American Gastroenterological Association Technical Review on the Role of the Gastroenterologist in the Management of Esophageal Carcinoma
Article Outline
- Significance of Esophageal Cancer
- Screening and Surveillance for Esophageal Cancer
- Chemoprevention for Esophageal Cancer
- Diagnosis and Staging of Esophageal Cancer
- Treatment of Esophageal Cancer
- Palliation of Esophageal Cancer
- Future Directions
- Summary
- Acknowledgment
- References
- Copyright
Abbreviations used in this paper: CI, confidence interval , CT, computed tomography , EUS, endoscopic ultrasonography , FDA, Food and Drug Administration , Nd:YAG, neodymium:yttrium-aluminum-garnet , OCT, optical coherence tomography , PAR, population attributable risk , PDT, photodynamic therapy , PET, positron emission tomography , QALY, quality-adjusted life year , SEMS, self-expanding metal stents
The goal of this evidence-based review was to examine the clinical practice of the gastroenterologist in the management of patients with esophageal carcinoma. The methods for this review were to search and review the literature available on MEDLINE and PREMEDLINE on the topics of esophageal neoplasm, esophageal cancer, and Barrett’s esophagus from 1968 to 2004. Bibliographies of significant reports were also reviewed to ensure that the pertinent literature was reviewed. Recommendations are graded as to the level of evidence available on a scale of I–V. Level I evidence is the presence of at least one prospective, randomized, controlled trial, level II evidence is based on well-designed cohort or case-controlled studies, level III evidence is based on case series or flawed clinical trials, level IV evidence is based on opinions of respected authorities or expert committees, and level V evidence is insufficient evidence to form any opinions.
Significance of Esophageal Cancer
Esophageal cancer is associated with one of the highest cancer mortality rates in the United States. In 2000, the last year of complete data available from the national cancer Surveillance, Epidemiology, and End Results database, the 5-year relative survival rates from esophageal cancer were the fifth lowest at 15.4%. In addition, the incidence of esophageal cancer is still significantly trending upward in white men with a 0.4% annual percentage increase from 1992 to 2000. This can be compared with colon cancer, which has actually had a significant decrease of 0.9% annual percentage change over the same period. Esophageal cancer is a predominantly male condition with a male/female incidence of 3.6:1. Esophageal cancers affect older patients, with the peak incidence in those 65–74 years old. It is estimated that, in 2003, there were 13,900 new cases of esophageal cancer and 13,000 deaths due to esophageal cancer. The mortality rate of esophageal cancer is significantly higher in minority populations than in white people.
There are 2 major types of esophageal cancer: adenocarcinoma and squamous cell cancer. The primary known risk factors for adenocarcinoma of the esophagus are smoking, chronic gastroesophageal reflux disease, and Barrett’s esophagus. Known risk factors for squamous cell cancer of the esophagus include smoking, alcohol use, exposure to nitrosamines, ingestion of lye, Fanconi’s anemia, achalasia, Plummer–Vincent webs, and tylosis.
Screening and Surveillance for Esophageal Cancer
Screening for Esophageal Cancer
AdenocarcinomaScreening for esophageal cancer depends on the determination of the patient’s risk for cancer, the cost and efficacy of the screening procedure, the stage at which the cancer can be diagnosed, and the treatment options available. At the current time, there is no direct evidence that has validated the use of screening for esophageal cancer in the United States. Screening for esophageal adenocarcinoma has been primarily focused on the detection of Barrett’s esophagus with subsequent surveillance. Although screening for Barrett’s esophagus has not been proven to decrease the risk of cancer, it has become accepted that surveillance for Barrett’s esophagus can detect disease at earlier stages.1, 2, 3 Barrett’s esophagus has traditionally been found to be associated with chronic gastroesophageal reflux disease, and case series have found increasing incidences of Barrett’s esophagus depending on the number of years of reflux symptoms.4 However, a single-center study of 110 subjects found that 7% of asymptomatic individuals had long-segment (>3 cm) Barrett’s esophagus.5 A multicenter study of 536 subjects found that long-segment Barrett’s esophagus was only present in 0.36% of subjects, although short-segment Barrett’s esophagus was found in 5.6%.6 This study did find that patients with heartburn had a significantly higher prevalence of long-segment Barrett’s esophagus than those who did not. This is significant because past studies have shown that the degree of neoplasia found in Barrett’s esophagus appears to be correlated with the length of Barrett’s esophagus.7 Other groups that may be at risk would include those with familial occurrence of adenocarcinoma, but this has only been described in a limited number of families. The cost-efficacy of screening family members because of a history of Barrett’s esophagus has not been demonstrated.8, 9, 10, 11, 12
Screening methods for detection of Barrett’s esophagus have included standard endoscopy, unsedated endoscopy with ultrathin endoscopes, catheter-based cytology, and balloon cytology.13, 14, 15, 16 Although preliminary studies indicate some promise with these technologies in terms of screening for adenocarcinoma, there have not been any definitive trials to allow recommendation of these techniques.
Squamous cell cancerScreening for squamous cell cancer in the general population of the United States cannot be justified because of the low incidence of this form of cancer. However, specific subgroups may be identified that warrant screening endoscopy for squamous cell cancer. The most likely to benefit from screening would be those who have tylosis, which is a genetic defect in the 17q25 region that is found in patients with thickened palms and soles.17, 18 This group is likely to develop cancer by the age of 65 years and should undergo screening for squamous cell cancer. Patients with lye-induced or caustic strictures develop cancers approximately 46 years after ingestion and have been described to have an 8% incidence of cancer.19, 20 The development of cancer in patients with long-standing achalasia is infrequent, especially in women, and it is unclear if surveillance is warranted in these patients.21 Most patients with achalasia are found to have prevalent cancers because they are usually diagnosed when obstruction and esophageal dilation are found.22 Fanconi’s anemia has also been associated with the development of esophageal cancer and may become more common as patients survive longer after bone marrow transplantation.23 Patients with existing aerodigestive tumors, especially those of the oral cavity, who have had long-term extensive exposure to alcohol and tobacco might benefit from screening for cancers of the esophagus, although the rationale for this is based on case series.24 Screening for esophageal cancer should be performed at the time of diagnosis of the head-and-neck cancer. Extensive alcohol consumption alone has been found to be an important criterion for screening in Asian patient populations.25 Partial gastrectomies have been associated with an increased incidence of squamous cell cancers of the esophagus; these reports stem from areas of the world where squamous cell cancer is commonly found, and there is no convincing evidence to support the screening of patients in the United States.26 The occurrence of squamous cell cancer is not decreasing in minority populations in the United States and remains the most frequent form of esophageal cancer in black and Hispanic populations.27, 28 Other conditions such as Plummer–Vinson webs have also been identified as being associated with an increased risk for squamous cell cancers, but the decreasing frequency of these webs makes this almost a historical footnote in Western countries.29
Screening methods such as cytologic balloons or sponges for screening for squamous cell cancers have been extensively tested in Asia. Balloons appear to be better than sponges, with an increased sensitivity of 44% compared with 18% for sponges.30 This technology has been used as the primary screening tool in high-risk areas of China.31
Summary of Evidence—There is level III evidence that endoscopic screening of male white patients older than 50 years of age with symptoms of gastroesophageal reflux may be cost-effective. Patients with tylosis, lye-induced strictures, or Fanconi’s anemia would benefit from screening endoscopy for squamous cell cancers (level III evidence). In addition, patients with long-term tobacco and alcohol use, achalasia, or prior head-and-neck cancers could be considered for screening, depending on their other risk factors (level III evidence). The interval for surveillance of these patients has not been established, but yearly investigations would seem to be reasonable (level IV evidence).
Surveillance for Esophageal Cancer
Significance of surveillanceThe importance of Barrett’s esophagus derives from its association with esophageal adenocarcinoma.32, 33 Approximately 5%–10% of patients diagnosed with Barrett’s esophagus may develop esophageal adenocarcinoma based on older studies.32, 34, 35 The incidence of cancer will most likely decrease with the increasing detection of Barrett’s esophagus through screening programs. Surveillance of Barrett’s esophagus can detect dysplasia in Barrett’s esophagus, which can predict the risk of future diagnosis of esophageal cancer in these patients.36, 37
The incidence of cancer in patients with Barrett’s esophagus is low in general, which makes surveillance cost-ineffective unless at-risk populations can be identified.38, 39 At the current time, dysplasia is used as the primary means to discriminate at-risk patients. A systematic endoscopic biopsy protocol, generally accepted to be 4 quadrant biopsy specimens taken every 2 cm of Barrett’s mucosa, can provide tissue for histologic diagnosis of dysplasia. The grading system used to classify dysplasia in Barrett’s esophagus is based on the system developed for ulcerative colitis.40, 41, 42 Although molecular markers have shown promise, dysplasia is currently the best indicator for the risk of cancer. Increasing grade and extent of dysplasia are associated with increasing risk of cancer.37, 43, 44, 45, 46, 47, 48 Information from several prospective studies and a Barrett’s esophagus registry provide a total of 783 patients with a follow-up of 2.7–7.3 years.37, 43, 45, 47, 49, 50 These combined series indicate that 2% of patients without dysplasia progressed to cancer. Progression from low-grade dysplasia to cancer was noted in 7% of patients and from high-grade dysplasia to cancer in 22% of patients. Unfortunately, it is difficult to obtain true cancer incidence per year of observation based on the data provided in these series. It is also apparent that low-grade dysplasia had a wide range of rates of progression between the series. This may be because of the variability in interpretation of low-grade dysplasia.46
Other findings on endoscopy that have been shown to predict the development of esophageal cancer include the presence of any mucosal abnormalities noted on endoscopy and the extent of high-grade dysplasia noted on histology.48 The presence of mucosal nodularity has been associated with a 2.5-fold increased risk of cancer development in patients with high-grade dysplasia (P = .01). Focal high-grade dysplasia, defined as involvement of ≤5 crypts in one biopsy specimen from the entire set of biopsy specimens, has been found to be associated with significantly less risk of cancer development than those with greater amounts of high-grade dysplasia (P = .02).48
Unfortunately, the classification of dysplasia is subjective and does have significant observer variation. Interobserver pathologic agreement can improve to 85%–87% when the degree of dysplasia is placed in a 2-tier system. This is done by combining high-grade dysplasia and intramucosal carcinoma in one category and low-grade dysplasia, indefinite for dysplasia, and no dysplasia in another.51 This was substantiated by a recent study using a group of expert pathologists.52 In this study, when analysis was performed using 2 broad diagnostic categories (Barrett’s esophagus without dysplasia, indefinite and low-grade dysplasia vs high-grade dysplasia and carcinoma), intraobserver agreement was near perfect (mean κ = 0.82 and 0.80) and interobserver agreement was substantial (κ = 0.66–0.70). When the analysis was performed using the 4 separate classifiers (Barrett’s without dysplasia, indefinite for dysplasia and low-grade dysplasia, high-grade dysplasia, and carcinoma), the mean intraobserver κ was once again substantial (0.64–0.68) but the mean interobserver κ was only 0.43–0.46 (moderate agreement). Because of this difficulty in determining the presence of dysplasia, using recent recommendations to screen and perform surveillance only if dysplasia is found may be ineffective if histologic interpretation is not accurate.53
Despite the difficulties with surveillance, the detection of high-grade dysplasia or early cancer has been shown to have the potential to improve survival in patients with Barrett’s esophagus.54, 55 Cancers confined to the esophagus are associated with a 5-year survival rate of 70% compared with a survival rate of 20% for patients with more invasive cancers.56 Nodal involvement, which helps determine prognosis, is far less likely to occur in patients who are found to have cancer on surveillance endoscopies compared with those patients who are not undergoing surveillance.1, 3, 56, 57 This leads to significantly improved survival in surveyed patients compared with those patients who underwent surgery for symptomatic disease. Retrospective studies of patients in surveillance programs suggest that the patients with incidental cancers detected during surveillance are likely to have earlier staged disease than those who present because of symptoms.58, 59 Although these case series seem convincing, there are several concerns. Many of the retrospective studies compared patients in surveillance groups with historical controls. Patients of advanced age or with significant comorbidity are less likely to be enrolled in a surveillance program. On the other hand, subjects enrolled in surveillance programs might have healthier lifestyles, might have health-seeking behaviors, or were selected because of overall better health status. Survival differences between these 2 groups may well be due to selection bias. In addition, earlier detection of cancer can lead to a false increase in survival time because of lead-time bias, which results from an early diagnosis of preclinical cancer rather than any true effect of detection on subsequent mortality.
