 5 yearsas $98,000 per quality-adjusted life year (QALY)ained, comparable to the incremental cost-effectivenessatios of accepted practices.

Another detailed cost-utility analysis assessed thetrategy of surveillance of Barrett’s esophagus detecteduring screening.53 The strategy of surveillance of onlyatients with dysplasia appears to be cost-effective rela-ive to other currently accepted medical practices. Thetrategy yielded an incremental cost-effectiveness ratio of10,440 per QALY saved compared with no screening. Atrategy of no screening would incur direct medical costsf caring for those developing cancer of $16 million.creening and surveillance of patients with dysplasiaould prevent 2580 deaths caused by esophageal adeno-

arcinoma at a cost of $262 million. Fifty-nine patientsould need to be screened and surveyed to prevent oneeath from cancer. Although this model was thorough, its limited by several assumptions, such as that surveil-ance for patients with high-grade dysplasia can ceasefter 2 years and that there are no adverse effects on theuality of life of patients undergoing surveillance, whichther studies have shown to be decreased.63

Biopsy method. Patients who are undergoingurveillance should follow a systematic endoscopic biopsyrotocol after they are free from esophagitis.64 The evi-ence for this is based on expert opinion, limited data,nd the outcome of cohorts of patients managed empir-
cally. Biopsy specimens are first taken from any mucosal w
bnormality, followed by rigorous sampling from each ofhe 4 quadrants of the esophagus every 1–2 cm startingt the gastroesophageal junction and stopping at thequamocolumnar junction using standard or jumbo bi-psy forceps. The goal is to determine if the patient hasigh-grade dysplasia or early cancer so that appropriateanagement can be initiated. The effectiveness of taking

-quadrant biopsy specimens every 1 cm along theength of the Barrett’s segment with jumbo biopsy for-eps instead of the traditional standard biopsy forceps haseen assessed.42 In a retrospective analysis of the Seattlerotocol, it was shown that taking 4-quadrant biopsypecimens every 2 cm would have missed 50% of theancers that were found by taking 4-quadrant biopsypecimens every 1 cm.65 Jumbo biopsy forceps acquireore tissue in a single biopsy than regular biopsy forceps

nd have not been associated with increased complica-ions.66 The use of jumbo biopsy forceps has not beenhown to decrease the number of samples necessary forurveillance, and they require the use of a therapeuticndoscope. The need for use of jumbo biopsy forceps haseen questioned, and one study found no statistical dif-erence in the rate of unsuspected cancers found at esoph-gectomy when patients with Barrett’s esophagus withigh-grade dysplasia underwent preoperative endoscopysing jumbo biopsy forceps versus standard biopsyorceps.67

It is generally accepted that patients with mucosalbnormalities in Barrett’s esophagus should undergo en-oscopic mucosal resection to increase detection of neo-lasia. In one small series, endoscopic mucosal resectionf suspicious lesions diagnosed superficial adenocarci-oma in 13 patients (52%) and high-grade dysplasia in(16%) of 25 patients with Barrett’s esophagus.68

Methods of surveillance. Several methods haveeen studied to perform surveillance. These includerush cytology, chromoendoscopy, magnification endos-opy, and optical imaging techniques. All of these tech-iques have certain potential advantages over routineiopsy.

Brush cytology. Brush cytology has been advocatedn the surveillance of patients with Barrett’s esophagusecause it is faster to perform and it can sample morehan the 1% of the total Barrett’s mucosal area typicallychieved with standard biopsy. The diagnostic value ofytology in patients with Barrett’s esophagus was as-essed using 66 pairs of endoscopic biopsy specimens andytology specimens.69 Cytologic analysis was used toorrectly identify 7 of 8 esophageal cancers, with onealse-negative sample described on analysis as highlyuspicious for cancer. In other studies, cytologic brushing
as found to be a complementary technique in detecting

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erious Barrett’s lesions when combined with the histo-ogic examination of esophageal biopsy specimens.70,71

owever, there was only 72% (47/65) concordance be-ween the 2 diagnostic techniques. In the 18 cases thatere discordant, cytologic analysis diagnosed 13 at aigher level of abnormality than the biopsy diagnosis andnderdiagnosed 5. There is potential to further improvehe efficacy of cytology by using objective assessmentools such as digital image analysis, which involves aomputerized analysis of the digitized microscopic im-ge.72,73 This has been demonstrated in China, whereuantitative DNA fluorescence has been found to en-ance detection of squamous cell cancers when applied toytology taken in a high-risk population.74 As men-ioned previously, balloon cytology for the surveillance ofquamous cell cancers has become an accepted part ofractice in high incidence areas, although such devicesave not been shown to be beneficial in Westernopulations.30,75

Chromoendoscopy. Chromoendoscopy involves theopical application of dyes during endoscopy in an efforto enhance the detection of mucosal patterns or lesions onhe basis of their staining characteristics.76 Stains arelassified as vital (absorptive), contrast, or reactive, ac-ording to their mode of action. Vital stains (e.g., Lugol’solution and methylene blue) enter specific cell types byreferential absorption or diffusion across the cell mem-rane. Contrast stains (e.g., indigo carmine and aceticcid) seep into mucosal interstices to highlight mucosalopography. Reactive stains chemically react with cellu-ar constituents.

The body of the literature regarding chromoendoscopyn the esophagus consists primarily of staining withugol’s solution for detection of squamous dysplasia anduperficial carcinoma and staining with methylene blueor assessment of Barrett’s esophagus. Lugol’s solution isn iodine-based vital dye that has an affinity for glycogenontained in nonkeratinized squamous epithelium. Chro-oendoscopy with Lugol’s solution has been used pri-arily to screen individuals at high risk for squamous

ell cancer.77–80 The application of Lugol’s solution dur-ng endoscopy is not standardized, with nonuniformoncentrations (1%–3%) and volumes (10–50 mL) asell as variable definitions of “unstained” areas thaterit biopsy.77–80 Despite these differences, these studies

n aggregate show unstained lesions to have a highensitivity (91%–100%) and moderate specificity (40%–5%) for squamous dysplasia and carcinoma.77 Lesionsre found to be more clearly defined and can be signifi-antly larger after staining,81 providing critical informa-ion, particularly if local therapy, such as endoscopic
ucosal resection, is contemplated. Studies of chromoen- a
oscopy with Lugol’s solution in Western populationsre sparse. A prospective analysis of a French cohort of58 alcoholic and/or smoking patients showed no signif-cant advantage of staining with Lugol’s solution relativeo the visual diagnostic accuracy achieved by videoen-oscopy alone.81 Lugol’s-assisted endoscopy may be use-ul in populations living in highly endemic regions forsophageal squamous cell cancer.

Methylene blue stains absorptive cells (intestinal-typepithelium), including specialized intestinal metaplasia,ut does not stain normal squamous or gastric epithe-ium. Methylene blue may be particularly useful in theiagnosis of short segments of columnar-lined esopha-us.82 Other uses include identifying dysplastic fociithin Barrett’s epithelium and identifying residual focif Barrett’s esophagus following mucosal ablative ther-py. Chromoendoscopy with methylene blue requiresretreatment of the mucosa with a mucolytic agent, awell time for the dye to take effect, and a rinse phase toemove excess dye. In general, methylene blue stainingdds 5–10 minutes to the procedure time, but the ac-essories required are inexpensive.83 Specialized intesti-al metaplasia typically stains blue, while a “lighter”ntensity and increased heterogeneity in the stainingattern predict high-grade dysplasia and/or cancer.84 Fo-al unstained areas may represent dysplastic foci within aackground of heterogeneous methylene blue staining.85

hese findings, however, are not consistently replicatedn other studies, and the reproducibility of stainingatterns among Barrett’s tissue types remains debat-ble.86 This technique has been used to allow the gas-roenterologist to perform fewer biopsies to find signif-cantly more dysplasia or cancer in a biopsy specimen12% vs 6%) compared with the random biopsy tech-ique.85 However, 2 prospective trials comparing theethylene blue–guided biopsy technique with the ran-

om biopsy technique found no significant differences inhe detection of dysplasia or early cancer between the 2echniques.87,88 Methylene blue has also recently beenhown to induce oxidative damage of DNA because ofhotoactivation of the dye by the white light of thendoscope, which certainly increases the risk of its use inremalignant tissue.89

Magnification endoscopy. Most new electronicideoendoscopes are equipped with charge-coupled de-ice chips of high pixel density (400K), enabling high-mage resolution (ability to discriminate 2 closelypproximated points). Megapixel density (850K) endo-copes have recently been introduced, which may furthernhance detection. Magnification endoscopy enlarges themage, which enhances mucosal detailing and is gener-
lly used in combination with chromoscopy. Magnifica-

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ion chromoendoscopy has been used primarily to char-cterize Barrett’s esophagus.90–93 Ridged or villousucosal patterns observed under magnification endos-

opy using a variety of stains have been correlated withntestinal metaplasia or dysplasia in case series.91–93

hether magnification endoscopy will decrease the needor endoscopic biopsy or significantly enhance the diag-ostic yield over conventional techniques remains to beetermined in large controlled trials.

Optical biopsy. Optical biopsy is a term that en-ompasses a variety of techniques that use light to en-ance detection of dysplastic lesions. Included in thisategory are spectroscopic techniques and low coherencenterferometry (optical coherence tomography [OCT]).pectroscopy is a light-based diagnostic technique thatxploits properties of light-tissue interactions, such asuorescence, elastic scattering, and Raman scattering, forissue characterization. Collected in the form of spectra,hese optical (light) signals are sensitive to microstruc-ural and/or molecular changes accompanying varioustages of tissue pathology, and spectral differences canhen be correlated to specific histopathologic diagnoses.