In at least 2 small surveillance cohorts, esophageal cancer has been reported to be an uncommon cause of death in patients with Barrett’s esophagus.60, 61 Therefore, the morbidity and mortality from surveillance and subsequent treatment might overshadow any advantage that surveillance provides by early detection of cancer. However, a retrospective population-based cohort study of endoscopic surveillance in 23 patients with Barrett’s esophagus among 589 patients with adenocarcinoma found an improved survival benefit.62 Eleven of 15 patients who were diagnosed with cancer while in surveillance programs were alive compared with none of 8 patients not under surveillance. None of the deaths in the surveillance group were from cancer compared with 4 deaths in the nonsurveillance group that were directly related to cancer. Three patients in the surveillance group and one patient in the nonsurveillance group died as a result of complications of surgery.
Allocation of resources based on risk stratification has the potential to make surveillance more cost-effective. A recent decision analysis model examined the cost-utility ratio for different surveillance strategies.38 A cohort of 50-year-old patients with Barrett’s esophagus without dysplasia was evaluated for surveillance strategies every 1–5 years and no surveillance, with esophagectomy performed if high-grade dysplasia was diagnosed. This study suggested that, with an annual cancer risk of 0.4%, surveillance every 5 years was the only cost-effective strategy. More frequent surveillance was associated with more cost and yielded a lower life expectancy. The incremental cost-utility ratio for surveillance every 5 years was $98,000 per quality-adjusted life year (QALY) gained, comparable to the incremental cost-effectiveness ratios of accepted practices.
Another detailed cost-utility analysis assessed the strategy of surveillance of Barrett’s esophagus detected during screening.53 The strategy of surveillance of only patients with dysplasia appears to be cost-effective relative to other currently accepted medical practices. The strategy yielded an incremental cost-effectiveness ratio of $10,440 per QALY saved compared with no screening. A strategy of no screening would incur direct medical costs of caring for those developing cancer of $16 million. Screening and surveillance of patients with dysplasia would prevent 2580 deaths caused by esophageal adenocarcinoma at a cost of $262 million. Fifty-nine patients would need to be screened and surveyed to prevent one death from cancer. Although this model was thorough, it is limited by several assumptions, such as that surveillance for patients with high-grade dysplasia can cease after 2 years and that there are no adverse effects on the quality of life of patients undergoing surveillance, which other studies have shown to be decreased.63
Biopsy methodPatients who are undergoing surveillance should follow a systematic endoscopic biopsy protocol after they are free from esophagitis.64 The evidence for this is based on expert opinion, limited data, and the outcome of cohorts of patients managed empirically. Biopsy specimens are first taken from any mucosal abnormality, followed by rigorous sampling from each of the 4 quadrants of the esophagus every 1–2 cm starting at the gastroesophageal junction and stopping at the squamocolumnar junction using standard or jumbo biopsy forceps. The goal is to determine if the patient has high-grade dysplasia or early cancer so that appropriate management can be initiated. The effectiveness of taking 4-quadrant biopsy specimens every 1 cm along the length of the Barrett’s segment with jumbo biopsy forceps instead of the traditional standard biopsy forceps has been assessed.42 In a retrospective analysis of the Seattle protocol, it was shown that taking 4-quadrant biopsy specimens every 2 cm would have missed 50% of the cancers that were found by taking 4-quadrant biopsy specimens every 1 cm.65 Jumbo biopsy forceps acquire more tissue in a single biopsy than regular biopsy forceps and have not been associated with increased complications.66 The use of jumbo biopsy forceps has not been shown to decrease the number of samples necessary for surveillance, and they require the use of a therapeutic endoscope. The need for use of jumbo biopsy forceps has been questioned, and one study found no statistical difference in the rate of unsuspected cancers found at esophagectomy when patients with Barrett’s esophagus with high-grade dysplasia underwent preoperative endoscopy using jumbo biopsy forceps versus standard biopsy forceps.67
It is generally accepted that patients with mucosal abnormalities in Barrett’s esophagus should undergo endoscopic mucosal resection to increase detection of neoplasia. In one small series, endoscopic mucosal resection of suspicious lesions diagnosed superficial adenocarcinoma in 13 patients (52%) and high-grade dysplasia in 4 (16%) of 25 patients with Barrett’s esophagus.68
Methods of surveillanceSeveral methods have been studied to perform surveillance. These include brush cytology, chromoendoscopy, magnification endoscopy, and optical imaging techniques. All of these techniques have certain potential advantages over routine biopsy.
Brush cytology
Brush cytology has been advocated in the surveillance of patients with Barrett’s esophagus because it is faster to perform and it can sample more than the 1% of the total Barrett’s mucosal area typically achieved with standard biopsy. The diagnostic value of cytology in patients with Barrett’s esophagus was assessed using 66 pairs of endoscopic biopsy specimens and cytology specimens.69 Cytologic analysis was used to correctly identify 7 of 8 esophageal cancers, with one false-negative sample described on analysis as highly suspicious for cancer. In other studies, cytologic brushing was found to be a complementary technique in detecting serious Barrett’s lesions when combined with the histologic examination of esophageal biopsy specimens.70, 71 However, there was only 72% (47/65) concordance between the 2 diagnostic techniques. In the 18 cases that were discordant, cytologic analysis diagnosed 13 at a higher level of abnormality than the biopsy diagnosis and underdiagnosed 5. There is potential to further improve the efficacy of cytology by using objective assessment tools such as digital image analysis, which involves a computerized analysis of the digitized microscopic image.72, 73 This has been demonstrated in China, where quantitative DNA fluorescence has been found to enhance detection of squamous cell cancers when applied to cytology taken in a high-risk population.74 As mentioned previously, balloon cytology for the surveillance of squamous cell cancers has become an accepted part of practice in high incidence areas, although such devices have not been shown to be beneficial in Western populations.30, 75
Chromoendoscopy
Chromoendoscopy involves the topical application of dyes during endoscopy in an effort to enhance the detection of mucosal patterns or lesions on the basis of their staining characteristics.76 Stains are classified as vital (absorptive), contrast, or reactive, according to their mode of action. Vital stains (e.g., Lugol’s solution and methylene blue) enter specific cell types by preferential absorption or diffusion across the cell membrane. Contrast stains (e.g., indigo carmine and acetic acid) seep into mucosal interstices to highlight mucosal topography. Reactive stains chemically react with cellular constituents.
The body of the literature regarding chromoendoscopy in the esophagus consists primarily of staining with Lugol’s solution for detection of squamous dysplasia and superficial carcinoma and staining with methylene blue for assessment of Barrett’s esophagus. Lugol’s solution is an iodine-based vital dye that has an affinity for glycogen contained in nonkeratinized squamous epithelium. Chromoendoscopy with Lugol’s solution has been used primarily to screen individuals at high risk for squamous cell cancer.77, 78, 79, 80 The application of Lugol’s solution during endoscopy is not standardized, with nonuniform concentrations (1%–3%) and volumes (10–50 mL) as well as variable definitions of “unstained” areas that merit biopsy.77, 78, 79, 80 Despite these differences, these studies in aggregate show unstained lesions to have a high sensitivity (91%–100%) and moderate specificity (40%–95%) for squamous dysplasia and carcinoma.77 Lesions are found to be more clearly defined and can be significantly larger after staining,81 providing critical information, particularly if local therapy, such as endoscopic mucosal resection, is contemplated. Studies of chromoendoscopy with Lugol’s solution in Western populations are sparse. A prospective analysis of a French cohort of 158 alcoholic and/or smoking patients showed no significant advantage of staining with Lugol’s solution relative to the visual diagnostic accuracy achieved by videoendoscopy alone.81 Lugol’s-assisted endoscopy may be useful in populations living in highly endemic regions for esophageal squamous cell cancer.
Methylene blue stains absorptive cells (intestinal-type epithelium), including specialized intestinal metaplasia, but does not stain normal squamous or gastric epithelium. Methylene blue may be particularly useful in the diagnosis of short segments of columnar-lined esophagus.82 Other uses include identifying dysplastic foci within Barrett’s epithelium and identifying residual foci of Barrett’s esophagus following mucosal ablative therapy. Chromoendoscopy with methylene blue requires pretreatment of the mucosa with a mucolytic agent, a dwell time for the dye to take effect, and a rinse phase to remove excess dye. In general, methylene blue staining adds 5–10 minutes to the procedure time, but the accessories required are inexpensive.83 Specialized intestinal metaplasia typically stains blue, while a “lighter” intensity and increased heterogeneity in the staining pattern predict high-grade dysplasia and/or cancer.84 Focal unstained areas may represent dysplastic foci within a background of heterogeneous methylene blue staining.85 These findings, however, are not consistently replicated in other studies, and the reproducibility of staining patterns among Barrett’s tissue types remains debatable.86 This technique has been used to allow the gastroenterologist to perform fewer biopsies to find significantly more dysplasia or cancer in a biopsy specimen (12% vs 6%) compared with the random biopsy technique.85 However, 2 prospective trials comparing the methylene blue–guided biopsy technique with the random biopsy technique found no significant differences in the detection of dysplasia or early cancer between the 2 techniques.87, 88 Methylene blue has also recently been shown to induce oxidative damage of DNA because of photoactivation of the dye by the white light of the endoscope, which certainly increases the risk of its use in premalignant tissue.89
Magnification endoscopy
Most new electronic videoendoscopes are equipped with charge-coupled device chips of high pixel density (400K), enabling high-image resolution (ability to discriminate 2 closely approximated points). Megapixel density (850K) endoscopes have recently been introduced, which may further enhance detection. Magnification endoscopy enlarges the image, which enhances mucosal detailing and is generally used in combination with chromoscopy. Magnification chromoendoscopy has been used primarily to characterize Barrett’s esophagus.90, 91, 92, 93 Ridged or villous mucosal patterns observed under magnification endoscopy using a variety of stains have been correlated with intestinal metaplasia or dysplasia in case series.91, 92, 93 Whether magnification endoscopy will decrease the need for endoscopic biopsy or significantly enhance the diagnostic yield over conventional techniques remains to be determined in large controlled trials.
Optical biopsy
Optical biopsy is a term that encompasses a variety of techniques that use light to enhance detection of dysplastic lesions. Included in this category are spectroscopic techniques and low coherence interferometry (optical coherence tomography [OCT]). Spectroscopy is a light-based diagnostic technique that exploits properties of light-tissue interactions, such as fluorescence, elastic scattering, and Raman scattering, for tissue characterization. Collected in the form of spectra, these optical (light) signals are sensitive to microstructural and/or molecular changes accompanying various stages of tissue pathology, and spectral differences can then be correlated to specific histopathologic diagnoses.
Assessment of optical spectroscopic techniques in the esophagus has been limited to small-scale, proof-of-principle studies.94, 95, 96, 97, 98, 99, 100, 101, 102 Most studies deal with fluorescence spectroscopy, which shows moderate to high sensitivity (75%–100%) and specificity (65%–95%) in differentiating high-risk (high-grade dysplasia/adenocarcinoma) from low-risk (nondysplastic to low-grade dysplasia) samples of Barrett’s esophagus.94, 95, 96, 97, 98 False positives occur in the presence of inflammatory or reactive changes.94 The range of diagnostic accuracies primarily relates to methodological differences, because the technique has yet to be optimized for Barrett’s esophagus. It is also unclear whether fluorescence spectroscopy, aided by an exogenously administered fluorescent agent with affinity for neoplastic tissues (e.g., porfimer sodium or 5-aminolevulinic acid), improves discrimination of Barrett’s epithelia over naturally occurring tissue fluorescence (autofluorescence).99, 100, 101, 103 Future comparative studies are required to address this issue. Other emerging spectroscopic techniques, including elastic scattering spectroscopy,102 Raman spectroscopy,103 and multimodal optical spectroscopy,104 have shown initial promise in differentiating Barrett’s epithelia in feasibility studies.
Fluorescence endoscopy is an extension of its spectroscopic counterpart into an imaging technique, which consists of sensitive cameras capturing the emitted fluorescence emanating from a mucosal field of view approaching that of a conventional endoscope. The obvious advantage over point spectroscopy is the ability to perform widespread assessment of the mucosa for areas likely to harbor dysplastic or early cancerous changes. Recent studies of fluorescence endoscopy, however, have showed limited diagnostic utility in Barrett’s esophagus.88, 105 In a small prospective study of 35 patients, the sensitivity and specificity of autofluorescence imaging for the diagnosis of dysplasia or cancer versus Barrett’s mucosa without dysplasia were 21% and 91%, respectively.88 A prospective, randomized, crossover study of 50 patients with Barrett’s esophagus, published in abstract form, showed no significant benefit of fluorescence-guided biopsies over a standard surveillance biopsy protocol for the detection of high-grade dysplasia and early adenocarcinoma.105 Fluorescence endoscopy is an evolving technology. Optical biopsy and imaging techniques are not yet optimized for clinical use.
OCT is analogous to ultrasonography but uses light instead of sound waves to produce high-resolution, cross-sectional imaging of tissue. The spatial resolution of 10–25 μm achieved by endoscopic OCT systems is 10-fold better than that of high-frequency ultrasonography but at the expense of a limited sampling depth (∼2 mm).106, 107, 108, 109 Current endoscopic OCT devices are catheter based (2–2.7 mm in diameter), allowing scanning of the esophagus in a linear,107 transverse,106 or radial108 fashion. Using predetermined OCT criteria for specialized intestinal metaplasia, the linear scanning OCT system was found to be 97% sensitive and 92% specific for identifying specialized intestinal metaplasia.110 A quantitative analysis of the OCT signal seemed to identify high-grade dysplasia with high sensitivity (100%) and specificity (85%) in a small retrospective study, which will require prospective validation on a larger sample size.110 Similar to spectroscopy, OCT is a technique in evolution, and further refinements are anticipated that may improve its diagnostic accuracy for the detection of preneoplastic lesions.
Frequency of surveillanceThe frequency of endoscopic surveillance in patients with Barrett’s esophagus has been debated without the benefit of well-constructed studies. Surveillance intervals recommended in this section are supported by limited evidence, which is based on our understanding of the natural history of development of esophageal adenocarcinoma depending on the grade and extent of dysplasia in Barrett’s esophagus. The goal of surveillance is to identify patients at risk and assess them in a timely fashion to prevent or detect cancer at an earlier treatable stage. Summaries of the studies that have investigated the incidence of cancer in Barrett’s esophagus appear in Table 1, Table 2, Table 3, Table 4. Patients with nondysplastic Barrett’s esophagus should undergo repeat endoscopy 1 year after the initial endoscopy. Patients with persistent nondysplastic Barrett’s esophagus should have periodic surveillance at 5-year intervals, depending on the patient’s health. The rationale of repeating surveillance twice in the first year is to diagnose any prevalent dysplasia that may have been missed during initial endoscopy. Most initial procedures that diagnose Barrett’s esophagus do not involve complete surveillance biopsies because the diagnosis has not been established. The reason to increase the surveillance interval to 5 years is based on decision analysis models showing that surveillance in this group of patients is not cost-effective. The caveat is that this recommendation is based on set assumptions made in the cost-utility model, and any major change in these assumptions in the future will require modification of the surveillance interval in patients with nondysplastic Barrett’s esophagus.38 This is different from prior gastrointestinal societal guidelines, which suggested that surveillance should be performed at more frequent intervals, but there has not been sufficient evidence to support prior recommendations.64 Therefore, we recommend ending surveillance when the anticipated life expectancy is limited (<1 year) or the patient is unable to tolerate any therapeutic measures. Even younger patients may not warrant surveillance if therapy for cancer cannot be performed.
Table 1. Diagnosis of Prevalent or Incidental Cancer on Follow-up of Patients With No Dysplasia
| Institute or geographic area | Study type | Study duration | No. of patients | Mean or median age (y) | Duration of follow-up | Total cancers (%) | Incidental cancers (%) | Comments | Reference |
|---|---|---|---|---|---|---|---|---|---|
| University of Chile, Santiago, Chile | Prospective | 1978–1991 | 152 | 52 | 100 mo (mean) | 4 (2.6) | 4(2.6) | LGD developed in 15 patients on follow-up | Csendes et al,115 1998 |
| University of Otago Medical School, Dunedin, New Zealand | Prospective | 1980–1986 | 52 | 63 | 16.4 mo (mean) | 0 | 0 | Cooper et al,182 1987 | |
| Deutsche Klinik fur Diagnostik, Wiesbaden, Germany | Prospective | 1980–1999 | 60 | 61 | 10 y (mean) | 2(3.3) | 2(3.3) | 5 patients developed LGD | Eckardt et al,340 2001 |
| University Hospital, El Palmar, Murcia, Spain | Prospective | 1982–1993 | 59 | 37 | 287 patient-years | 2(3.3) | 2(3.3) | Ortiz et al,341 1996 | |
| VA Medical Center and University of Kansas Medical Center | Prospective | — | 80 | 61 | 40 mo (mean) or 362 patient-years | 2(2.5) | 2(2.5) | One patient developed HGD, 3 had persistent LGD, 18 had transient LGD, and 56 remained nondysplastic. Patients with prevalent cancer diagnosed at entry or within the first 6 months were excluded | Weston et al,45 1999 |
| Fred Hutchinson Cancer Research Center, University of Washington | Prospective cohort | 1983–1998 | 129 | 62 | 2.4 y (median) or 3.9 y (mean) for those who did not develop cancer | 5(3.9) | 5(3.9) | 5-year cumulative incidence of cancer was reported to be 1.7% and 8-year cumulative incidence was reported to be 8.4% | Reid et al,43 2000 |
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 Single Dysplasia Category
| Institute or geographic area | Study type | Study duration | No. of patients | Mean or median age (y) | Duration of follow-up | Total cancers (%) | Incidental cancers (%) | Comments | Reference |
|---|---|---|---|---|---|---|---|---|---|
| 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 University School of Medicine, and Tufts University School of Medicine | Retrospective | 1962–1983 | 115 | 58 | 3.3 y(mean) | 11(9.5) | 2(1.9) | 4 patients had LGD at baseline; one of them progressed to HGD and finally to cancer. HGD developed in 7 patients | Spechler et al,34 1984 |
| VA Outcomes Group, Dartmouth-Hitchcock Medical Center | Retrospective | 1970–1994 | 102 | 63 | 4.8 y(median) | 3(3) | 3(3) | 8% of nondysplastic patients developed dysplasia. In 2 patients, HGD developed before cancer | Katz et al,343 1998 |
| Castle Hill Hospital, Cottingham, United Kingdom | 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 dysplasia on follow-up | Williamson et al,33 1991 |
| University of Rotterdam, Dutch cohort | Retrospective cohort | 1973–1994 | 155 | 42 | 9.3 y(mean) or 1440 patient-years | 8(5.3) | 8(5.3) | Van der burgh et al,60 1996 | |
| Helsinki University, Central Hospital, 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 underwent fundoplication; one patient developed 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 baseline and a total of 12 had dysplasia on follow-up | Iftikhar et al,347 1992 |
| Ninewells Hospital and Medical School, Dundee | Retrospective | 1976–1986 | 44 | 58 | 9.5 y(mean) | 2(4.5) | 2(4.5) | Patients were not in formal surveillance 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 one with LGD developed cancer. Five patients developed HGD, and 24 developed LGD. | O’Connor et al,50 1999 |
| Academic Medical Center, University of Amsterdam | Prospective | — | 50 | 59 | 5.2 y(mean) | 5(10) | 5(10) | 6 patients had LGD and one had HGD at 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 at esophagectomy | Streitz et al,350 1998 |
| Princess Alexandra Hospital, Brisbane, Australia | Prospective | 1981–1988 | 81 | 63 | 3.6 y(mean) | 3(3.7) | 3(3.7) | 2 patients had HGD at baseline, and both progressed to adenocarcinoma. Ten patients had LGD, and one progressed to adenocarcinoma. | Miros et al,37 1991 |
| VA Medical Center, Arizona Health Sciences Center | Prospective cohort | 1982–1995 | 177 | 62 | 4.8 y(mean) or 834 patient-years | 11(6.2) | 4(2.3) | All patients who progressed to cancer developed dysplasia before the development 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 cancer was present at baseline or within the first 6 months | Bani-Hani et al,59 2000 |
| VA Cooperative Study Group | Retrospective | 1986–1999 | 108 | 58 | 1037 patient-years | 4(3.7) | 4(3.7) | Patients were not in formal surveillance program | Spechler et al,125 2001 |
| GOSPE, Torino, Italy | Prospective cohort | 1987–1995 | 187 | — | 36 mo(mean) | 3(1.6) | 3(1.6) | 3 patients had LGD at baseline. 5 patients developed LGD, and 2 developed HGD | Ferraris et al,352 1997 |
Table 3. Diagnosis of Prevalent or Incidental Cancer on Follow-up of Patients With Low-Grade Dysplasia
| Institute or geographic area | Study type | Study duration | No. of patients | Mean or median age (y) | Duration of follow-up | Total cancers (%) | Incidental cancers (%) | Comments | Reference |
|---|---|---|---|---|---|---|---|---|---|
| VA Outcomes Group, Dartmouth-Hitchcock Medical Center | Retrospective | 1970–1994 | 24 | 63 | 4.8 y (median) | ⁎ | ⁎ | 3 patients had HGD or cancer. Cancer and HGD were pooled together | Katz et al,343 1998 |
| Fred Hutchinson Cancer Research Center, University of Washington | Prospective cohort | 1983–1998 | 43 | 62 | 2.4 y (median) or 3.9 y (mean) for those who did not develop cancer | 3 (7) | 3 (7) | 5- and 8-year cumulative incidence of cancer was reported to be 12% | Reid et al,43 2000 |
| Cleveland Clinic | Retrospective | 1986–1997 | 25 | 67 | 11 mo (median) | 2 (8) | 2 (8) | An additional 5 patients developed HGD. When pathologists agreed on the diagnosis of LGD, 7 of 17 progressed to HGD or cancer | Skacel et al,46 2000 |
| VA Medical Center and University of Kansas Medical Center | Prospective | — | 48 | 62 | 41 mo (mean) | 4 (8); one patient had definite and 3 had suspected intramucosal cancer | 4 (8); one patient had definite and 3 had suspected intramucosal cancer | 4 patients progressed to extensive HGD. 12 patients had persistent LGD. 31 patients regressed to no dysplasia Patients with prevalent cancer diagnosed at entry were excluded | Weston et al,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. |
Table 4. Diagnosis of Prevalent or Incidental Cancer on Follow-up of Patients With High-Grade Dysplasia
| Institute or geographic area | Study type | Study duration | No. of patients | Mean or median age (y) | Duration of follow-up | Total cancers (%) | Incidental cancers (%) | Comments | Reference |
|---|---|---|---|---|---|---|---|---|---|
| VA Hospital, Hines, IL | Prospective cohort | 1979–1996 | 75 | 62 | 7.3 y(mean) | 12(16) | 12(16) | 4 patients in whom cancer was detected in the first year of surveillance were excluded and considered to have prevalent cancers | Schnell et al,47 2001 |
| Johns Hopkins | Retrospective | 1982–1994 | 30 | 61 | — | 13(43) | — | Esophagectomy. No surveillance | Heitmiller et al,354 1996 |
| Fred Hutchinson Cancer Research Center, University of Washington | Prospective cohort | 1983–1998 | 76 | 62 | 2.4 y(median) or 3.9 y(mean) for those who did not develop cancer | 33(43.4) | 33(43.4) | 5-year cumulative incidence of cancer was reported to be 59% | Reid et al,43 2000 |
| University of Louisville, Louisville, KY | Retrospective | 1985–1995 | 11 | 61 | — | 8(72.7) | — | Esophagectomy. No surveillance | Edwards et al,355 1996 |
| VA Medical Center and University of Kansas Medical Center | Prospective | — | 15 | 61 | 37 mo(mean) | 7(470; 4 patients had definitive cancer and 3 had possible intramucosal cancer) | 7(470; 4 patients had definitive cancer and 3 had possible intramucosal cancer) | Patients had unifocal HGD. In 4 patients, the extent of dysplasia increased. 5 patients became nondysplastic, and 2 had LGD. Patients with prevalent cancer diagnosed at entry were excluded | Weston et al,356 2000 |
| Mayo Clinic, Rochester, MN | Retrospective cohort | 1991–1999 | 100 | 67.5 | 30 mo(mean) for focal HGD and 15 mo(mean) for diffuse HGD | 32(32%) | 13(16) after excluding cancers that were detected in the first 6 months | Patients with cancer at entry were excluded. 4 patients with focal and 28 patients with diffuse HGD were diagnosed with cancer | Buttar et al, 200148 |
Patients with low-grade dysplasia should undergo repeat endoscopy twice in the first year, and those patients who have persistent low-grade dysplasia in Barrett’s esophagus should have periodic surveillance at 1- to 2-year intervals until the age of 80 years, depending on health status. The risk of cancer development in patients with low-grade dysplasia is intermediate.46 Patients with low-grade dysplasia whose diagnosis is agreed on by 2 pathologists carry a relatively higher risk of cancer diagnosis; therefore, we recommend a surveillance interval of 1 year for this group of patients. Patients whose diagnosis of low-grade dysplasia is not agreed on by 2 pathologists but who do not have any evidence of high-grade dysplasia can be surveyed at 2-year intervals.