Assessment of optical spectroscopic techniques in thesophagus has been limited to small-scale, proof-of-prin-iple studies.94–102 Most studies deal with fluorescencepectroscopy, which shows moderate to high sensitivity75%–100%) and specificity (65%–95%) in differenti-ting high-risk (high-grade dysplasia/adenocarcinoma)rom low-risk (nondysplastic to low-grade dysplasia)amples of Barrett’s esophagus.94–98 False positives occurn the presence of inflammatory or reactive changes.94

he range of diagnostic accuracies primarily relates toethodological differences, because the technique has

et to be optimized for Barrett’s esophagus. It is alsonclear whether fluorescence spectroscopy, aided by anxogenously administered fluorescent agent with affinityor neoplastic tissues (e.g., porfimer sodium or 5-amin-levulinic acid), improves discrimination of Barrett’s ep-thelia over naturally occurring tissue fluorescenceautofluorescence).99–101,103 Future comparative studiesre required to address this issue. Other emerging spec-roscopic techniques, including elastic scattering spec-roscopy,102 Raman spectroscopy,103 and multimodal op-ical spectroscopy,104 have shown initial promise inifferentiating Barrett’s epithelia in feasibility studies.Fluorescence endoscopy is an extension of its spectro-

copic counterpart into an imaging technique, whichonsists of sensitive cameras capturing the emitted flu-rescence emanating from a mucosal field of view ap-roaching that of a conventional endoscope. The obviousdvantage over point spectroscopy is the ability to per-
orm widespread assessment of the mucosa for areas likely t
o harbor dysplastic or early cancerous changes. Recenttudies of fluorescence endoscopy, however, have showedimited diagnostic utility in Barrett’s esophagus.88,105 Insmall prospective study of 35 patients, the sensitivity

nd specificity of autofluorescence imaging for the diag-osis of dysplasia or cancer versus Barrett’s mucosa with-ut dysplasia were 21% and 91%, respectively.88 Arospective, randomized, crossover study of 50 patientsith Barrett’s esophagus, published in abstract form,

howed no significant benefit of fluorescence-guided bi-psies over a standard surveillance biopsy protocol for theetection of high-grade dysplasia and early adenocarci-oma.105 Fluorescence endoscopy is an evolving technol-gy. Optical biopsy and imaging techniques are not yetptimized for clinical use.

OCT is analogous to ultrasonography but uses lightnstead of sound waves to produce high-resolution, cross-ectional imaging of tissue. The spatial resolution of0–25 �m achieved by endoscopic OCT systems is0-fold better than that of high-frequency ultrasonogra-hy but at the expense of a limited sampling depth (�2m).106–109 Current endoscopic OCT devices are cathe-

er based (2–2.7 mm in diameter), allowing scanning ofhe esophagus in a linear,107 transverse,106 or radial108

ashion. Using predetermined OCT criteria for special-zed intestinal metaplasia, the linear scanning OCT sys-em was found to be 97% sensitive and 92% specific fordentifying specialized intestinal metaplasia.110 A quan-itative analysis of the OCT signal seemed to identifyigh-grade dysplasia with high sensitivity (100%) andpecificity (85%) in a small retrospective study, whichill require prospective validation on a larger sample

ize.110 Similar to spectroscopy, OCT is a technique involution, and further refinements are anticipated thatay improve its diagnostic accuracy for the detection of

reneoplastic lesions.Frequency of surveillance. The frequency of en-

oscopic surveillance in patients with Barrett’s esopha-us has been debated without the benefit of well-con-tructed studies. Surveillance intervals recommended inhis section are supported by limited evidence, which isased on our understanding of the natural history ofevelopment of esophageal adenocarcinoma dependingn the grade and extent of dysplasia in Barrett’s esoph-gus. The goal of surveillance is to identify patients atisk and assess them in a timely fashion to prevent oretect cancer at an earlier treatable stage. Summaries ofhe studies that have investigated the incidence of cancern Barrett’s esophagus appear in Tables 1–4. Patientsith nondysplastic Barrett’s esophagus should undergo

epeat endoscopy 1 year after the initial endoscopy. Pa-
ients with persistent nondysplastic Barrett’s esophagus

Table 1. Diagnosis of Prevalent or Incidental Cancer on Follow-up of Patients With No Dysplasia

Institute or geographicarea Study type

Studyduration

No. ofpatients

Mean ormedianage (y) Duration of follow-up

Totalcancers (%)

Incidentalcancers (%) Comments Reference

University of Chile,Santiago, Chile Prospective 1978–1991 152 52 100 mo (mean) 4 (2.6) 4 (2.6)

LGD developed in 15patients on follow-up

Csendes et al,115

1998University of Otago

Medical School,Dunedin, NewZealand Prospective 1980–1986 52 63 16.4 mo (mean) 0 0 Cooper et al,182 1987

Deutsche Klinik furDiagnostik,Wiesbaden,Germany Prospective 1980–1999 60 61 10 y (mean) 2 (3.3) 2 (3.3)

5 patients developedLGD Eckardt et al,340 2001

University Hospital, ElPalmar, Murcia,Spain Prospective 1982–1993 59 37 287 patient-years 2 (3.3) 2 (3.3) Ortiz et al,341 1996

VA Medical Centerand University ofKansas MedicalCenter Prospective — 80 61

40 mo (mean) or362 patient-years 2 (2.5) 2 (2.5)

One patient developedHGD, 3 hadpersistent LGD, 18had transient LGD,and 56 remainednondysplastic.Patients withprevalent cancerdiagnosed at entry orwithin the first 6months wereexcluded Weston et al,45 1999

Fred HutchinsonCancer ResearchCenter, University ofWashington

Prospectivecohort 1983–1998 129 62

2.4 y (median) or3.9 y (mean) forthose who did notdevelop cancer 5 (3.9) 5 (3.9)

5-year cumulativeincidence of cancerwas reported to be1.7% and 8-yearcumulative incidencewas reported to be8.4% Reid et al,43 2000

LGD, low-grade dysplasia; HGD, high-grade dysplasia.

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Table 2. Diagnosis of Prevalent or Incidental Cancer on Follow-up of Patients in Which the Degree of Dysplasia Was Not Defined or There Were �10 Patients in a SingleDysplasia Category


Studyduration

No. ofpatients

Mean ormedianage (y)

Duration offollow-up

Totalcancers (%)


Mayo Clinic, Rochester,MN

Retrospective 1960–1983 122 58 8.5 y (mean) 20 (16) 2 (1.9) Cameron et al,342 1985

Boston VA Medical Center,Boston UniversitySchool of Medicine, andTufts University Schoolof Medicine

Retrospective 1962–1983 115 58 3.3 y (mean) 11 (9.5) 2 (1.9) 4 patients had LGD at baseline; one ofthem progressed to HGD and finallyto cancer. HGD developed in 7patients

Spechler et al,34 1984

VA Outcomes Group,Dartmouth-HitchcockMedical Center

Retrospective 1970–1994 102 63 4.8 y (median) 3 (3) 3 (3) 8% of nondysplastic patientsdeveloped dysplasia. In 2 patients,HGD developed before cancer

Katz et al,343 1998

Castle Hill Hospital,Cottingham, UnitedKingdom

Retrospective 1971–1991 26 62 11.5 y (mean) 4 (15.4) 4 (15.4) Moghissi et al,344 1993

Lahey Clinic, Burlington,MA

Retrospective 1973–1989 176 56 3 y (median) 5 (2.8) 5 (2.8) 11% of patients developed dysplasiaon follow-up

Williamson et al,33 1991

University of Rotterdam,Dutch cohort

Retrospectivecohort

1973–1994 155 42 9.3 y (mean)or 1440patient-years

8 (5.3) 8 (5.3) Van der burgh et al,60

1996

Helsinki University, CentralHospital, Finland

Retrospective 1975–1985 32 59 166 patient-years

3 (9.3) 3 (9.3) Ovaska et al,345 1989

Mayo Clinic, Rochester,MN

Retrospective 1975–1994 113 68 6.5 y (median) 3 (2.6) 3 (2.6) Patients in this study underwentfundoplication; one patientdeveloped HGD

McDonald et al,346 1996

University Hospital,Nottingham, England

Prospective 1976–1990 102 63 54 mo (mean) 4 (3.9) 4 (3.9) 2 patients had dysplasia at baselineand a total of 12 had dysplasia onfollow-up

Iftikhar et al,347 1992

Ninewells Hospital andMedical School, Dundee

Retrospective 1976–1986 44 58 9.5 y (mean) 2 (4.5) 2 (4.5) Patients were not in formalsurveillance program

Rana et al,348 2000

Cleveland Clinic Registry 1979–1995 136 58 4.2 y (mean) 2 (1.4) 2 (1.4) One patient without dysplasia and onewith LGD developed cancer. Fivepatients developed HGD, and 24developed LGD.

O’Connor et al,50 1999

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Table 2 (continued). Diagnosis of Prevalent or Incidental Cancer on Follow-up of Patients in Which the Degree of Dysplasia Was Not Defined or There Were �10Patients in a Single Dysplasia Category


Studyduration

No. ofpatients



Totalcancers (%)


Academic Medical Center,University of Amsterdam

Prospective — 50 59 5.2 y (mean) 5 (10) 5 (10) 6 patients had LGD and one had HGDat baseline. At the end of the study,10 had LGD and 3 had HGD

Hameeteman et al,349

1989

University of Minnesota,Duluth Clinic

Retrospective 1980–1995 149 — 510 patient-years

20 (13.4) 7 (5) 13 prevalent cancers were detected atesophagectomy

Streitz et al,350 1998

Princess AlexandraHospital, Brisbane,Australia

Prospective 1981–1988 81 63 3.6 y (mean) 3 (3.7) 3 (3.7) 2 patients had HGD at baseline, andboth progressed to adenocarcinoma.Ten patients had LGD, and oneprogressed to adenocarcinoma.

Miros et al,37 1991

VA Medical Center, ArizonaHealth Sciences Center

Prospectivecohort

1982–1995 177 62 4.8 y (mean)or 834patient-years

11 (6.2) 4 (2.3) All patients who progressed to cancerdeveloped dysplasia before thedevelopment of cancer

Drewitz et al,351 1997

University of Leeds,Leeds, England

Retrospective 1984–1995 307 58 72 mo (mean) 12 (3.9) 12 (3.9) Patients were excluded if the cancerwas present at baseline or withinthe first 6 months

Bani-Hani et al,59 2000

VA Cooperative StudyGroup

Retrospective 1986–1999 108 58 1037 patient-years

4 (3.7) 4 (3.7) Patients were not in formalsurveillance program

Spechler et al,125 2001

GOSPE, Torino, Italy Prospectivecohort

1987–1995 187 — 36 mo (mean) 3 (1.6) 3 (1.6) 3 patients had LGD at baseline. 5patients developed LGD, and 2developed HGD

Ferraris et al,352 1997

LGD, low-grade dysplasia; HGD, high-grade dysplasia.

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Table 3. Diagnosis of Prevalent or Incidental Cancer on Follow-up of Patients With Low-Grade Dysplasia


Studyduration

No. ofpatients


Duration offollow-up Total cancers (%) Incidental cancers (%) Comments Reference

VA Outcomes Group,Dartmouth-Hitchcock MedicalCenter Retrospective 1970–1994 24 63 4.8 y (median) * *

3 patients had HGDor cancer. Cancerand HGD werepooled together

Katz et al,343

1998


Prospectivecohort 1983–1998 43 62

2.4 y (median)or 3.9 y(mean) forthose whodid notdevelopcancer 3 (7) 3 (7)

5- and 8-yearcumulativeincidence of cancerwas reported to be12%

Reid et al,43

2000

Cleveland Clinic Retrospective 1986–1997 25 6711 mo

(median) 2 (8) 2 (8)

An additional 5patients developedHGD. Whenpathologists agreedon the diagnosis ofLGD, 7 of 17progressed to HGDor cancer

Skacel etal,46 2000

VA Medical Centerand University ofKansas MedicalCenter Prospective — 48 62 41 mo (mean)

4 (8); one patienthad definite and 3had suspectedintramucosalcancer

4 (8); one patienthad definite and 3had suspectedintramucosalcancer

4 patients progressedto extensive HGD.12 patients hadpersistent LGD. 31patients regressedto no dysplasiaPatients withprevalent cancerdiagnosed at entrywere excluded

Weston etal,353 2001

*Not defined in manuscript, 24 patients developed LGD anytine during follow up, the high grade dysplasia or cancers were pooled; HGD, high-grade dysplasia; LGD, low-grade dysplasia.

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Table 4. Diagnosis of Prevalent or Incidental Cancer on Follow-up of Patients With High-Grade Dysplasia


Studyduration

No. ofpatients



Totalcancers (%) Incidental cancers (%) Comments Reference

VA Hospital, Hines, IL Prospectivecohort

1979–1996 75 62 7.3 y (mean) 12 (16) 12 (16) 4 patients in whom cancer wasdetected in the first year ofsurveillance were excludedand considered to haveprevalent cancers

Schnell et al,47

2001

Johns Hopkins Retrospective 1982–1994 30 61 — 13 (43) — Esophagectomy. Nosurveillance

Heitmiller etal,354 1996


Prospectivecohort

1983–1998 76 62 2.4y (median)or 3.9y (mean)for thosewho did notdevelopcancer

33 (43.4) 33 (43.4) 5-year cumulative incidence ofcancer was reported to be59%

Reid et al,43

2000

University ofLouisville,Louisville, KY

Retrospective 1985–1995 11 61 — 8 (72.7) — Esophagectomy. Nosurveillance

Edwards etal,355 1996

VA Medical Centerand University ofKansas MedicalCenter

Prospective — 15 61 37mo (mean)

7 (470; 4patientshaddefinitivecancerand 3 hadpossibleintramucosalcancer)

7 (470; 4 patients haddefinitive cancer and 3 hadpossible intramucosalcancer)

Patients had unifocal HGD. In4 patients, the extent ofdysplasia increased. 5patients becamenondysplastic, and 2 hadLGD. Patients with prevalentcancer diagnosed at entrywere excluded

Weston etal,356 2000

Mayo Clinic,Rochester, MN

Retrospectivecohort

1991–1999 100 67.5 30mo (mean)for focalHGD and15mo (mean)for diffuseHGD

32 (32%) 13 (16) after excludingcancers that were detectedin the first 6 months

Patients with cancer at entrywere excluded. 4 patientswith focal and 28 patientswith diffuse HGD werediagnosed with cancer

Buttar et al,200148

HGD, high-grade dysplasia; LGD, low-grade dysplasia.

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hould have periodic surveillance at 5-year intervals,epending on the patient’s health. The rationale of re-eating surveillance twice in the first year is to diagnoseny prevalent dysplasia that may have been missed dur-ng initial endoscopy. Most initial procedures that diag-ose Barrett’s esophagus do not involve complete sur-eillance biopsies because the diagnosis has not beenstablished. The reason to increase the surveillance in-erval to 5 years is based on decision analysis modelshowing that surveillance in this group of patients is notost-effective. The caveat is that this recommendation isased on set assumptions made in the cost-utility model,nd any major change in these assumptions in the futureill require modification of the surveillance interval inatients with nondysplastic Barrett’s esophagus.38 This isifferent from prior gastrointestinal societal guidelines,hich suggested that surveillance should be performed atore frequent intervals, but there has not been sufficient

vidence to support prior recommendations.64 Therefore,e recommend ending surveillance when the anticipated

ife expectancy is limited (�1 year) or the patient isnable to tolerate any therapeutic measures. Evenounger patients may not warrant surveillance if therapyor cancer cannot be performed.

Patients with low-grade dysplasia should undergo re-eat endoscopy twice in the first year, and those patientsho have persistent low-grade dysplasia in Barrett’s

sophagus should have periodic surveillance at 1- to-year intervals until the age of 80 years, depending onealth status. The risk of cancer development in patientsith low-grade dysplasia is intermediate.46 Patients with

ow-grade dysplasia whose diagnosis is agreed on by 2athologists carry a relatively higher risk of cancer diag-osis; therefore, we recommend a surveillance interval ofyear for this group of patients. Patients whose diagno-

is of low-grade dysplasia is not agreed on by 2 pathol-gists but who do not have any evidence of high-gradeysplasia can be surveyed at 2-year intervals.Patients with high-grade dysplasia in Barrett’s esoph-

gus that has been confirmed by 2 experienced patholo-ists should be recommended to proceed with definitiveurgical or endoscopic management, especially if theigh-grade dysplasia is diffuse or mucosal abnormalitiesre found on endoscopy. If the patient does not wish toroceed with definitive treatment until the diagnosis ofancer is made, surveillance should be considered. Sur-eillance endoscopy should be repeated every 3 monthsn the first 2 years, followed by 6-month intervals indef-nitely. The rationale for recommending immediate sur-ical or endoscopic therapy is that many patients maylready have coexisting esophageal cancer that was not
etected due to the limitations of surveillance.111 The y
ationale for repeating surveillance every 3 months forhe first 2 years is to capture any prevalent cancers thatere not detected initially. This surveillance interval

hould be used even if ablative procedures are performedor high-grade dysplasia or cancer because of the risk ofecurrence of the disease.112,113 The reason to increase theurveillance interval to 6 months after the first 2 years ishat the majority of cancers detected in patients withigh-grade dysplasia are within the first year and the riskf incidental cancer after the first 2 years of surveillances low.47,48 After ablative therapy, surveillance should beontinued as per the preablative recommendation be-ause the long-term consequences of ablation are as yetndetermined and because of reports of recurrent neo-lasia after ablation.Summary of Evidence—The use of surveillance in pa-

ients with Barrett’s esophagus is supported by level IIvidence, although it seems that the most cost-effectivepproach is to target patients at higher risk for develop-ent of cancer. Surveillance should be performed using

-quadrant biopsy specimens taken every 1–2 cm ofarrett’s mucosa, depending on the degree of dysplasia

based on level III evidence). The use of jumbo biopsyorceps in routine surveillance is not recommended basedn existing evidence. The use of jumbo biopsy forceps inatients with high-grade dysplasia has not been proveno provide increased benefit. There are as yet insufficientata to recommend chromoendoscopy with Lugol’s solu-ion over conventional videoendoscopy in Western co-orts at risk for esophageal squamous cell cancer (basedn level III evidence). Methylene blue–assisted chro-oendoscopy is not clearly beneficial and should not be

sed in the routine assessment of Barrett’s esophagusbased on level II evidence). Magnification, optical spec-roscopy, and imaging techniques are still being devel-ped and should be considered research tools at theurrent time (based on level III evidence). Surveillance ofondysplastic Barrett’s mucosa established by 2 endos-opies should be at 5-year intervals (based on level IIIvidence). Surveillance of patients with low-grade dys-lasia established by 2 endoscopies should be at 1- to-year intervals, depending on whether or not the diag-osis is confirmed by 2 pathologists. If both pathologistsoncur that low-grade dysplasia is present, 1-year sur-eillance intervals should be used; if agreement cannot beeached (dysplasia is not believed to be present by at leastne pathologist), 2-year intervals should be sufficientbased on level IV evidence). High-grade dysplasiahould be confirmed in a second endoscopy and reviewedy expert pathologists. If this is confirmed, the patientan be offered surveillance at 3-month intervals for 2
ears and then every 6 months (based on level III evi-

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ence). Any mucosal abnormality should be carefullynvestigated and removed for diagnosis. Surgical resec-ion should be recommended and mucosal ablation withhotodynamic therapy (PDT) can be offered for patientsith confirmed high-grade dysplasia (based on level III

vidence).