Patients with high-grade dysplasia in Barrett’s esophagus that has been confirmed by 2 experienced pathologists should be recommended to proceed with definitive surgical or endoscopic management, especially if the high-grade dysplasia is diffuse or mucosal abnormalities are found on endoscopy. If the patient does not wish to proceed with definitive treatment until the diagnosis of cancer is made, surveillance should be considered. Surveillance endoscopy should be repeated every 3 months in the first 2 years, followed by 6-month intervals indefinitely. The rationale for recommending immediate surgical or endoscopic therapy is that many patients may already have coexisting esophageal cancer that was not detected due to the limitations of surveillance.111 The rationale for repeating surveillance every 3 months for the first 2 years is to capture any prevalent cancers that were not detected initially. This surveillance interval should be used even if ablative procedures are performed for high-grade dysplasia or cancer because of the risk of recurrence of the disease.112, 113 The reason to increase the surveillance interval to 6 months after the first 2 years is that the majority of cancers detected in patients with high-grade dysplasia are within the first year and the risk of incidental cancer after the first 2 years of surveillance is low.47, 48 After ablative therapy, surveillance should be continued as per the preablative recommendation because the long-term consequences of ablation are as yet undetermined and because of reports of recurrent neoplasia after ablation.
Summary of Evidence—The use of surveillance in patients with Barrett’s esophagus is supported by level II evidence, although it seems that the most cost-effective approach is to target patients at higher risk for development of cancer. Surveillance should be performed using 4-quadrant biopsy specimens taken every 1–2 cm of Barrett’s mucosa, depending on the degree of dysplasia (based on level III evidence). The use of jumbo biopsy forceps in routine surveillance is not recommended based on existing evidence. The use of jumbo biopsy forceps in patients with high-grade dysplasia has not been proven to provide increased benefit. There are as yet insufficient data to recommend chromoendoscopy with Lugol’s solution over conventional videoendoscopy in Western cohorts at risk for esophageal squamous cell cancer (based on level III evidence). Methylene blue–assisted chromoendoscopy is not clearly beneficial and should not be used in the routine assessment of Barrett’s esophagus (based on level II evidence). Magnification, optical spectroscopy, and imaging techniques are still being developed and should be considered research tools at the current time (based on level III evidence). Surveillance of nondysplastic Barrett’s mucosa established by 2 endoscopies should be at 5-year intervals (based on level III evidence). Surveillance of patients with low-grade dysplasia established by 2 endoscopies should be at 1- to 2-year intervals, depending on whether or not the diagnosis is confirmed by 2 pathologists. If both pathologists concur that low-grade dysplasia is present, 1-year surveillance intervals should be used; if agreement cannot be reached (dysplasia is not believed to be present by at least one pathologist), 2-year intervals should be sufficient (based on level IV evidence). High-grade dysplasia should be confirmed in a second endoscopy and reviewed by expert pathologists. If this is confirmed, the patient can be offered surveillance at 3-month intervals for 2 years and then every 6 months (based on level III evidence). Any mucosal abnormality should be carefully investigated and removed for diagnosis. Surgical resection should be recommended and mucosal ablation with photodynamic therapy (PDT) can be offered for patients with confirmed high-grade dysplasia (based on level III evidence).
Chemoprevention for Esophageal Cancer
Acid Inhibition
Because esophageal cancer is uncommon and interventions are usually only warranted in high-risk groups, strategies for chemoprevention of this condition are being advocated. These include the use of acid suppression, nonsteroidal anti-inflammatory drugs (NSAIDs), and lifestyle modifications. Antireflux surgery or prolonged acid suppression using high doses of proton pump inhibitors result in the appearance of squamous islands in Barrett’s esophageal segment but have not consistently been shown to regress metaplastic epithelium or prevent esophageal adenocarcinoma.114, 115, 116, 117 Although the rationale for intensive antireflux therapy seems reasonable, there is not good clinical evidence to support this approach. The primary rationale for these proposals is that proton pump inhibitors incompletely suppress gastric acid and fail to completely reduce duodenal-esophageal bile reflux.118, 119 Acid and bile salts can activate several key cellular pathways in Barrett’s esophagus that are normally associated with progression of neoplasia in Barrett’s esophagus, and inhibition of these pathways may prevent the development of adenocarcinoma of the esophagus in an animal model of Barrett’s esophagus.120, 121, 122, 123 In patients with Barrett’s esophagus who were asymptomatic on acid suppressive therapy and also had normalization of intraesophageal acid exposure on pH monitoring, there was significantly more differentiation and less proliferation compared with patients who continued to have abnormal intraesophageal acid exposure.124 However, even on high dosages of proton pump inhibitors, acid inhibition may be difficult to achieve, with 4 of 25 patients having pathologic acid reflux on 80 mg/day of omeprazole.119 Fundoplication is not successful in controlling acid reflux on a long-term basis and did not prevent development of cancer, as demonstrated by a follow-up to a randomized prospective trial comparing medical with surgical therapy.125 Epidemiologic studies involving more than 66,000 patients with reflux treated medically compared with 11,000 patients treated with fundoplication in Sweden found no protective effect of surgery in decreasing the development of adenocarcinoma of the esophagus.126
Ablation Therapy
Ablation therapy in conjunction with acid control has been promoted for the treatment of Barrett’s esophagus to decrease the risk for esophageal cancer.127, 128 This is based on the observation that elimination of the metaplastic epithelium can result in squamous mucosa regeneration.129 Multiple ablation therapies have been proposed and involve the use of multipolar coagulation, argon plasma coagulation, neodymium:yttrium-aluminum-garnet (Nd:YAG) laser coagulation, and PDT. Multipolar coagulation has been performed in a prospective multicenter study with 58 patients that eliminated histologic evidence of Barrett’s mucosa in 78% of treated patients.130 Argon plasma coagulation has been used in one randomized, nonblinded, prospective trial in 40 patients after fundoplication for acid control.131 Barrett’s mucosa was initially found underneath squamous mucosa in this study in more than 35% of patients 1 month after treatment but decreased to 5% at 1 year. Patients who did not achieve complete ablation had 95% regression in the amount of Barrett’s mucosa. Multiple case series of argon plasma coagulation have been reported with significant reduction in Barrett’s mucosa and decrease in dysplasia.132, 133, 134, 135, 136, 137, 138, 139 Many ablation trials emphasize that reduction in the length or area of Barrett’s mucosa should correspond with a decreased risk for cancer, although this has not been shown in a prospective study. PDT has been approved by the Food and Drug Administration (FDA) for use in patients with high-grade dysplasia to decrease the risk of cancer formation. Case series of patients with high-grade dysplasia treated with PDT using sodium porfimer have found that dysplasia can be eliminated in 78% of patients with elimination of 75%–80% of the Barrett’s mucosa, but esophageal strictures occurred in 34% of patients.140 Unfortunately, the residual Barrett’s mucosa after ablation therapy has been found to contain genetic mutations similar to those found before ablation, suggesting that histologic improvement may not correlate with elimination of cancer risk.113 A prospective randomized trial studied PDT using 2 different dosages of 5-aminolevulinic acid (a less potent agent than sodium porfimer) followed by argon plasma coagulation compared with argon plasma coagulation alone in 40 patients.141 These investigators found that argon plasma coagulation alone or in combination with PDT was only effective in eliminating about 70% of the Barrett’s mucosa.
NSAIDs
The rationale for the use of NSAIDs to prevent cancer in Barrett’s esophagus is based on experimental and epidemiologic evidence. No randomized controlled trials have found aspirin to be effective for prevention of cancer. It has been shown that bile salts in a pH-dependent manner can activate the arachidonic acid pathway and may promote neoplasia in Barrett’s esophagus.121, 122 The activation of the arachidonic acid pathway leads to increased production of prostaglandin E2, which increases cellular proliferation.142, 143 Inhibition of prostaglandin E2 normalizes proliferation in Barrett’s epithelial cells and decreases it to a level that is seen in normal squamous epithelium.143 Inhibition of the cyclooxygenase enzyme with selective and nonselective cyclooxygenase inhibitors has been shown to reduce the risk of adenocarcinoma of the esophagus in an animal model of Barrett’s esophagus.123 Finally, cyclooxygeanse-2 expression has also been shown to parallel the progression of neoplasia in human Barrett’s esophagus.144
Epidemiologic studies have found that NSAIDs protect against the risk of esophageal cancer.145, 146, 147, 148, 149 Case-controlled studies have shown a 36%–90% relative risk reduction for esophageal cancer in patients using aspirin or other NSAIDs occasionally or on a long-term basis.145, 146, 147, 149 A decision analysis model has been used to evaluate the feasibility and cost-effectiveness of NSAIDs to prevent esophageal adenocarcinoma. It suggested that the high incidence of esophageal adenocarcinoma in Barrett’s esophagus with high-grade dysplasia renders chemoprevention a cost-effective option.150 NSAIDs were not a cost-effective measure in the general population of all patients with Barrett’s esophagus, but this was sensitive to variations in the cost of chemoprevention, the incidence of cancer, and the efficacy of the NSAID in prevention of cancer. In patients with gastroesophageal reflux, a chemopreventive approach will only be cost-effective if the agents are very safe and effective to prevent the development of adenocarcinoma of the esophagus.
Lifestyle
Lifestyle factors for the development of esophageal cancer have been identified through epidemiologic studies. Obesity seems to be one of the most important risk factors associated with esophageal cancer.151, 152 In a recently completed study of patients with esophageal and gastric cancer, smoking and dietary habits were found to be important risk factors.152 Smoking was found to have a population attributable risk (PAR) of 39.7% (95% confidence interval [CI], 25.6%–55.8%). The frequency of gastroesophageal reflux disease symptoms also showed a positive trend in the PAR, with symptoms at least once per day accounting for almost one half of the PAR associated with the presence of any gastroesophageal reflux disease symptoms (29.7%; 95% CI, 19.5%–42.3%). Consumption of fruits and vegetables less than twice a day on average had a modest PAR of 15.3% (95% CI, 5.8%–34.6%). In this population, 78.7% (95% CI, 66.5%–87.3%) of esophageal adenocarcinoma cases could be attributed to one or more of these well-established risk factors, with smoking and body mass index contributing the most.
Summary of Evidence—Based on level II evidence, fundoplication should not be recommended solely to prevent esophageal cancer in patients with gastroesophageal reflux disease. The use of high-dose proton pump inhibitors to prevent esophageal cancers in patients with gastroesophageal reflux disease has also not been established and cannot be recommended in clinical practice (based on level III evidence). Level II evidence suggests that ablation therapy may decrease dysplasia in Barrett’s esophagus and could potentially decrease cancer risk. NSAIDs should not be recommended at the current time solely for the prevention of esophageal adenocarcinoma but have promise as a chemopreventative agent, which might be beneficial if required for other medical indications (based on level II evidence). Patients at risk for esophageal cancer should be counseled to adapt healthier lifestyles, in particular attaining normal weight and eliminating tobacco use (based on level II evidence).