Chemoprevention for EsophagealCancer

Acid Inhibition

Because esophageal cancer is uncommon and in-erventions are usually only warranted in high-riskroups, strategies for chemoprevention of this conditionre being advocated. These include the use of acid sup-ression, nonsteroidal anti-inflammatory drugsNSAIDs), and lifestyle modifications. Antireflux surgeryr prolonged acid suppression using high doses of protonump inhibitors result in the appearance of squamousslands in Barrett’s esophageal segment but have notonsistently been shown to regress metaplastic epithe-ium or prevent esophageal adenocarcinoma.114–117 Al-hough the rationale for intensive antireflux therapyeems reasonable, there is not good clinical evidence toupport this approach. The primary rationale for theseroposals is that proton pump inhibitors incompletelyuppress gastric acid and fail to completely reduce duo-enal-esophageal bile reflux.118,119 Acid and bile salts canctivate several key cellular pathways in Barrett’s esoph-gus that are normally associated with progression ofeoplasia in Barrett’s esophagus, and inhibition of theseathways may prevent the development of adenocarci-oma of the esophagus in an animal model of Barrett’ssophagus.120–123 In patients with Barrett’s esophagusho were asymptomatic on acid suppressive therapy and

lso had normalization of intraesophageal acid exposuren pH monitoring, there was significantly more differ-ntiation and less proliferation compared with patientsho continued to have abnormal intraesophageal acid

xposure.124 However, even on high dosages of protonump inhibitors, acid inhibition may be difficult tochieve, with 4 of 25 patients having pathologic acideflux on 80 mg/day of omeprazole.119 Fundoplication isot successful in controlling acid reflux on a long-termasis and did not prevent development of cancer, asemonstrated by a follow-up to a randomized prospectiverial comparing medical with surgical therapy.125 Epide-iologic studies involving more than 66,000 patientsith reflux treated medically compared with 11,000atients treated with fundoplication in Sweden found norotective effect of surgery in decreasing the develop-
ent of adenocarcinoma of the esophagus.126 c
Ablation Therapy

Ablation therapy in conjunction with acid controlas been promoted for the treatment of Barrett’s esoph-gus to decrease the risk for esophageal cancer.127,128 Thiss based on the observation that elimination of the meta-lastic epithelium can result in squamous mucosa regen-ration.129 Multiple ablation therapies have been pro-osed and involve the use of multipolar coagulation,rgon plasma coagulation, neodymium:yttrium-alumi-um-garnet (Nd:YAG) laser coagulation, and PDT.ultipolar coagulation has been performed in a prospec-

ive multicenter study with 58 patients that eliminatedistologic evidence of Barrett’s mucosa in 78% of treatedatients.130 Argon plasma coagulation has been used inne randomized, nonblinded, prospective trial in 40atients after fundoplication for acid control.131 Barrett’sucosa was initially found underneath squamous mucosa

n this study in more than 35% of patients 1 month afterreatment but decreased to 5% at 1 year. Patients whoid not achieve complete ablation had 95% regression inhe amount of Barrett’s mucosa. Multiple case series ofrgon plasma coagulation have been reported with sig-ificant reduction in Barrett’s mucosa and decrease inysplasia.132–139 Many ablation trials emphasize that re-uction in the length or area of Barrett’s mucosa shouldorrespond with a decreased risk for cancer, although thisas not been shown in a prospective study. PDT has beenpproved by the Food and Drug Administration (FDA)or use in patients with high-grade dysplasia to decreasehe risk of cancer formation. Case series of patients withigh-grade dysplasia treated with PDT using sodiumorfimer have found that dysplasia can be eliminated in8% of patients with elimination of 75%–80% of thearrett’s mucosa, but esophageal strictures occurred in4% of patients.140 Unfortunately, the residual Barrett’sucosa after ablation therapy has been found to contain

enetic mutations similar to those found before ablation,uggesting that histologic improvement may not corre-ate with elimination of cancer risk.113 A prospectiveandomized trial studied PDT using 2 different dosagesf 5-aminolevulinic acid (a less potent agent than sodiumorfimer) followed by argon plasma coagulation com-ared with argon plasma coagulation alone in 40 pa-ients.141 These investigators found that argon plasmaoagulation alone or in combination with PDT was onlyffective in eliminating about 70% of the Barrett’s mu-osa.

NSAIDs

The rationale for the use of NSAIDs to prevent
ancer in Barrett’s esophagus is based on experimental

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nd epidemiologic evidence. No randomized controlledrials have found aspirin to be effective for prevention ofancer. It has been shown that bile salts in a pH-ependent manner can activate the arachidonic acidathway and may promote neoplasia in Barrett’s esoph-gus.121,122 The activation of the arachidonic acid path-ay leads to increased production of prostaglandin E2,hich increases cellular proliferation.142,143 Inhibition ofrostaglandin E2 normalizes proliferation in Barrett’spithelial cells and decreases it to a level that is seen inormal squamous epithelium.143 Inhibition of the cyclo-xygenase enzyme with selective and nonselective cyclo-xygenase inhibitors has been shown to reduce the risk ofdenocarcinoma of the esophagus in an animal model ofarrett’s esophagus.123 Finally, cyclooxygeanse-2 expres-

ion has also been shown to parallel the progression ofeoplasia in human Barrett’s esophagus.144

Epidemiologic studies have found that NSAIDsrotect against the risk of esophageal cancer.145–149

ase-controlled studies have shown a 36%–90% rel-tive risk reduction for esophageal cancer in patientssing aspirin or other NSAIDs occasionally or on aong-term basis.145–147,149 A decision analysis modelas been used to evaluate the feasibility and cost-ffectiveness of NSAIDs to prevent esophageal adeno-arcinoma. It suggested that the high incidence ofsophageal adenocarcinoma in Barrett’s esophagusith high-grade dysplasia renders chemoprevention a

ost-effective option.150 NSAIDs were not a cost-ef-ective measure in the general population of all pa-ients with Barrett’s esophagus, but this was sensitiveo variations in the cost of chemoprevention, the in-idence of cancer, and the efficacy of the NSAID inrevention of cancer. In patients with gastroesopha-eal reflux, a chemopreventive approach will only beost-effective if the agents are very safe and effective torevent the development of adenocarcinoma of thesophagus.

Lifestyle

Lifestyle factors for the development of esophagealancer have been identified through epidemiologic stud-es. Obesity seems to be one of the most important riskactors associated with esophageal cancer.151,152 In a re-ently completed study of patients with esophageal andastric cancer, smoking and dietary habits were found toe important risk factors.152 Smoking was found to havepopulation attributable risk (PAR) of 39.7% (95%

onfidence interval [CI], 25.6%–55.8%). The frequencyf gastroesophageal reflux disease symptoms also showedpositive trend in the PAR, with symptoms at least once
er day accounting for almost one half of the PAR n
ssociated with the presence of any gastroesophagealeflux disease symptoms (29.7%; 95% CI,9.5%–42.3%). Consumption of fruits and vegetablesess than twice a day on average had a modest PAR of5.3% (95% CI, 5.8%–34.6%). In this population,8.7% (95% CI, 66.5%–87.3%) of esophageal adeno-arcinoma cases could be attributed to one or more ofhese well-established risk factors, with smoking andody mass index contributing the most.Summary of Evidence—Based on level II evidence, fun-

oplication should not be recommended solely to preventsophageal cancer in patients with gastroesophageal re-ux disease. The use of high-dose proton pump inhibi-ors to prevent esophageal cancers in patients with gas-roesophageal reflux disease has also not been establishednd cannot be recommended in clinical practice (basedn level III evidence). Level II evidence suggests thatblation therapy may decrease dysplasia in Barrett’ssophagus and could potentially decrease cancer risk.SAIDs should not be recommended at the current time

olely for the prevention of esophageal adenocarcinomaut have promise as a chemopreventative agent, whichight be beneficial if required for other medical indica-

ions (based on level II evidence). Patients at risk forsophageal cancer should be counseled to adapt healthierifestyles, in particular attaining normal weight andliminating tobacco use (based on level II evidence).

Diagnosis and Staging ofEsophageal Cancer

Diagnosis

Most patients with esophageal cancer present at aate stage when the diagnosis of cancer is made, withysphagia as the cardinal symptom.153 In particular,ersistent dysphagia that progresses from solids to liq-ids should heighten suspicion for esophageal cancer andrompt an endoscopic evaluation. Up to 75% of patientsave experienced anorexia and weight loss when seekingedical attention. Patients may also present with

dynophagia, chest pain, or gastrointestinal bleeding.ough aggravated by swallowing raises the possibility ofn esophagopulmonary fistula, a devastating complica-ion associated with a high 30-day mortality rate.154

The diagnosis of esophageal cancer is established byexible endoscopy with biopsy. The features, location,nd size of the tumor can be more accurately assessed byndoscopy than by radiographic studies.155 Barium swal-ow as an initial diagnostic test is of limited value.156,157

owever, it may be useful to confirm the presence ofsophagopulmonary fistulas or document complete lumi-
al obstruction when clinically suspected. In patients

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ith advanced cancers, esophageal dilation may be re-uired to allow for a standard (OD, 9.8 mm) endoscopeo traverse the obstructed lumen. Alternatively, an ul-rathin (OD, 5.3–6 mm) endoscope may pass throughhe stenosis and allow completion of the examination in5% of cases.158

Biopsy specimens are required for histologic confirma-ion. The diagnostic yield reaches 100% when 6 or moreamples are obtained using a standard endoscopic biopsyorceps.159,160 Biopsy specimens of necrotic or fibroticreas should be avoided. The adequacy of biopsy speci-ens obtained via ultrathin endoscopes has not been

ormally assessed. As an adjunct, brush cytology can beelpful in sampling tight malignant strictures, whichay not be easily accessible by conventional biopsy

echniques.161 Brushings should be collected before bi-psy to maximize the diagnostic yield.162 Endoscopicltrasonography (EUS) should be considered when stan-ard biopsy and/or brush cytology fail to confirm theiagnosis in the setting of high clinical suspicion (e.g.,ubmucosal tumors).163 Fine-needle aspiration or Tru-cutiopsy can be performed at the time of EUS.

Staging

The staging of esophageal cancer is critical touide further therapy for the patient. Patients with can-er confined to the mucosa or superficial submucosa cane treated using surgical resection or potentially endo-copic therapy.137,164 However, patients who have moredvanced disease will require surgical resection or che-oradiation.165,166 None of the currently available stag-

ng technologies have been shown to be able to stage allspects of the tumor. The selection of the best stagingests depends on the probability of detecting metastaticancer. Although endoscopy is not a staging tool, it can

Figure 1. Algorithm for staging of advanced cancers.

e helpful to guide the gastroenterologist toward which

dditional staging studies are needed. In one series of09 patients, endoscopy was 89% accurate in determin-ng tumor staging compared with surgical or EUS stag-ng.167 Patients with large bulky circumferential tumorsho present with dysphagia are likely to have advancedisease and will require tests to confirm this. Patientsho have cancers that are �2 cm in diameter and are

symptomatic are more likely to have early disease. Al-orithms for evaluation of advanced and early esophagealancers are found in Figures 1 and 2.

The most commonly used staging procedure in esoph-geal cancer is computed tomography (CT). The partic-lar strength of this test is the ability to detect distantetastatic disease.168 The primary reason this is used as

he first staging study is because of its availability andhe change in the treatment course that would occurhould metastasis or invasion of other organs be detected.n initial presentation, most patients with metastaticisease had involvement of abdominal lymph nodes45%), liver (35%), lung (20%), and cervical lymphodes (18%) based on findings at esophagectomy.169 CTf the chest and abdomen correctly identified metastaticisease in only 69% of the cases. In this series, patientsithout metastasis on CT did not have involvement of

he bones or brain. CT has limited accuracy in staginghe extent of tumor invasion, with correct staging foundn 50%–90%.170–172 CT has been shown to produce falseegatives in 30%–60% of patients.173 Even with im-rovements in technology such as the helical CT scanner,omparisons with EUS and fine-needle aspiration indi-ate that it is still not as sensitive for detecting celiacymph node disease or T4 carcinoma.174

EUS consists of 3 fundamentally different devices thatay not be available to all gastroenterologists. There are

robes that can be placed within the endoscope or useds stand-alone instruments, radial scanning echoendo-copes, and linear array echoendoscopes that permit fine-

Figure 2. Algorithm for staging of early cancers.

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eedle aspiration. EUS can be directed primarily at theucosa with the use of probes that usually involve

igh-frequency scanning at 20–30 MHz or can be di-ected to more distant structures by scanning at 7.5–12Hz with the radial echoendoscopes. The diagnostic

tility of EUS is in determining the depth of tumornvasion and the presence of local-regional adenopathy.his technology is limited in terms of detecting distantetastasis because visualization of other organ systems,

articularly the lung, is not possible because air disruptsltrasound conduction. Identification of abnormal-ap-earing lymph nodes has been found to be specific (85%–7%) for nodal metastasis but not very sensitive (72%–7%) in case series.175,176 If abnormalities are found,iopsies can be performed on the lesions using a smallspiration needle positioned in a linear array instrument.he sensitivity of this technique in tumor staging haseen reported in clinical series between 59% and 90%.ome of this variation can be attributed to the difficultyn passing the ultrasound instrument through a malig-ant stricture.177 Histologic confirmation of nodal dis-ase altered planned therapy in only 13% of patientsith esophageal cancer in one retrospective case series.178

his may be because the majority of esophageal cancersre found at an advanced stage. Miniprobes that haveigher resolution are the best at defining early-stageancer.179 Decision analysis models have been used toetermine the value of EUS in assessment of esophagealancer. These models have found that EUS is a moreost-effective initial staging strategy if the probabilityhat EUS can find advanced disease is �30% or if theost of EUS is less than 3.5 times that of CT.180 Addi-ional analysis based on the use of EUS in a nationalatabase found that preoperative use of this techniqueould prevent 26% of patients from unnecessary com-ined-modality therapy.181

Positron emission tomography (PET) is a technologyhat uses 18F-fluorodeoxyglucose for the detection ofodal or distant metastasis in esophageal cancer.182 Thiss used to detect neoplastic tissues because they normallyetabolize glucose at a faster rate than normal tissues.owever, inflammatory tissues are also fast glucose me-

abolizers and metastases often have to be differentiatedrom inflamed tissue, leading to false positives.183 Aumber of case series have found that PET is not asensitive as EUS or CT for locoregional disease.184–189

his technology cannot define the tumor stage because itannot resolve the layers of the esophagus. In addition,atients with hyperglycemia are not good candidates forET. Because of these factors, PET cannot be envisioneds an initial staging tool in esophageal cancer. New
dvances in PET technology include fusion PET, which C
ctually combines the CT image with the PET image tollow better tumor localization. This may increase thepecificity of the test.

Other staging procedures that have been investigatednclude minimally invasive surgery or laparoscopic stag-ng before esophagectomy. Case series have found thaterformance of laparoscopic- or thoracoscopic-guided bi-psies of lymph nodes increases the detection of meta-tatic disease and can change management in 17% ofatients.171,190–196 Thoracoscopy has a significant advan-age in detecting thoracic lymph nodes and when com-ined with laparoscopy appears to be superior to EUS,ET, and CT staging.171,192,197 These series generally doot have uniform staging procedures performed beforehe laparoscopy, which makes it difficult to assess theole of these procedures in relation to the standard stag-ng modalities. Bronchoscopy has been suggested as ataging procedure for patients with tumors that areound above the tracheal bifurcation. In one prospectivetudy, almost 10% of patients were found to have tra-heal involvement on the basis of bronchoscopy alone,lthough EUS was not used in this study.198 Magneticesonance endoscopy has also been used in staging esoph-geal cancer but as yet has not been shown to be superioro existing tests.199,200 Recent cost analyses of thesearious staging modalities alone and in combination haveuggested that CT combined with EUS with fine-needlespiration if appropriate offered the least expensive andeasonable efficacy in terms of QALYs.201 PET and EUSlus fine-needle aspiration offered more QALYs but waslso more expensive at $60,544 per QALY.

Summary of Evidence—Given the state of the currentnformation, we recommend the following strategy. CTf the chest and upper abdomen should be the firsttaging procedure, followed by EUS and fine-needle as-iration if no evidence of distant metastasis is found onT and the procedure is available. If surgical resection is

till considered, PET can be considered if available due tots increased sensitivity for distant metastasis. This isased on level III evidence. In patients with potentiallyarly-stage disease (tumors �2 cm and nonobstructing),US with endoscopic mucosal resection may be consid-red as an alternative staging procedure if available foristologic staging of the cancer and potential therapy.

Treatment of Esophageal Cancer

Treatment of Early Cancers

Early esophageal cancers, those confined in theucosa or upper submucosa of the esophagus, are termed1, N0, M0 by the American Joint Commission on
ancer terminology (see Table 5). There have not been

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ny randomized treatment trials for these cancers becausehey are rare, accounting for �5% of esophageal cancersiagnosed in most series. In Japan, there has been aurther division in T1 lesions. An early cancer is termed1m if confined to the mucosa and T1sm if submucosal

nvasion is found. There has even been further division of1sm lesions into penetration into the upper third

sm1), the middle third (sm2), or the lower third (sm3)f the submucosa.202 In the Japanese experience withquamous cell cancers, penetration of the superficial sub-ucosa is associated with a 6% risk of metastasis. How-

ver, if deeper penetration of the submucosa is found, theisk of metastasis increased to 47%. There is a problemn the interpretation of some of the literature fromapan.203 Overall, Japanese pathologists will diagnosentramucosal carcinoma based primarily on patterns ofhe cell nucleus rather than on the demonstration ofnvasion as required by Western pathologists. Some ofhe data concerning the lack of metastatic potential forarly cancers may be biased by the inclusion of cases ofhat would be classified by Western pathologists as

able 5. Staging According to the American JointCommission on Cancer

umor staging for esophageal cancerT0 No evidence of primary tumorTis Carcinoma in situT1 Tumor invades lamina propria or submucosaT2 Tumor invades muscularis propriaT3 Tumor invades adventitiaT4 Tumor invades adjacent structures

odal stagingN0 No evidence of lymph nodesN1 Evidence of regional lymph nodesetastasisM0 No evidence of distant metastasisM1 Evidence of distant metastasisM1a For lesions in the lower thorax indicates metastasis to the

celiac nodesM1a For lesions in the upper thorax indicates cervical lymph

nodesM1b For lesions in the midthorax indicates nonregional or other

nodal groupsM1b For lower esophagus or upper thorax lesions indicates

distant metastasisX designation in any area indicates that the lesion was unable to

be assessed.taging of esophageal cancersStage 0 Tis,N0,M0Stage 1 T1,N0,M0Stage 2a T2-3,N0,M0Stage 2b T1-2,N1,M0Stage 3T3, N1,M0

T4, any N,M0Stage 4 Any T, any N, M1Stage 4a Any T, any N, M1aStage 4b Any T, any N, M1b

igh-grade or even low-grade dysplasia. p

The traditional approach for these squamous cell can-ers has been surgical resection because cure can bechieved in �90% of T1m cancers.204,205 A survey ofajor medical centers in Europe found that 253 patientsith early cancers treated with esophagectomy had aortality rate of 9.1%.205 Patients with intraepithelial

ancers had a 5-year survival rate of 93%, while thoseith intramucosal cancers had a decreased survival rate of3%. If cancer progressed into the submucosa, the sur-ival rate further decreased to 44%. Twenty of 21 pa-ients with recurrent disease had submucosal involve-ent with cancer. These results are similar to those

ound in Japan.There is less information available regarding surgical

esection of early adenocarcinoma. Early cancers haverimarily been reported as part of larger surgical series.verall, limited reports have results with a 100% rate of

otal excision without any operative mortality.206–211

owever, this is likely to be influenced by reporting bias.he reported mortality rate for esophagectomy per-

ormed on patients with high-grade dysplasia is between% and 6%.212,213 The major concern with surgicalherapy for high-grade dysplasia is the 40% incidence oforbidity associated with the procedure. Possible proce-

ure-related complications include anastomotic stric-ures, leaks, chronic aspiration, infection, and chylotho-ax.

Endoscopic mucosal resection has been performed on aumber of patients with early cancers, particularly insia, where the technique has been established for earlyastric cancers. Studies have shown that squamous cellancers confined to the mucosa or upper submucosa coulde treated successfully with endoscopic therapy.214 Five-ear cure rates for patients with intramucosal cancersere 100%, while those who had cancers that penetrated

nto the deep submucosa had 5-year survival rates of9%–54% in a series of 152 cases. Reports from othernstitutions for superficial cancers in Japan reported a5%–100% 5-year survival rate with recurrences esti-ated at 3%–7%. Even these recurrences were believed

o be treatable with additional endoscopic therapy.215 Insurvey of 143 Japanese medical institutions, endoscopicucosal resection was regarded as the treatment of choice

or intramucosal cancers.216 Complications in 2418 pa-ients were primarily stenosis, hemorrhage, or perfora-ion, which were found in 7% of patients. The mostmportant predictors of stenosis were resection of morehan three fourths of the circumference of the esophagealumen or if the lesion was �3 cm in length.217

Early mucosal resections were performed using a trans-arent overtube through which an endoscope could be
ositioned.218 The lesion was first identified visually, and