Diagnosis and Staging of Esophageal Cancer
Diagnosis
Most patients with esophageal cancer present at a late stage when the diagnosis of cancer is made, with dysphagia as the cardinal symptom.153 In particular, persistent dysphagia that progresses from solids to liquids should heighten suspicion for esophageal cancer and prompt an endoscopic evaluation. Up to 75% of patients have experienced anorexia and weight loss when seeking medical attention. Patients may also present with odynophagia, chest pain, or gastrointestinal bleeding. Cough aggravated by swallowing raises the possibility of an esophagopulmonary fistula, a devastating complication associated with a high 30-day mortality rate.154
The diagnosis of esophageal cancer is established by flexible endoscopy with biopsy. The features, location, and size of the tumor can be more accurately assessed by endoscopy than by radiographic studies.155 Barium swallow as an initial diagnostic test is of limited value.156, 157 However, it may be useful to confirm the presence of esophagopulmonary fistulas or document complete luminal obstruction when clinically suspected. In patients with advanced cancers, esophageal dilation may be required to allow for a standard (OD, 9.8 mm) endoscope to traverse the obstructed lumen. Alternatively, an ultrathin (OD, 5.3–6 mm) endoscope may pass through the stenosis and allow completion of the examination in 75% of cases.158
Biopsy specimens are required for histologic confirmation. The diagnostic yield reaches 100% when 6 or more samples are obtained using a standard endoscopic biopsy forceps.159, 160 Biopsy specimens of necrotic or fibrotic areas should be avoided. The adequacy of biopsy specimens obtained via ultrathin endoscopes has not been formally assessed. As an adjunct, brush cytology can be helpful in sampling tight malignant strictures, which may not be easily accessible by conventional biopsy techniques.161 Brushings should be collected before biopsy to maximize the diagnostic yield.162 Endoscopic ultrasonography (EUS) should be considered when standard biopsy and/or brush cytology fail to confirm the diagnosis in the setting of high clinical suspicion (e.g., submucosal tumors).163 Fine-needle aspiration or Tru-cut biopsy can be performed at the time of EUS.
Staging
The staging of esophageal cancer is critical to guide further therapy for the patient. Patients with cancer confined to the mucosa or superficial submucosa can be treated using surgical resection or potentially endoscopic therapy.137, 164 However, patients who have more advanced disease will require surgical resection or chemoradiation.165, 166 None of the currently available staging technologies have been shown to be able to stage all aspects of the tumor. The selection of the best staging tests depends on the probability of detecting metastatic cancer. Although endoscopy is not a staging tool, it can be helpful to guide the gastroenterologist toward which additional staging studies are needed. In one series of 209 patients, endoscopy was 89% accurate in determining tumor staging compared with surgical or EUS staging.167 Patients with large bulky circumferential tumors who present with dysphagia are likely to have advanced disease and will require tests to confirm this. Patients who have cancers that are <2 cm in diameter and are asymptomatic are more likely to have early disease. Algorithms for evaluation of advanced and early esophageal cancers are found in Figure 1, Figure 2.
Figure 1.
Algorithm for staging of advanced cancers.
Figure 2.
Algorithm for staging of early cancers.
The most commonly used staging procedure in esophageal cancer is computed tomography (CT). The particular strength of this test is the ability to detect distant metastatic disease.168 The primary reason this is used as the first staging study is because of its availability and the change in the treatment course that would occur should metastasis or invasion of other organs be detected. On initial presentation, most patients with metastatic disease had involvement of abdominal lymph nodes (45%), liver (35%), lung (20%), and cervical lymph nodes (18%) based on findings at esophagectomy.169 CT of the chest and abdomen correctly identified metastatic disease in only 69% of the cases. In this series, patients without metastasis on CT did not have involvement of the bones or brain. CT has limited accuracy in staging the extent of tumor invasion, with correct staging found in 50%–90%.170, 171, 172 CT has been shown to produce false negatives in 30%–60% of patients.173 Even with improvements in technology such as the helical CT scanner, comparisons with EUS and fine-needle aspiration indicate that it is still not as sensitive for detecting celiac lymph node disease or T4 carcinoma.174
EUS consists of 3 fundamentally different devices that may not be available to all gastroenterologists. There are probes that can be placed within the endoscope or used as stand-alone instruments, radial scanning echoendoscopes, and linear array echoendoscopes that permit fine-needle aspiration. EUS can be directed primarily at the mucosa with the use of probes that usually involve high-frequency scanning at 20–30 MHz or can be directed to more distant structures by scanning at 7.5–12 MHz with the radial echoendoscopes. The diagnostic utility of EUS is in determining the depth of tumor invasion and the presence of local-regional adenopathy. This technology is limited in terms of detecting distant metastasis because visualization of other organ systems, particularly the lung, is not possible because air disrupts ultrasound conduction. Identification of abnormal-appearing lymph nodes has been found to be specific (85%–97%) for nodal metastasis but not very sensitive (72%–77%) in case series.175, 176 If abnormalities are found, biopsies can be performed on the lesions using a small aspiration needle positioned in a linear array instrument. The sensitivity of this technique in tumor staging has been reported in clinical series between 59% and 90%. Some of this variation can be attributed to the difficulty in passing the ultrasound instrument through a malignant stricture.177 Histologic confirmation of nodal disease altered planned therapy in only 13% of patients with esophageal cancer in one retrospective case series.178 This may be because the majority of esophageal cancers are found at an advanced stage. Miniprobes that have higher resolution are the best at defining early-stage cancer.179 Decision analysis models have been used to determine the value of EUS in assessment of esophageal cancer. These models have found that EUS is a more cost-effective initial staging strategy if the probability that EUS can find advanced disease is >30% or if the cost of EUS is less than 3.5 times that of CT.180 Additional analysis based on the use of EUS in a national database found that preoperative use of this technique could prevent 26% of patients from unnecessary combined-modality therapy.181
Positron emission tomography (PET) is a technology that uses 18F-fluorodeoxyglucose for the detection of nodal or distant metastasis in esophageal cancer.182 This is used to detect neoplastic tissues because they normally metabolize glucose at a faster rate than normal tissues. However, inflammatory tissues are also fast glucose metabolizers and metastases often have to be differentiated from inflamed tissue, leading to false positives.183 A number of case series have found that PET is not as sensitive as EUS or CT for locoregional disease.184, 185, 186, 187, 188, 189 This technology cannot define the tumor stage because it cannot resolve the layers of the esophagus. In addition, patients with hyperglycemia are not good candidates for PET. Because of these factors, PET cannot be envisioned as an initial staging tool in esophageal cancer. New advances in PET technology include fusion PET, which actually combines the CT image with the PET image to allow better tumor localization. This may increase the specificity of the test.
Other staging procedures that have been investigated include minimally invasive surgery or laparoscopic staging before esophagectomy. Case series have found that performance of laparoscopic- or thoracoscopic-guided biopsies of lymph nodes increases the detection of metastatic disease and can change management in 17% of patients.171, 190, 191, 192, 193, 194, 195, 196 Thoracoscopy has a significant advantage in detecting thoracic lymph nodes and when combined with laparoscopy appears to be superior to EUS, PET, and CT staging.171, 192, 197 These series generally do not have uniform staging procedures performed before the laparoscopy, which makes it difficult to assess the role of these procedures in relation to the standard staging modalities. Bronchoscopy has been suggested as a staging procedure for patients with tumors that are found above the tracheal bifurcation. In one prospective study, almost 10% of patients were found to have tracheal involvement on the basis of bronchoscopy alone, although EUS was not used in this study.198 Magnetic resonance endoscopy has also been used in staging esophageal cancer but as yet has not been shown to be superior to existing tests.199, 200 Recent cost analyses of these various staging modalities alone and in combination have suggested that CT combined with EUS with fine-needle aspiration if appropriate offered the least expensive and reasonable efficacy in terms of QALYs.201 PET and EUS plus fine-needle aspiration offered more QALYs but was also more expensive at $60,544 per QALY.
Summary of Evidence—Given the state of the current information, we recommend the following strategy. CT of the chest and upper abdomen should be the first staging procedure, followed by EUS and fine-needle aspiration if no evidence of distant metastasis is found on CT and the procedure is available. If surgical resection is still considered, PET can be considered if available due to its increased sensitivity for distant metastasis. This is based on level III evidence. In patients with potentially early-stage disease (tumors <2 cm and nonobstructing), EUS with endoscopic mucosal resection may be considered as an alternative staging procedure if available for histologic staging of the cancer and potential therapy.
Treatment of Esophageal Cancer
Treatment of Early Cancers
Early esophageal cancers, those confined in the mucosa or upper submucosa of the esophagus, are termed T1, N0, M0 by the American Joint Commission on Cancer terminology (see Table 5). There have not been any randomized treatment trials for these cancers because they are rare, accounting for <5% of esophageal cancers diagnosed in most series. In Japan, there has been a further division in T1 lesions. An early cancer is termed T1m if confined to the mucosa and T1sm if submucosal invasion is found. There has even been further division of T1sm lesions into penetration into the upper third (sm1), the middle third (sm2), or the lower third (sm3) of the submucosa.202 In the Japanese experience with squamous cell cancers, penetration of the superficial submucosa is associated with a 6% risk of metastasis. However, if deeper penetration of the submucosa is found, the risk of metastasis increased to 47%. There is a problem in the interpretation of some of the literature from Japan.203 Overall, Japanese pathologists will diagnose intramucosal carcinoma based primarily on patterns of the cell nucleus rather than on the demonstration of invasion as required by Western pathologists. Some of the data concerning the lack of metastatic potential for early cancers may be biased by the inclusion of cases of what would be classified by Western pathologists as high-grade or even low-grade dysplasia.
Table 5. Staging According to the American Joint Commission on Cancer
| Tumor staging for esophageal cancer | |
| T0 No evidence of primary tumor | |
| Tis Carcinoma in situ | |
| T1 Tumor invades lamina propria or submucosa | |
| T2 Tumor invades muscularis propria | |
| T3 Tumor invades adventitia | |
| T4 Tumor invades adjacent structures | |
| Nodal staging | |
| N0 No evidence of lymph nodes | |
| N1 Evidence of regional lymph nodes | |
| Metastasis | |
| M0 No evidence of distant metastasis | |
| M1 Evidence of distant metastasis | |
| M1a For lesions in the lower thorax indicates metastasis to the celiac nodes | |
| M1a For lesions in the upper thorax indicates cervical lymph nodes | |
| M1b For lesions in the midthorax indicates nonregional or other nodal groups | |
| M1b For lower esophagus or upper thorax lesions indicates distant metastasis | |
| X designation in any area indicates that the lesion was unable to be assessed. | |
| Staging of esophageal cancers | |
| Stage 0 | Tis,N0,M0 |
| Stage 1 | T1,N0,M0 |
| Stage 2a | T2-3,N0,M0 |
| Stage 2b | T1-2,N1,M0 |
| Stage 3T3, N1,M0 | |
| T4, any N,M0 | |
| Stage 4 | Any T, any N, M1 |
| Stage 4a | Any T, any N, M1a |
| Stage 4b | Any T, any N, M1b |
The traditional approach for these squamous cell cancers has been surgical resection because cure can be achieved in >90% of T1m cancers.204, 205 A survey of major medical centers in Europe found that 253 patients with early cancers treated with esophagectomy had a mortality rate of 9.1%.205 Patients with intraepithelial cancers had a 5-year survival rate of 93%, while those with intramucosal cancers had a decreased survival rate of 73%. If cancer progressed into the submucosa, the survival rate further decreased to 44%. Twenty of 21 patients with recurrent disease had submucosal involvement with cancer. These results are similar to those found in Japan.
There is less information available regarding surgical resection of early adenocarcinoma. Early cancers have primarily been reported as part of larger surgical series. Overall, limited reports have results with a 100% rate of total excision without any operative mortality.206, 207, 208, 209, 210, 211 However, this is likely to be influenced by reporting bias. The reported mortality rate for esophagectomy performed on patients with high-grade dysplasia is between 2% and 6%.212, 213 The major concern with surgical therapy for high-grade dysplasia is the 40% incidence of morbidity associated with the procedure. Possible procedure-related complications include anastomotic strictures, leaks, chronic aspiration, infection, and chylothorax.