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hen a fluid cushion was created under the lesion bynjecting saline and epinephrine submucosally beneathhe lesion. If the lesion could not be elevated from theemainder of the esophageal wall, the resection could note performed. Later developments involved the use ofand ligation and eventually the cap-fitted endoscope.219

ew variations of this technique have been described andermed endoscopic submucosal dissection, including these of an insulated tipped electrocautery knife, needlenife, or triangular tipped knife that can completelyesect the lesion with the use of a special snare designedo resect the lesion without any need for suction.220,221

hese techniques were all designed for the relatively flatesions associated with early squamous cell cancers. En-oscopic mucosal resection performed in the Unitedtates involves the use of variceal band ligation, whichllows the formation of a pseudopolyp that can be re-ected by a regular snare. A second common techniquenvolves the use of a specialized cap that can be fittednto an endoscope. This requires the use of a crescentnare that is designed to form a loop around the lip of theistal end of the cap. The targeted tissue can then beuctioned into the cap and the snare closed to performhe resection. A prospective comparison study of these 2echniques in 100 resections performed in 72 patientsith early cancers did not find any differences in terms of

ize of the specimen or complication rates.222

Early esophageal adenocarcinomas have been endo-copically treated in the setting of Barrett’s esophagus.hese have been described in large case series usingucosal resection alone or in combination withDT.223,224 Lesions most amenable to mucosal resectionre those that are polypoid, elevated, �2 cm in size, andaving a low-grade cancer.223 Mucosal resection was usedn 115 patients (83% with early cancers) and resulted in3-year overall survival rate of 88%.137 Complications

ccurred in 9% of patients, including decreases in he-oglobin and stricture formation. However, becausearrett’s esophagus without high-grade dysplasia or can-er was left untreated, 30% of the patients developeddditional neoplastic lesions. For this reason, it is gen-rally advised that the remainder of the Barrett’s esoph-gus be treated after resection of a cancer. PDT has beensed for this purpose, with 94% initial success rates at 1ear.224 Although not widely performed, mucosal resec-ion has been performed to completely eliminate thearrett’s segment in 2 reports.225,226 Circumferentialucosal resection does tend to generate strictures; this

as been reported in 3 of the 13 reported cases.Endoscopic therapy using PDT, laser therapy, and

rgon plasma coagulation has also been reported.227–233

hese treatments have had limited success in completely r

liminating Barrett’s esophagus and cancer, with re-ponse rates of 25%–94%. These small case reports havead a wide variation in the depth of invasion of theseancers (T0–T2) and the type of therapy delivered. Laserherapy with Nd:YAG, which operates at a wavelengthf 1063 nm, penetrates quite deeply and has been favoredor tumor ablation. Lasers that operate in the 540-nmavelength, such as the argon or KTP-YAG lasers, havemuch more limited depth of penetration. Thermal

herapies, such as argon plasma coagulation applied atigh-power settings, have also been used to treat earlyancers. PDT is influenced by the type of photosensitizersed for therapy. Aminolevulinic acid is not approved inhe United States at this time, but it has found favor inurope because it is not associated with the prolongedutaneous photosensitivity that is found with the sodiumorfimer that is used in the United States. Due to its veryimited depth of penetration, aminolevulinic acid hasnly been found to be useful for cancer therapy if thehickness of the cancer is �2 mm.230

Other treatments that have been reported in case seriesor the treatment of patients with superficial cancersnclude radiation therapy and brachytherapy. Radiationherapy has been used in Japan as a single-modalityherapy for superficial squamous cell cancers. Five-yearurvival rates after treatment in 2 series with a total of83 patients ranged from 39% to 45%.234,235 Thesetudies have also shown a trend toward nodal recurrencef cancer in patients who have had submucosal penetra-ion.234 Patients with cancer strictly confined to theucosa did not have nodal recurrence. Brachytherapy

lone and in combination with external beam radiationas also been reported, although the 3-year survival raten these patients is only 14%.236

Treatment of Advanced Cancers

The gastroenterologist is often asked to determinehether there is a role for oncologists before surgical

esection. There has been substantial controversy over these of neoadjuvant therapy before esophagectomy for thereatment of patients with locally advanced esophagealarcinoma, primarily patients with stage IIb or III dis-ase (Table 5). Primary surgical therapy for cancers lim-ted to the esophagus, stage I or IIa disease, has had goodesults without the need for or morbidity of chemother-py.205,208,237,238 Surgical therapy for more advanced can-er has been performed as either a limited resection orn-bloc removal of lymph nodes, which can be performedia a transhiatal or transthoracic (Ivor–Lewis) ap-roach.239,240 Extensive resection of lymph nodes haseen more commonly practiced in Asia and involves
emoving nodes in the neck, chest, and abdomen in a

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-field lymph node dissection.241 This procedure is rarelyracticed in the United States because of the prolongedperating times and the morbidity associated with therocedure. An en-bloc lymph node dissection of thetomach and chest is practiced in the United States in anttempt to achieve complete surgical removal of tumornd appears in small series to eliminate recurrence ofumor in the resected area.242 In general, esophagectomyor squamous cell cancer seems to have been more suc-essful in Asia than in Western countries in terms ofurvival and operative mortality.243,244 Minimally inva-ive esophagectomy has recently been promoted for re-ection of esophageal cancer with the use of laparoscopyor gastric mobilization and resection.245,246 The gastro-sophageal anastomosis is accomplished with a thoraco-cope or manually. Although the procedure has not beenhown to improve patient outcomes in terms of morbid-ty or mortality, it has been attractive to patients withuperficial cancer or high-grade dysplasia who desire anmproved cosmetic result.

It has been well recognized that survival is related toisease stage.240,247 Thus, it is not surprising that theoncept of neoadjuvant (preoperative) chemotherapy andadiation had significant appeal to oncologists and sur-eons. By reducing the number of involved lymph nodesnd decreasing cancer stage, neoadjuvant therapy couldnhance the ability of surgical resection to cure patients.

number of prospective, randomized, controlled trialsave investigated the use of neoadjuvant therapy fol-owed by surgery versus surgery alone, and these areummarized in Table 6.248–254 Only one of these studies,hat by Walsh et al., actually showed an advantage tohemotherapy and radiation with an odds ratio of 8.44nd a 95% CI that does not cross 1.251 This study haseen criticized for its high surgical mortality rate thatiases against the surgical therapy alone group. A recenteta-analysis combined all of these studies and con-

luded that neoadjuvant therapy increased patient sur-ival at 3 years with an odds ratio of 2.5 (P � .04) and

able 6. Summary of Randomized Controlled Trials ComparinSurgical Resection With Surgical Resection Alone

ReferenceNo. of

patientsSurvival

period (y)Surgery

alone (%)

ygaard et al248 186 3 9e Prise et al249 86 3 13.8pinop et al250 69 5 10alsh et al251 113 3 6osset et al252 282 5 32elsen et al253 440 2 35rba et al254 100 3 16

ad a decreased risk of locoregional recurrence with an c

dds ratio of 0.83 (P � .01).255 This study found thathere was a nonsignificant trend toward an increase inreatment mortality. The concurrent administration ofhemotherapy and radiation therapy was believed to beignificantly better than sequential therapy. A significantercentage (21%) of the patients in these series had aomplete pathologic response at the time of resection.

With these high pathologic response rates with radi-tion and chemotherapy alone, it has been questionedhether surgical therapy is needed in the treatment ofatients with more advanced cancers. Initial studies com-aring neoadjuvant regimens found that the smallroups of patients who refused surgery after chemother-py and radiation had a 5-year survival rate of 18% ifhey had squamous cancers but no 5-year survival if theyad adenocarcinomas.256 The Intergroup 0123 trial stud-ed a nonsurgical approach to esophageal cancer usingigh-dose radiation (64.8 Gy) versus standard-dose radi-tion (50.4 Gy) in combination with 5-fluorouracil andis-platinum in 216 evaluable patients.257 The trial waserminated after interim analysis because the results in-icated that 50.5-Gy radiation was as effective as theigher dose, with 2-year survival rates of 40%.The need for combined chemotherapy and radiation

herapy has been best established in a randomized pro-pective trial from the Radiation Therapy Oncologyroup 85-01 study, which examined 134 patients ran-omized to radiation alone versus radiation in combina-ion with chemotherapy with 5-fluorouracil and cis-latinum.258 This trial clearly established that combinedherapy with a 5-year survival rate of 26% was superioro radiation therapy alone with a 0% 5-year survival rate.he odds ratio of this study was 0.02 (95% CI, 0.00–.38). One caveat from this study was that only 68% ofhe patients who planned to undergo chemotherapy wereble to complete the treatment course.

Summary of Evidence—Patients with early esophagealancers confined to the mucosa should be treated withurgical resection, with consideration of endoscopic mu-

oadjuvant Chemotherapy and Radiation in Addition to

Chemoradiationand surgery (%) P value

Oddsratio

95% Confidenceinterval

17 .30 2.81 0.61–12.9519.2 .56 1.57 0.50–5.0024 .40 3.1 0.74–12.832 .01 8.44 2.33–30.5733 .78 1.06 0.64–1.7437 .53 1.1 0.74–1.6330 .15 2.25 0.85–5.93

g Ne

osal resection with adjuvant mucosal treatment for any

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emaining preneoplastic tissue (ie, Barrett’s esophagus)based on level III evidence). Patients with early esoph-geal cancers that penetrate into the upper third of theubmucosa can be treated with endoscopic mucosal re-ection if surgical mortality is anticipated to be �6%based on level III evidence). Patients with stage IIb andII disease may benefit from concomitant chemotherapynd radiation therapy before surgical therapy (based onevel II evidence). Patients with stage I and IIa diseaseho are good candidates for surgical therapy do not

equire neoadjuvant therapy before esophagectomybased on level II evidence). Patients with more ad-anced-stage cancer may be treated with chemotherapynd radiation therapy or be considered for palliativeherapy.

Palliation of Esophageal Cancer

Esophageal cancer is usually diagnosed at an ad-anced and incurable stage. Patients with locally unre-ectable cancer or patients who are surgically unfit mayndergo palliation by a variety of nonoperative means.he goals of palliation in this setting are to alleviateysphagia, aid in nutrition, and improve quality of life.alliation can be achieved by external beam radiotherapyr intraluminal brachytherapy, with or without chemo-herapy. However, patients may not tolerate these ther-pies or improvement in dysphagia may be slow.259

Endoscopic therapy plays an important role in thealliation of malignant dysphagia. Several endoscopicechniques have been applied, but limited informationxists as to the optimal approach. The choice is primarilyictated by tumor characteristics, patient preference, andvailable expertise. Treatment must be individualized,nd different methods of palliation may be appropriate atarious stages of the patient’s illness.