Endoscopic mucosal resection has been performed on a number of patients with early cancers, particularly in Asia, where the technique has been established for early gastric cancers. Studies have shown that squamous cell cancers confined to the mucosa or upper submucosa could be treated successfully with endoscopic therapy.214 Five-year cure rates for patients with intramucosal cancers were 100%, while those who had cancers that penetrated into the deep submucosa had 5-year survival rates of 59%–54% in a series of 152 cases. Reports from other institutions for superficial cancers in Japan reported a 95%–100% 5-year survival rate with recurrences estimated at 3%–7%. Even these recurrences were believed to be treatable with additional endoscopic therapy.215 In a survey of 143 Japanese medical institutions, endoscopic mucosal resection was regarded as the treatment of choice for intramucosal cancers.216 Complications in 2418 patients were primarily stenosis, hemorrhage, or perforation, which were found in 7% of patients. The most important predictors of stenosis were resection of more than three fourths of the circumference of the esophageal lumen or if the lesion was >3 cm in length.217
Early mucosal resections were performed using a transparent overtube through which an endoscope could be positioned.218 The lesion was first identified visually, and then a fluid cushion was created under the lesion by injecting saline and epinephrine submucosally beneath the lesion. If the lesion could not be elevated from the remainder of the esophageal wall, the resection could not be performed. Later developments involved the use of band ligation and eventually the cap-fitted endoscope.219 New variations of this technique have been described and termed endoscopic submucosal dissection, including the use of an insulated tipped electrocautery knife, needle knife, or triangular tipped knife that can completely resect the lesion with the use of a special snare designed to resect the lesion without any need for suction.220, 221 These techniques were all designed for the relatively flat lesions associated with early squamous cell cancers. Endoscopic mucosal resection performed in the United States involves the use of variceal band ligation, which allows the formation of a pseudopolyp that can be resected by a regular snare. A second common technique involves the use of a specialized cap that can be fitted onto an endoscope. This requires the use of a crescent snare that is designed to form a loop around the lip of the distal end of the cap. The targeted tissue can then be suctioned into the cap and the snare closed to perform the resection. A prospective comparison study of these 2 techniques in 100 resections performed in 72 patients with early cancers did not find any differences in terms of size of the specimen or complication rates.222
Early esophageal adenocarcinomas have been endoscopically treated in the setting of Barrett’s esophagus. These have been described in large case series using mucosal resection alone or in combination with PDT.223, 224 Lesions most amenable to mucosal resection are those that are polypoid, elevated, <2 cm in size, and having a low-grade cancer.223 Mucosal resection was used in 115 patients (83% with early cancers) and resulted in a 3-year overall survival rate of 88%.137 Complications occurred in 9% of patients, including decreases in hemoglobin and stricture formation. However, because Barrett’s esophagus without high-grade dysplasia or cancer was left untreated, 30% of the patients developed additional neoplastic lesions. For this reason, it is generally advised that the remainder of the Barrett’s esophagus be treated after resection of a cancer. PDT has been used for this purpose, with 94% initial success rates at 1 year.224 Although not widely performed, mucosal resection has been performed to completely eliminate the Barrett’s segment in 2 reports.225, 226 Circumferential mucosal resection does tend to generate strictures; this has been reported in 3 of the 13 reported cases.
Endoscopic therapy using PDT, laser therapy, and argon plasma coagulation has also been reported.227, 228, 229, 230, 231, 232, 233 These treatments have had limited success in completely eliminating Barrett’s esophagus and cancer, with response rates of 25%–94%. These small case reports have had a wide variation in the depth of invasion of these cancers (T0–T2) and the type of therapy delivered. Laser therapy with Nd:YAG, which operates at a wavelength of 1063 nm, penetrates quite deeply and has been favored for tumor ablation. Lasers that operate in the 540-nm wavelength, such as the argon or KTP-YAG lasers, have a much more limited depth of penetration. Thermal therapies, such as argon plasma coagulation applied at high-power settings, have also been used to treat early cancers. PDT is influenced by the type of photosensitizer used for therapy. Aminolevulinic acid is not approved in the United States at this time, but it has found favor in Europe because it is not associated with the prolonged cutaneous photosensitivity that is found with the sodium porfimer that is used in the United States. Due to its very limited depth of penetration, aminolevulinic acid has only been found to be useful for cancer therapy if the thickness of the cancer is <2 mm.230
Other treatments that have been reported in case series for the treatment of patients with superficial cancers include radiation therapy and brachytherapy. Radiation therapy has been used in Japan as a single-modality therapy for superficial squamous cell cancers. Five-year survival rates after treatment in 2 series with a total of 183 patients ranged from 39% to 45%.234, 235 These studies have also shown a trend toward nodal recurrence of cancer in patients who have had submucosal penetration.234 Patients with cancer strictly confined to the mucosa did not have nodal recurrence. Brachytherapy alone and in combination with external beam radiation has also been reported, although the 3-year survival rate in these patients is only 14%.236
Treatment of Advanced Cancers
The gastroenterologist is often asked to determine whether there is a role for oncologists before surgical resection. There has been substantial controversy over the use of neoadjuvant therapy before esophagectomy for the treatment of patients with locally advanced esophageal carcinoma, primarily patients with stage IIb or III disease (Table 5). Primary surgical therapy for cancers limited to the esophagus, stage I or IIa disease, has had good results without the need for or morbidity of chemotherapy.205, 208, 237, 238 Surgical therapy for more advanced cancer has been performed as either a limited resection or en-bloc removal of lymph nodes, which can be performed via a transhiatal or transthoracic (Ivor–Lewis) approach.239, 240 Extensive resection of lymph nodes has been more commonly practiced in Asia and involves removing nodes in the neck, chest, and abdomen in a 3-field lymph node dissection.241 This procedure is rarely practiced in the United States because of the prolonged operating times and the morbidity associated with the procedure. An en-bloc lymph node dissection of the stomach and chest is practiced in the United States in an attempt to achieve complete surgical removal of tumor and appears in small series to eliminate recurrence of tumor in the resected area.242 In general, esophagectomy for squamous cell cancer seems to have been more successful in Asia than in Western countries in terms of survival and operative mortality.243, 244 Minimally invasive esophagectomy has recently been promoted for resection of esophageal cancer with the use of laparoscopy for gastric mobilization and resection.245, 246 The gastroesophageal anastomosis is accomplished with a thoracoscope or manually. Although the procedure has not been shown to improve patient outcomes in terms of morbidity or mortality, it has been attractive to patients with superficial cancer or high-grade dysplasia who desire an improved cosmetic result.
It has been well recognized that survival is related to disease stage.240, 247 Thus, it is not surprising that the concept of neoadjuvant (preoperative) chemotherapy and radiation had significant appeal to oncologists and surgeons. By reducing the number of involved lymph nodes and decreasing cancer stage, neoadjuvant therapy could enhance the ability of surgical resection to cure patients. A number of prospective, randomized, controlled trials have investigated the use of neoadjuvant therapy followed by surgery versus surgery alone, and these are summarized in Table 6.248, 249, 250, 251, 252, 253, 254 Only one of these studies, that by Walsh et al., actually showed an advantage to chemotherapy and radiation with an odds ratio of 8.44 and a 95% CI that does not cross 1.251 This study has been criticized for its high surgical mortality rate that biases against the surgical therapy alone group. A recent meta-analysis combined all of these studies and concluded that neoadjuvant therapy increased patient survival at 3 years with an odds ratio of 2.5 (P = .04) and had a decreased risk of locoregional recurrence with an odds ratio of 0.83 (P < .01).255 This study found that there was a nonsignificant trend toward an increase in treatment mortality. The concurrent administration of chemotherapy and radiation therapy was believed to be significantly better than sequential therapy. A significant percentage (21%) of the patients in these series had a complete pathologic response at the time of resection.
Table 6. Summary of Randomized Controlled Trials Comparing Neoadjuvant Chemotherapy and Radiation in Addition to Surgical Resection With Surgical Resection Alone
| Reference | No. of patients | Survival period (y) | Surgery alone (%) | Chemoradiation and surgery (%) | P value | Odds ratio | 95% Confidence interval |
|---|---|---|---|---|---|---|---|
| Nygaard et al248 | 186 | 3 | 9 | 17 | .30 | 2.81 | 0.61–12.95 |
| Le Prise et al249 | 86 | 3 | 13.8 | 19.2 | .56 | 1.57 | 0.50–5.00 |
| Apinop et al250 | 69 | 5 | 10 | 24 | .40 | 3.1 | 0.74–12.8 |
| Walsh et al251 | 113 | 3 | 6 | 32 | .01 | 8.44 | 2.33–30.57 |
| Bosset et al252 | 282 | 5 | 32 | 33 | .78 | 1.06 | 0.64–1.74 |
| Kelsen et al253 | 440 | 2 | 35 | 37 | .53 | 1.1 | 0.74–1.63 |
| Urba et al254 | 100 | 3 | 16 | 30 | .15 | 2.25 | 0.85–5.93 |
With these high pathologic response rates with radiation and chemotherapy alone, it has been questioned whether surgical therapy is needed in the treatment of patients with more advanced cancers. Initial studies comparing neoadjuvant regimens found that the small groups of patients who refused surgery after chemotherapy and radiation had a 5-year survival rate of 18% if they had squamous cancers but no 5-year survival if they had adenocarcinomas.256 The Intergroup 0123 trial studied a nonsurgical approach to esophageal cancer using high-dose radiation (64.8 Gy) versus standard-dose radiation (50.4 Gy) in combination with 5-fluorouracil and cis-platinum in 216 evaluable patients.257 The trial was terminated after interim analysis because the results indicated that 50.5-Gy radiation was as effective as the higher dose, with 2-year survival rates of 40%.
The need for combined chemotherapy and radiation therapy has been best established in a randomized prospective trial from the Radiation Therapy Oncology Group 85-01 study, which examined 134 patients randomized to radiation alone versus radiation in combination with chemotherapy with 5-fluorouracil and cis-platinum.258 This trial clearly established that combined therapy with a 5-year survival rate of 26% was superior to radiation therapy alone with a 0% 5-year survival rate. The odds ratio of this study was 0.02 (95% CI, 0.00–0.38). One caveat from this study was that only 68% of the patients who planned to undergo chemotherapy were able to complete the treatment course.
Summary of Evidence—Patients with early esophageal cancers confined to the mucosa should be treated with surgical resection, with consideration of endoscopic mucosal resection with adjuvant mucosal treatment for any remaining preneoplastic tissue (ie, Barrett’s esophagus) (based on level III evidence). Patients with early esophageal cancers that penetrate into the upper third of the submucosa can be treated with endoscopic mucosal resection if surgical mortality is anticipated to be >6% (based on level III evidence). Patients with stage IIb and III disease may benefit from concomitant chemotherapy and radiation therapy before surgical therapy (based on level II evidence). Patients with stage I and IIa disease who are good candidates for surgical therapy do not require neoadjuvant therapy before esophagectomy (based on level II evidence). Patients with more advanced-stage cancer may be treated with chemotherapy and radiation therapy or be considered for palliative therapy.
Palliation of Esophageal Cancer
Esophageal cancer is usually diagnosed at an advanced and incurable stage. Patients with locally unresectable cancer or patients who are surgically unfit may undergo palliation by a variety of nonoperative means. The goals of palliation in this setting are to alleviate dysphagia, aid in nutrition, and improve quality of life. Palliation can be achieved by external beam radiotherapy or intraluminal brachytherapy, with or without chemotherapy. However, patients may not tolerate these therapies or improvement in dysphagia may be slow.259
Endoscopic therapy plays an important role in the palliation of malignant dysphagia. Several endoscopic techniques have been applied, but limited information exists as to the optimal approach. The choice is primarily dictated by tumor characteristics, patient preference, and available expertise. Treatment must be individualized, and different methods of palliation may be appropriate at various stages of the patient’s illness.