Malignant esophageal stenoses can be dilated usinghrough-the-scope balloons or wire-guided polyvinyl di-ators (e.g., Savary dilators), with or without the aid ofuoroscopy. Dilation can be complicated by perforationn up to 10% of cases.260–262 Blind passage of Maloneyilators is not recommended in complex malignant stric-ures due to a higher risk of perforation.263 Most patientsan be dilated to a luminal diameter that allows passagef a liquid to soft diet (�9–12 mm), but improvements brief and typically measured in days. Dilation is usedostly as an adjunct to other modalities, such as in

acilitating placement of an esophageal stent or in pa-ients awaiting improvement in swallowing followinghemoradiation therapy.264

Among endoscopic modalities, esophageal stenting
as assumed a primary role as a palliative technique s
ecause of its effectiveness in rapidly relieving dysphagian one procedure. In the United States and abroad,elf-expanding metal stents (SEMS) have largely sup-lanted conventional plastic semirigid prostheses.265,266

n contrast to plastic semirigid stents, SEMS requireinimal to no preplacement dilation and are easier to

nsert.267–269 SEMS also expand the obstructed lumen togreater degree (18–23 mm) than that provided by

lastic semirigid stents bounded by fixed internal diam-ters (10–12 mm). Both SEMS and plastic semirigidtents have a highly successful rate of insertion (90%–00%). They are also similarly effective at alleviatingysphagia in �90% of patients; most are able to toleratet least liquids following stent placement.270–272 How-ver, the collective experience gathered from prospectiveandomized trials has shown SEMS to be associated withewer procedure-related complications (10%–43% vs%–16%), shorter hospital stays, and trends towardetter quality of life and survival.269–274 Although SEMSre more expensive than plastic semirigid stents, this costifference was not found to be significant in the overallanagement of dysphagia.274

A self-expanding plastic stent (Polyflex; Boston Scientificnc, Natick, MA) has been approved by the FDA for pal-iation of malignant dysphagia and, more recently, for be-ign disease. The potential advantage is its removability,ut it is priced similar to available SEMS. Initial studiesave shown the Polyflex stent to be efficacious in relievingalignant dysphagia.275–278 Prospective randomized trials,

owever, are needed to assess the cost-effectiveness of self-xpanding plastic stents versus SEMS.

Three FDA-approved SEMS are currently available inhe United States. These SEMS differ in design andelivery systems, with additional refinements for partic-lar indications (Table 7). The EsophaCoil stentMedtronic InStent Inc, Eden Prairie, MN) is no longerommercially available. Endoscopic placement of SEMSan be performed with or without the assistance ofuoroscopy.279,280 The majority of SEMS currently in usere partially covered with a thin silicone or polyurethaneembrane to prevent tumor ingrowth. In a prospective

andomized study of 62 patients, membrane-coveredtents offered significantly better palliation than uncov-red stents due to decreased rates of tumor ingrowth (3%s 30%) and decreased need for endoscopic reinterven-ions (0% vs 27%) for recurrent dysphagia.281 Coveredtents, however, tend to migrate more frequently thanncovered ones (26% vs 0%), particularly when placed inhe distal esophagus.282 Modifications in design, such ashe conical-shaped Flamingo Wallstent and Ultraflextent with proximal flaring, have improved anchoring of
tents to tissue and have made covered SEMS more

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igration resistant.283,284 These 2 stents have been useduccessfully for palliation of distal esophageal cancersith an overall migration rate of 6%.284

There are limited prospective randomized studiesomparing various SEMS for palliation of malignantysphagia.284,285 In a study of 100 patients, success ratesn alleviating dysphagia were similar among patientsho received the Z-stents, Flamingo Wallstents, or Ul-

raflex stents.285 Although complication rates wereigher in the Z-stents group (36%) than in the Ultraflexr Flamingo Wallstent groups (24% and 18%, respec-ively), these differences did not reach statistical signif-cance. In a study of 53 patients, Flamingo Wallstentsnd Ultraflex stents were equally effective at palliatingysphagia with similar complication rates.284 There ares yet insufficient data that convincingly show the supe-iority of one SEMS over another. Currently, the choiceor a particular SEMS primarily depends on device avail-bility, familiarity, and personal preference.286

Types and rates of SEMS-related complications varyidely among studies. Results of a national survey and

eview of complications from compiled case serieshowed immediate technical complication rates of 5%–7%, including misplacement (0.3%–5%), failed expan-ion (4%–7%), failed deployment (1%–3%), and migra-ion (0.3%–2%).268 Immediate patient complicationsccurred in 7%–15% of cases, including chest pain (6%–2%), bleeding (0.2%–0.6%), perforation (0.6%–1%),nd death (0.5%–1.4%). Delayed technical complica-ions occurred in 9%–18% of cases, including tumorngrowth/overgrowth (6%–11%) and stent migration3%–7%). Delayed patient complications occurred in upo 27% of patients, including reflux symptoms (4%–%), recurrent dysphagia (8%–9%), tracheoesophagealstulas (1%–3%), bleeding (0.5%–4%), perforation0.5%–0.8%), and death as a result of underlying ma-

able 7. FDA-Approved SEMS

Ultraflexa

aterial Nickel titanium (nitinoesign Meshovered Yesadial force �elivery system (F) 16ength (cm) 10, 12, 15lare-end diameter (mm) 23, 28haft diameter (mm) 18, 23egree of shortening (%) 30–40istula closure Yes

dapted and reprinted with permission from Baron.286

Microvasive/Boston Scientific Inc (Natick, MA).Wilson-Cook Medical (Winston-Salem, NC).

ignancy occurring within 30 days (7%). r

Tumor ingrowth or overgrowth causing recurrent dys-hagia can be managed by placement of another stent orumor ablation using a variety of endoscopic modalities,ncluding laser therapy, argon plasma coagulation ther-py, and PDT.287–290 Care must be taken to avoid dam-ging the indwelling stent when thermal modalities aresed.There are conflicting reports on whether stent-relatedorbidity is increased in patients who have been treated

reviously with radiation and/or chemotherapy. Sometudies have shown an increased rate of stent-relatedife-threatening complications in patients who have hadrior chemoradiation therapy, whereas others haveot.272,285,291–295 Data are limited regarding the use ofalliative chemoradiation therapy after insertion oftents. In a small study of 29 patients, the group ofatients undergoing chemoradiation therapy followingtent placement survived longer (median, 331 days vs57 days; P � .05) than the stent-only group.296 On thether hand, a high risk of major complications was notedn patients undergoing radiotherapy after stent place-ent.297 The major complications found were creation oftracheal-esophageal fistula and massive hematemesis

rom stent erosion into the aorta. Placement of SEMSefore radiation therapy should be performed with cau-ion. Comparisons between available studies are difficultecause of differences in types of stents used and studyesigns.Stents are ideal for obstructing midesophageal cancers.

ollowing stent placement, patients are advised to mod-fy their diet and avoid solid boluses (e.g., meat andread) that could potentially become impacted withinhe stent. Stents that straddle the esophagogastric junc-ion may lead to severe reflux symptoms. Therefore, strictntireflux lifestyle precautions and administration of an-isecretory medications (ie, proton pump inhibitors) are

Wallstent IIa Z-Stentb

Elgiloy Stainless steelMesh ZigzagYes Yes�� 18 3110, 15 8, 10, 12, 1428 2520 1830 0–10Yes Yes

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uced Dua stent (Z-stent with a windsock-like antirefluxalve) is limited, but the device seems beneficial inalliating dysphagia and controlling reflux in patientsith distal esophageal cancers.298,299 Stenting of esoph-

geal cancers in proximity of the upper esophagealphincter can be problematic, although tumors involvinghe cervical esophagus occur in �5% of all patients.300

mall case series have reported successful placement ofEMS to palliate cancers within 2 cm of the uppersophageal sphincter, although this can be technicallyhallenging.292,301 Complications may include foreignody sensation, oropharyngeal aspiration, and trachealompression with airway compromise.285 Stent place-ent in this setting should only be attempted by an

xperienced operator, or alternative modalities should beonsidered.

Stents can be effective for palliating dysphagia second-ry to malignant extrinsic compression. Covered stentsan also be used to treat malignant tracheoesophagealstulas and constitute a unique advantage over otherndoscopic modalities in this setting. Covered SEMS areonsidered a primary form of therapy for this ominousondition. Successful closure of malignant tracheoesoph-geal fistulas using covered SEMS is seen in 90%–100%f patients.293,295,301,302 Patients with persistent tracheo-sophageal fistulas despite esophageal stenting may ben-fit from airway stenting (double stenting) to close thestula303 or esophageal bypass in surgically fit pa-ients.304 Malignant esophageal obstruction associatedith perforation during endoscopic procedures may bealliated successfully with covered SEMS.305

Intratumoral injection of absolute alcohol results inissue necrosis and sloughing. The technique is cheap,idely available, and relatively simple to perform. The

clerosant is typically injected in 0.5- to 1-mL aliquotssing a standard sclerotherapy needle, targeting exo-hytic parts of the tumor. Experience accrued from caseeries shows an initial success rate of 80%–100% inmproving dysphagia. However, the palliative effect ishort-term (�1 month), and repeated sessions are usuallyequired in most patients.306–310 Chest pain is commonfter therapy. Serious complications, including medias-initis and tracheoesophageal fistulas, occur in up to 5%f cases.308 Standardized dosimetry and local control ofherapy are problematic due to leaking at the injectionite or tracking of the sclerosant along tissue planes.lcohol injection is probably best reserved for short,rotuberant, and nonfibrotic tumors that are not amena-le to other endoscopic palliative therapies. Preliminaryeports of intratumoral injection of cisplatin/epinephrineel have shown limited and short-lived efficacy of the
ocally administered chemotherapeutic agent in relieving fi
ysphagia.311,312 This form of injection therapy remainsxperimental at this time.

Similar to injection therapy, short exophytic tumorsre more conducive to thermal modalities, which includeipolar electrocoagulation, argon plasma coagulation,nd laser therapy. The use of bipolar electrocautery (BI-AP probe) for esophageal tumor ablation has beenescribed but made unpopular by more user-friendly andqually effective thermal modalities such as the Nd:YAGaser.313–315

Argon plasma coagulation therapy is a form of non-ontact monopolar electrocautery delivered to tissue viaonized, electrically conductive argon gas. Palliation ofysphagia can initially be achieved in most patients withnoperable cancer, but the median range between rein-erventions is approximately 1 month, with an average of

treatment sessions per patient.316 Despite the limitedepth of injury achieved by argon plasma coagulation�2 mm), perforations have been reported to occur in%–2% of treatments. In one study, one third of theatients eventually required esophageal stenting as anlternative mode of palliative therapy.316 There is limitedenefit in treating advanced bulky tumors with argonlasma coagulation. On the other hand, argon plasmaoagulation may be helpful in controlling tumor bleed-ng and in staving off tumor ingrowth or overgrowthssociated with metal stents.