Malignant esophageal stenoses can be dilated using through-the-scope balloons or wire-guided polyvinyl dilators (e.g., Savary dilators), with or without the aid of fluoroscopy. Dilation can be complicated by perforation in up to 10% of cases.260, 261, 262 Blind passage of Maloney dilators is not recommended in complex malignant strictures due to a higher risk of perforation.263 Most patients can be dilated to a luminal diameter that allows passage of a liquid to soft diet (∼9–12 mm), but improvement is brief and typically measured in days. Dilation is used mostly as an adjunct to other modalities, such as in facilitating placement of an esophageal stent or in patients awaiting improvement in swallowing following chemoradiation therapy.264
Among endoscopic modalities, esophageal stenting has assumed a primary role as a palliative technique because of its effectiveness in rapidly relieving dysphagia in one procedure. In the United States and abroad, self-expanding metal stents (SEMS) have largely supplanted conventional plastic semirigid prostheses.265, 266 In contrast to plastic semirigid stents, SEMS require minimal to no preplacement dilation and are easier to insert.267, 268, 269 SEMS also expand the obstructed lumen to a greater degree (18–23 mm) than that provided by plastic semirigid stents bounded by fixed internal diameters (10–12 mm). Both SEMS and plastic semirigid stents have a highly successful rate of insertion (90%–100%). They are also similarly effective at alleviating dysphagia in ≥90% of patients; most are able to tolerate at least liquids following stent placement.270, 271, 272 However, the collective experience gathered from prospective randomized trials has shown SEMS to be associated with fewer procedure-related complications (10%–43% vs 0%–16%), shorter hospital stays, and trends toward better quality of life and survival.269, 270, 271, 272, 273, 274 Although SEMS are more expensive than plastic semirigid stents, this cost difference was not found to be significant in the overall management of dysphagia.274
A self-expanding plastic stent (Polyflex; Boston Scientific Inc, Natick, MA) has been approved by the FDA for palliation of malignant dysphagia and, more recently, for benign disease. The potential advantage is its removability, but it is priced similar to available SEMS. Initial studies have shown the Polyflex stent to be efficacious in relieving malignant dysphagia.275, 276, 277, 278 Prospective randomized trials, however, are needed to assess the cost-effectiveness of self-expanding plastic stents versus SEMS.
Three FDA-approved SEMS are currently available in the United States. These SEMS differ in design and delivery systems, with additional refinements for particular indications (Table 7). The EsophaCoil stent (Medtronic InStent Inc, Eden Prairie, MN) is no longer commercially available. Endoscopic placement of SEMS can be performed with or without the assistance of fluoroscopy.279, 280 The majority of SEMS currently in use are partially covered with a thin silicone or polyurethane membrane to prevent tumor ingrowth. In a prospective randomized study of 62 patients, membrane-covered stents offered significantly better palliation than uncovered stents due to decreased rates of tumor ingrowth (3% vs 30%) and decreased need for endoscopic reinterventions (0% vs 27%) for recurrent dysphagia.281 Covered stents, however, tend to migrate more frequently than uncovered ones (26% vs 0%), particularly when placed in the distal esophagus.282 Modifications in design, such as the conical-shaped Flamingo Wallstent and Ultraflex stent with proximal flaring, have improved anchoring of stents to tissue and have made covered SEMS more migration resistant.283, 284 These 2 stents have been used successfully for palliation of distal esophageal cancers with an overall migration rate of 6%.284
Table 7. FDA-Approved SEMS
| Ultraflexa | Wallstent IIa | Z-Stentb | |
|---|---|---|---|
| Material | Nickel titanium (nitinol) | Elgiloy | Stainless steel |
| Design | Mesh | Mesh | Zigzag |
| Covered | Yes | Yes | Yes |
| Radial force | + | +++ | ++ |
| Delivery system (F) | 16 | 18 | 31 |
| Length (cm) | 10, 12, 15 | 10, 15 | 8, 10, 12, 14 |
| Flare-end diameter (mm) | 23, 28 | 28 | 25 |
| Shaft diameter (mm) | 18, 23 | 20 | 18 |
| Degree of shortening (%) | 30–40 | 30 | 0–10 |
| Fistula closure | Yes | Yes | Yes |
a Microvasive/Boston Scientific Inc (Natick, MA). |
b Wilson-Cook Medical (Winston-Salem, NC). |
There are limited prospective randomized studies comparing various SEMS for palliation of malignant dysphagia.284, 285 In a study of 100 patients, success rates in alleviating dysphagia were similar among patients who received the Z-stents, Flamingo Wallstents, or Ultraflex stents.285 Although complication rates were higher in the Z-stents group (36%) than in the Ultraflex or Flamingo Wallstent groups (24% and 18%, respectively), these differences did not reach statistical significance. In a study of 53 patients, Flamingo Wallstents and Ultraflex stents were equally effective at palliating dysphagia with similar complication rates.284 There are as yet insufficient data that convincingly show the superiority of one SEMS over another. Currently, the choice for a particular SEMS primarily depends on device availability, familiarity, and personal preference.286
Types and rates of SEMS-related complications vary widely among studies. Results of a national survey and review of complications from compiled case series showed immediate technical complication rates of 5%–17%, including misplacement (0.3%–5%), failed expansion (4%–7%), failed deployment (1%–3%), and migration (0.3%–2%).268 Immediate patient complications occurred in 7%–15% of cases, including chest pain (6%–12%), bleeding (0.2%–0.6%), perforation (0.6%–1%), and death (0.5%–1.4%). Delayed technical complications occurred in 9%–18% of cases, including tumor ingrowth/overgrowth (6%–11%) and stent migration (3%–7%). Delayed patient complications occurred in up to 27% of patients, including reflux symptoms (4%–5%), recurrent dysphagia (8%–9%), tracheoesophageal fistulas (1%–3%), bleeding (0.5%–4%), perforation (0.5%–0.8%), and death as a result of underlying malignancy occurring within 30 days (7%).
Tumor ingrowth or overgrowth causing recurrent dysphagia can be managed by placement of another stent or tumor ablation using a variety of endoscopic modalities, including laser therapy, argon plasma coagulation therapy, and PDT.287, 288, 289, 290 Care must be taken to avoid damaging the indwelling stent when thermal modalities are used.
There are conflicting reports on whether stent-related morbidity is increased in patients who have been treated previously with radiation and/or chemotherapy. Some studies have shown an increased rate of stent-related life-threatening complications in patients who have had prior chemoradiation therapy, whereas others have not.272, 285, 291, 292, 293, 294, 295 Data are limited regarding the use of palliative chemoradiation therapy after insertion of stents. In a small study of 29 patients, the group of patients undergoing chemoradiation therapy following stent placement survived longer (median, 331 days vs 157 days; P < .05) than the stent-only group.296 On the other hand, a high risk of major complications was noted in patients undergoing radiotherapy after stent placement.297 The major complications found were creation of a tracheal-esophageal fistula and massive hematemesis from stent erosion into the aorta. Placement of SEMS before radiation therapy should be performed with caution. Comparisons between available studies are difficult because of differences in types of stents used and study designs.
Stents are ideal for obstructing midesophageal cancers. Following stent placement, patients are advised to modify their diet and avoid solid boluses (e.g., meat and bread) that could potentially become impacted within the stent. Stents that straddle the esophagogastric junction may lead to severe reflux symptoms. Therefore, strict antireflux lifestyle precautions and administration of antisecretory medications (ie, proton pump inhibitors) are required. Clinical experience with the recently introduced Dua stent (Z-stent with a windsock-like antireflux valve) is limited, but the device seems beneficial in palliating dysphagia and controlling reflux in patients with distal esophageal cancers.298, 299 Stenting of esophageal cancers in proximity of the upper esophageal sphincter can be problematic, although tumors involving the cervical esophagus occur in <5% of all patients.300 Small case series have reported successful placement of SEMS to palliate cancers within 2 cm of the upper esophageal sphincter, although this can be technically challenging.292, 301 Complications may include foreign body sensation, oropharyngeal aspiration, and tracheal compression with airway compromise.285 Stent placement in this setting should only be attempted by an experienced operator, or alternative modalities should be considered.
Stents can be effective for palliating dysphagia secondary to malignant extrinsic compression. Covered stents can also be used to treat malignant tracheoesophageal fistulas and constitute a unique advantage over other endoscopic modalities in this setting. Covered SEMS are considered a primary form of therapy for this ominous condition. Successful closure of malignant tracheoesophageal fistulas using covered SEMS is seen in 90%–100% of patients.293, 295, 301, 302 Patients with persistent tracheoesophageal fistulas despite esophageal stenting may benefit from airway stenting (double stenting) to close the fistula303 or esophageal bypass in surgically fit patients.304 Malignant esophageal obstruction associated with perforation during endoscopic procedures may be palliated successfully with covered SEMS.305
Intratumoral injection of absolute alcohol results in tissue necrosis and sloughing. The technique is cheap, widely available, and relatively simple to perform. The sclerosant is typically injected in 0.5- to 1-mL aliquots using a standard sclerotherapy needle, targeting exophytic parts of the tumor. Experience accrued from case series shows an initial success rate of 80%–100% in improving dysphagia. However, the palliative effect is short-term (<1 month), and repeated sessions are usually required in most patients.306, 307, 308, 309, 310 Chest pain is common after therapy. Serious complications, including mediastinitis and tracheoesophageal fistulas, occur in up to 5% of cases.308 Standardized dosimetry and local control of therapy are problematic due to leaking at the injection site or tracking of the sclerosant along tissue planes. Alcohol injection is probably best reserved for short, protuberant, and nonfibrotic tumors that are not amenable to other endoscopic palliative therapies. Preliminary reports of intratumoral injection of cisplatin/epinephrine gel have shown limited and short-lived efficacy of the locally administered chemotherapeutic agent in relieving dysphagia.311, 312 This form of injection therapy remains experimental at this time.
Similar to injection therapy, short exophytic tumors are more conducive to thermal modalities, which include bipolar electrocoagulation, argon plasma coagulation, and laser therapy. The use of bipolar electrocautery (BICAP probe) for esophageal tumor ablation has been described but made unpopular by more user-friendly and equally effective thermal modalities such as the Nd:YAG laser.313, 314, 315
Argon plasma coagulation therapy is a form of noncontact monopolar electrocautery delivered to tissue via ionized, electrically conductive argon gas. Palliation of dysphagia can initially be achieved in most patients with inoperable cancer, but the median range between reinterventions is approximately 1 month, with an average of 5 treatment sessions per patient.316 Despite the limited depth of injury achieved by argon plasma coagulation (∼2 mm), perforations have been reported to occur in 1%–2% of treatments. In one study, one third of the patients eventually required esophageal stenting as an alternative mode of palliative therapy.316 There is limited benefit in treating advanced bulky tumors with argon plasma coagulation. On the other hand, argon plasma coagulation may be helpful in controlling tumor bleeding and in staving off tumor ingrowth or overgrowth associated with metal stents.
The Nd:YAG laser causes deeper injury than argon plasma coagulation because it vaporizes tissue to recanalize the obstructed lumen. Short-segment exophytic lesions are ideal for laser therapy. The procedure is usually repeated 48 hours later for further treatment and debridement. Laser application is preferably performed in a retrograde fashion, which usually requires prelaser dilation for passage of the endoscope through the obstructed lumen.317 Tumors that are close to the upper esophageal sphincter may be more amenable to laser therapy than stenting. However, laser therapy is less successful than stenting for tumors involving the esophagogastric junction and cardia.318 Laser therapy is 70%–95% effective at relieving dysphagia.317, 319, 320 The duration of response ranges from 1 to 2 months, but multiple sessions are usually required due to tumor regrowth.321 Response can be enhanced by external beam radiation or brachytherapy.322, 323, 324 Minor complications of laser therapy include chest pain, transient worsening of dysphagia from treatment-related edema, and leukocytosis. Major complications include bleeding, perforation (0%–5%), and tracheoesophageal fistula (0%–6%). Laser equipment is expensive and may not be widely available. Unlike stenting, laser therapy is contraindicated in the presence of fistulas; is generally not suitable for long, tortuous, circumferentially narrowed tumors; and is not applicable for dysphagia caused by malignant extrinsic compression.
PDT has also been applied as a palliative technique for the management of malignant dysphagia.325, 326 PDT is not limited to bulky tumors; infiltrative or flat tumoral areas as well as long-segment tumors may be amenable to PDT. In addition, PDT using sodium porfimer may be easier to apply in cervical esophageal cancers than laser therapy or stenting. The response rate in dysphagia improvement ranges from 60% to 90%. Acute complications (5%–20%) include chest pain, odynophagia, nausea, fever, leukocytosis, and pleural effusion.259 A major obstacle to the use of sodium porfimer/PDT in advanced esophageal cancers is the duration of skin photosensitivity (4–6 weeks) associated with the therapy. This is a significant problem in a palliative setting. Costs related to initial purchasing of equipment and photosensitizers are additional drawbacks. PDT using aminolevulinic acid is attractive because of its limited duration of photosensitivity (48 hours), but this therapy has more limited depth of tissue necrosis. PDT with hematoporphyrin derivative (which is a compound similar to sodium porfimer) was significantly more effective than aminolevulinic acid in a nonrandomized study of 49 patients,327 Sodium porfimer is the only currently approved photosensitizer for gastrointestinal use in the United States.