The Nd:YAG laser causes deeper injury than argonlasma coagulation because it vaporizes tissue to recana-ize the obstructed lumen. Short-segment exophytic le-ions are ideal for laser therapy. The procedure is usuallyepeated 48 hours later for further treatment and de-ridement. Laser application is preferably performed in aetrograde fashion, which usually requires prelaser dila-ion for passage of the endoscope through the obstructedumen.317 Tumors that are close to the upper esophagealphincter may be more amenable to laser therapy thantenting. However, laser therapy is less successful thantenting for tumors involving the esophagogastric junc-ion and cardia.318 Laser therapy is 70%–95% effective atelieving dysphagia.317,319,320 The duration of responseanges from 1 to 2 months, but multiple sessions aresually required due to tumor regrowth.321 Response cane enhanced by external beam radiation or brachythera-y.322–324 Minor complications of laser therapy includehest pain, transient worsening of dysphagia from treat-ent-related edema, and leukocytosis. Major complica-

ions include bleeding, perforation (0%–5%), and tra-heoesophageal fistula (0%–6%). Laser equipment isxpensive and may not be widely available. Unlike stent-ng, laser therapy is contraindicated in the presence of
stulas; is generally not suitable for long, tortuous, cir-

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umferentially narrowed tumors; and is not applicableor dysphagia caused by malignant extrinsic compres-ion.

PDT has also been applied as a palliative technique forhe management of malignant dysphagia.325,326 PDT isot limited to bulky tumors; infiltrative or flat tumoralreas as well as long-segment tumors may be amenable toDT. In addition, PDT using sodium porfimer may beasier to apply in cervical esophageal cancers than laserherapy or stenting. The response rate in dysphagia im-rovement ranges from 60% to 90%. Acute complica-ions (5%–20%) include chest pain, odynophagia, nau-ea, fever, leukocytosis, and pleural effusion.259 A majorbstacle to the use of sodium porfimer/PDT in advancedsophageal cancers is the duration of skin photosensitiv-ty (4–6 weeks) associated with the therapy. This is aignificant problem in a palliative setting. Costs relatedo initial purchasing of equipment and photosensitizersre additional drawbacks. PDT using aminolevuliniccid is attractive because of its limited duration of pho-osensitivity (48 hours), but this therapy has more lim-ted depth of tissue necrosis. PDT with hematoporphyrinerivative (which is a compound similar to sodium por-mer) was significantly more effective than aminolevu-inic acid in a nonrandomized study of 49 patients,327

odium porfimer is the only currently approved photo-ensitizer for gastrointestinal use in the United States.

Studies comparing various endoscopic modalities foralliation of malignant dysphagia are few and conflict-ng. Retrospective studies comparing laser therapy withtenting have shown similar outcomes with regard toelief of dysphagia but higher complication rates in thetent group.328,329 These studies are limited by theiretrospective design and heterogeneous patient popula-ions. On the other hand, a prospective, randomized,ontrolled trial of laser therapy versus SEMS in 60 pa-ients with previously untreated esophageal cancer dem-nstrated a significant improvement in the degree ofysphagia and a reduction in the reintervention rate35.7% vs 100%) in favor of SEMS.282 A smaller pro-pective randomized study of 39 patients evaluatingEMS versus laser therapy combined with radiotherapyhowed the former to be more cost-effective.330 A studyf 65 patients, however, showed longer survival rates inatients undergoing thermal ablative therapy (laser pre-ominantly) compared with those who received stent-ng.331 Stenting cost less but was associated with areater deterioration of health-related quality of life. In 2mall prospective randomized trials comparing laserherapy with injection therapy, no significant differencesere noted with regard to improvement in dysphagia

core or complication rates.332,333 a

In a prospective randomized study involving 236 pa-ients, PDT and laser therapy were similarly efficaciousn terms of dysphagia relief, although there was a trendoward a better response with PDT for tumors located inhe upper and middle third of the esophagus and for longumors.325 PDT was associated with fewer perforationshan with laser therapy (1% vs 7%). However, PDT wasimited by photosensitivity in 19% of cases. Terminationf sessions due to adverse events occurred in 3% withDT versus 19% with laser therapy.Nutritional support is often required in support of

atients with esophageal carcinoma. There is evidencehat enteral nutrition is beneficial in patients with dys-hagia and in those receiving radiation therapy.334 En-eral nutrition is generally preferred to the parenteralpproach. A randomized prospective study was per-ormed using these 2 approaches in patients who under-ent surgery for gastrointestinal tumors.335 Althoughnly 10% of the 257 patients had esophageal cancer, theesults showed that enteral nutrition was less expensivend improved gut perfusion. Enteral nutrition can beccomplished by feeding tubes that can be placed withasogastric or nasojejunal approaches, although theseypes of tubes are associated with increased bodily con-erns by patients and could limit their social interac-ions.336 Percutaneous gastrostomy or jejunostomy tubesre preferred because there is less social stigma and theubes are better tolerated. A retrospective study of per-utaneous gastrostomy tubes in 229 patients with esoph-geal cancer found that they could be placed in 97% ofatients, although dilation was required in 45% of pa-ients, with 2 having fatal adverse events from perfora-ions.337 Although only anecdotal, radiologists have ad-ocated radiologic placement of fielding tubes in patientsith oropharyngeal cancers to decrease the possibility of

tomal metastasis.338

Finally, palliative care of patients with esophagealancer requires the involvement of physicians who arettentive to both physical and emotional needs. Dyspha-ia is a symptom that has significant impact on a pa-ient’s perception of health, as demonstrated in a recenttudy of health state utilities in 50 patients with esoph-geal cancer.339 Many patients feel abandoned by physi-ians after medical therapy has been unsuccessful andurther interventions are no longer indicated. These pa-ients require support from hospice personnel and de-erve physician attention and compassion. Until esoph-geal cancer can be effectively treated, compassion maye one of the most important “therapies” we can offer foralliation of this disease.Summary of Evidence—Endoscopic therapy is effective

t alleviating dysphagia. However, the selection of a

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articular endoscopic technique should be based on tu-or characteristics, patient preference, and available ex-

ertise. Esophageal dilation results in short-lived pallia-ion and is best used as an adjunct to other palliativeodalities (based on level III evidence). Esophageal

tenting is the preferred endoscopic modality in patientsith long malignant strictures more than 2 cm from thepper esophageal sphincter and/or with fistulas (alsoased on level III evidence). There is level I evidence thatEMS are superior to conventional semirigid plastictents in the management of malignant dysphagia. Otheralliative methods such as alcohol injection, laser ther-py, and PDT are similarly efficacious as tumor ablativeherapies (based on level II evidence).

Future Directions

It is clear that further research is needed in theetection, prevention, and treatment of esophageal car-inoma. The cause of the continued increase in incidencef adenocarcinoma of the esophagus still remains unde-ned. The need to stratify patients for esophageal cancerisk is essential to implement treatment and preventiontrategies. Although histologic evidence of dysplasia haseen the gold standard to define cancer risk, this is veryard to reproduce and is difficult to detect withoutaborious biopsy protocols. Biomarkers for cancer riskould be very attractive but will require large prospec-

ive studies to validate. Chemoprevention would be aiable strategy for patients at lower risk for developmentf cancer, and NSAIDs might a fruitful candidate. How-ver, due to the low risks for cancer, very large patientrials will be required to demonstrate benefit. In patientst high risk for cancer, ablative therapies have beenpplied with some initial promising results. The clinicalignificance of reduction of the amount of Barrett’s mu-osa, elimination of dysplasia, and development of subs-uamous areas of Barrett’s mucosa needs to be defined.he detection and staging of esophageal cancers could be

mproved with the advent of higher-resolution imagingodalities such as OCT and fluorescence spectroscopy.oth of these entities require further development before

hey can be clinically applied. Endoscopic therapy ofarly cancers seems to be achievable, but large prospec-ive studies are needed to define the best methods and toetermine the long-term outcome. Surgical therapy isvolving toward less invasive approaches, but improve-ents in chemotherapy and radiation might decrease the

eed for resection in advanced cancers. Palliation is re-uired for the majority of patients with esophageal can-
er, and the development of newer stents that prevent
eflux and conform better to the esophagus would beeneficial to patients.

Summary

Esophageal cancer is increasing in incidence and isssociated with a high mortality rate. The ability ofastroenterologists to increase survival in this diseaseill depend on earlier detection through screening and

urveillance strategies. Early cancers can be staged withUS and endoscopic mucosal resection. More advancedancers will require the addition of CT and possible PET.reatment of early cancers is increasingly shifting towardndoscopic treatment. More advanced but localized can-ers can be treated by surgical resection. Cancers withegional lymphadenopathy may require neoadjuvant che-otherapy and radiation therapy. Patients with more

dvanced cancers may respond to primary therapy withadiation and chemotherapy. Palliation of esophagealancers is based on stent therapy, but physicians shoulde attentive to the emotional needs of the dying patient.he future of therapy for esophageal cancer may rest with

he development of chemoprevention methods, althoughhere is not substantial evidence to support its use at thisime.

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Address requests for reprints to: Chair, Clinical Practice and Economicsommittee, AGA National Office, c/o Membership Department, 4930 Delay Avenue, Bethesda, Maryland 20814. Fax: (301) 654-5920.This literature review and the recommendations herein were pre-

ared for the American Gastroenterological Association Clinical Prac-ice and Economics Committee. The paper was approved by the Com-ittee on January 31, 2005, and by the AGA Governing Board onarch 20, 2005.The Clinical Practice and Economics Committee acknowledges the

ollowing individuals whose critiques of this review paper providedaluable guidance to the authors: David E. Fleischer, MD, Richard A.
ozarek, MD, and Gottumukkala S. Raju, MD, MRCP.

american gastroenterological association technical review on

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