Studies comparing various endoscopic modalities for palliation of malignant dysphagia are few and conflicting. Retrospective studies comparing laser therapy with stenting have shown similar outcomes with regard to relief of dysphagia but higher complication rates in the stent group.328, 329 These studies are limited by their retrospective design and heterogeneous patient populations. On the other hand, a prospective, randomized, controlled trial of laser therapy versus SEMS in 60 patients with previously untreated esophageal cancer demonstrated a significant improvement in the degree of dysphagia and a reduction in the reintervention rate (35.7% vs 100%) in favor of SEMS.282 A smaller prospective randomized study of 39 patients evaluating SEMS versus laser therapy combined with radiotherapy showed the former to be more cost-effective.330 A study of 65 patients, however, showed longer survival rates in patients undergoing thermal ablative therapy (laser predominantly) compared with those who received stenting.331 Stenting cost less but was associated with a greater deterioration of health-related quality of life. In 2 small prospective randomized trials comparing laser therapy with injection therapy, no significant differences were noted with regard to improvement in dysphagia score or complication rates.332, 333
In a prospective randomized study involving 236 patients, PDT and laser therapy were similarly efficacious in terms of dysphagia relief, although there was a trend toward a better response with PDT for tumors located in the upper and middle third of the esophagus and for long tumors.325 PDT was associated with fewer perforations than with laser therapy (1% vs 7%). However, PDT was limited by photosensitivity in 19% of cases. Termination of sessions due to adverse events occurred in 3% with PDT versus 19% with laser therapy.
Nutritional support is often required in support of patients with esophageal carcinoma. There is evidence that enteral nutrition is beneficial in patients with dysphagia and in those receiving radiation therapy.334 Enteral nutrition is generally preferred to the parenteral approach. A randomized prospective study was performed using these 2 approaches in patients who underwent surgery for gastrointestinal tumors.335 Although only 10% of the 257 patients had esophageal cancer, the results showed that enteral nutrition was less expensive and improved gut perfusion. Enteral nutrition can be accomplished by feeding tubes that can be placed with nasogastric or nasojejunal approaches, although these types of tubes are associated with increased bodily concerns by patients and could limit their social interactions.336 Percutaneous gastrostomy or jejunostomy tubes are preferred because there is less social stigma and the tubes are better tolerated. A retrospective study of percutaneous gastrostomy tubes in 229 patients with esophageal cancer found that they could be placed in 97% of patients, although dilation was required in 45% of patients, with 2 having fatal adverse events from perforations.337 Although only anecdotal, radiologists have advocated radiologic placement of fielding tubes in patients with oropharyngeal cancers to decrease the possibility of stomal metastasis.338
Finally, palliative care of patients with esophageal cancer requires the involvement of physicians who are attentive to both physical and emotional needs. Dysphagia is a symptom that has significant impact on a patient’s perception of health, as demonstrated in a recent study of health state utilities in 50 patients with esophageal cancer.339 Many patients feel abandoned by physicians after medical therapy has been unsuccessful and further interventions are no longer indicated. These patients require support from hospice personnel and deserve physician attention and compassion. Until esophageal cancer can be effectively treated, compassion may be one of the most important “therapies” we can offer for palliation of this disease.
Summary of Evidence—Endoscopic therapy is effective at alleviating dysphagia. However, the selection of a particular endoscopic technique should be based on tumor characteristics, patient preference, and available expertise. Esophageal dilation results in short-lived palliation and is best used as an adjunct to other palliative modalities (based on level III evidence). Esophageal stenting is the preferred endoscopic modality in patients with long malignant strictures more than 2 cm from the upper esophageal sphincter and/or with fistulas (also based on level III evidence). There is level I evidence that SEMS are superior to conventional semirigid plastic stents in the management of malignant dysphagia. Other palliative methods such as alcohol injection, laser therapy, and PDT are similarly efficacious as tumor ablative therapies (based on level II evidence).
Future Directions
It is clear that further research is needed in the detection, prevention, and treatment of esophageal carcinoma. The cause of the continued increase in incidence of adenocarcinoma of the esophagus still remains undefined. The need to stratify patients for esophageal cancer risk is essential to implement treatment and prevention strategies. Although histologic evidence of dysplasia has been the gold standard to define cancer risk, this is very hard to reproduce and is difficult to detect without laborious biopsy protocols. Biomarkers for cancer risk would be very attractive but will require large prospective studies to validate. Chemoprevention would be a viable strategy for patients at lower risk for development of cancer, and NSAIDs might a fruitful candidate. However, due to the low risks for cancer, very large patient trials will be required to demonstrate benefit. In patients at high risk for cancer, ablative therapies have been applied with some initial promising results. The clinical significance of reduction of the amount of Barrett’s mucosa, elimination of dysplasia, and development of subsquamous areas of Barrett’s mucosa needs to be defined. The detection and staging of esophageal cancers could be improved with the advent of higher-resolution imaging modalities such as OCT and fluorescence spectroscopy. Both of these entities require further development before they can be clinically applied. Endoscopic therapy of early cancers seems to be achievable, but large prospective studies are needed to define the best methods and to determine the long-term outcome. Surgical therapy is evolving toward less invasive approaches, but improvements in chemotherapy and radiation might decrease the need for resection in advanced cancers. Palliation is required for the majority of patients with esophageal cancer, and the development of newer stents that prevent reflux and conform better to the esophagus would be beneficial to patients.
Summary
Esophageal cancer is increasing in incidence and is associated with a high mortality rate. The ability of gastroenterologists to increase survival in this disease will depend on earlier detection through screening and surveillance strategies. Early cancers can be staged with EUS and endoscopic mucosal resection. More advanced cancers will require the addition of CT and possible PET. Treatment of early cancers is increasingly shifting toward endoscopic treatment. More advanced but localized cancers can be treated by surgical resection. Cancers with regional lymphadenopathy may require neoadjuvant chemotherapy and radiation therapy. Patients with more advanced cancers may respond to primary therapy with radiation and chemotherapy. Palliation of esophageal cancers is based on stent therapy, but physicians should be attentive to the emotional needs of the dying patient. The future of therapy for esophageal cancer may rest with the development of chemoprevention methods, although there is not substantial evidence to support its use at this time.
The Clinical Practice and Economics Committee acknowledges the following individuals whose critiques of this review paper provided valuable guidance to the authors: David E. Fleischer, MD, Richard A. Kozarek, MD, and Gottumukkala S. Raju, MD, MRCP.
References
- . Endoscopic surveillance of Barrett’s esophagus. Does it help? . J Thorac Cardiovasc Surg . 1993;105:383–387 discussion 387–388
- . The early diagnosis of oesophageal adenocarcinoma by endoscopic screening . Eur J Cancer Prev . 1992;1:327–330
- . Outcome of adenocarcinoma arising in Barrett’s esophagus in endoscopically surveyed and nonsurveyed patients . J Thorac Cardiovasc Surg . 1994;108:813–821 discussion 821–822
- . Risk factors for Barrett’s esophagus in community-based practice. GORGE consortium. Gastroenterology Outcomes Research Group in Endoscopy . Am J Gastroenterol . 1997;92:1293–1297
- . Prevalence of Barrett’s esophagus in asymptomatic individuals . Gastroenterology . 2002;123:461–467
- . Screening for Barrett’s esophagus in colonoscopy patients with and without heartburn . Gastroenterology . 2003;125:1670–1677
- . Length of Barrett’s oesophagus (an important factor in the development of dysplasia and adenocarcinoma) . (comment) Gut . 1992;33:1155–1158
- . Carcinoma arising in familial Barrett’s esophagus . Am J Gastroenterol . 1996;91:1855–1856
- . Familial Barrett esophagus and adenocarcinoma of the gastroesophageal junction . (published erratum appears in Cancer Epidemiol Biomarkers Prev 1993;2:505) Cancer Epidemiol Biomarkers Prev . 1993;2:397–399
- . Familial Barrett’s esophagus associated with adenocarcinoma . Gastroenterology . 1992;102:1400–1402
- . Familial aggregation of Barrett’s oesophagus, oesophageal adenocarcinoma, and oesophagogastric junctional adenocarcinoma in Caucasian adults . Gut . 2002;51:323–328
- . Familial factors in the etiology of gastroesophageal reflux disease, Barrett’s esophagus, and esophageal adenocarcinoma . Chest Surg Clin North Am . 2002;12:15–24
- . Unsedated transnasal endoscopy accurately detects Barrett’s metaplasia and dysplasia . Gastrointest Endosc . 2002;56:472–478
- . Surveillance of patients with Barrett’s esophagus for dysplasia and cancer with balloon cytology . (comment) Gastroenterology . 1997;112:1787–1797
- . Cytological screening for Barrett’s esophagus using a prototype flexible mesh catheter . Dig Dis Sci . 2001;46:2681–2686
- . Screening for Barrett’s esophagus by balloon cytology . Am J Gastroenterol . 1995;90:1230–1232
- . The tylosis esophageal cancer (TOC) locus (more than just a familial cancer gene) . Dis Esophagus . 1999;12:173–176
- . Early detection of neoplasia of the esophagus and gastroesophageal junction . Am J Gastroenterol . 1996;91:853–863
- . Late malignant transformation of chronic corrosive oesophageal strictures . Langenbecks Arch Chir . 1985;365:231–238
- . Oesophageal carcinoma associated with corrosive injury—prevention and treatment by oesophageal resection . Br J Surg . 1983;70:223–225
- . The risk of esophageal cancer in patients with achalasia. A population-based study . JAMA . 1995;274:1359–1362
- . Early cancer in achalasia . Dis Esophagus . 1998;11:239–247
- . Cancer incidence in persons with Fanconi anemia . (comment) Blood . 2003;101:822–826
- . Panendoscopy for second primaries in head and neck cancer . Ann Otol Rhinol Laryngol . 1981;90:460–464
- . Successful screening for early esophageal cancer in alcoholics using endoscopy and mucosa iodine staining . (comment) Cancer . 1995;76:928–934
- . Efficacy of endoscopic surveillance of the upper gastrointestinal tract following distal gastrectomy for early gastric cancer . Hepatogastroenterology . 2003;50:1704–1707
- . Changing trends in esophageal cancer (a 15-year experience in a single center) . Am J Gastroenterol . 1998;93:702–705
- . Epidemiologic pattern of esophageal cancer at an inner-city university hospital . J Assoc Acad Minor Phys . 1999;10:44–47
- . Relationship of Plummer-Vinson disease to cancer of the upper alimentary tract in Sweden . Cancer Res . 1975;35:3308–3316
- . Cytologic detection of esophageal squamous cell carcinoma and precursor lesions using balloon and sponge samplers in asymptomatic adults in Linxian, China . Cancer . 1997;80:2047–2059
- . Cytologic screening for esophageal cancer in a high-risk population in Anyang County, China . Acta Cytol . 2002;46:445–452
- . Epidemiology of columnar-lined esophagus and adenocarcinoma . Gastroenterol Clin North Am . 1997;26:487–494
- . Barrett’s esophagus. Prevalence and incidence of adenocarcinoma . Arch Intern Med . 1991;151:2212–2216
- . Adenocarcinoma and Barrett’s esophagus. An overrated risk? . Gastroenterology . 1984;87:927–933
- . Barrett’s esophagus and adenocarcinoma . Ann Rev Med . 1987;38:477–492
- . The relationship between columnar epithelial dysplasia and invasive adenocarcinoma arising in Barrett’s esophagus . Am J Clin Pathol . 1987;87:301–312
- . Only patients with dysplasia progress to adenocarcinoma in Barrett’s oesophagus . (comment) Gut . 1991;32:1441–1446
- . Barrett’s esophagus (a new look at surveillance based on emerging estimates of cancer risk) . Am J Gastroenterol . 1999;94:2043–2053
- . Upper endoscopy as a screening and surveillance tool in esophageal adenocarcinoma (a review of the evidence) . Am J Gastroenterol . 2002;97:1319–1327
- . Barrett’s esophagus. Correlation between flow cytometry and histology in detection of patients at risk for adenocarcinoma . Gastroenterology . 1987;93:1–11
- . Barrett’s esophagus. Correlation between mucin histochemistry, flow cytometry, and histologic diagnosis for predicting increased cancer risk . Am J Pathol . 1988;131:53–61
- . An endoscopic biopsy protocol can differentiate high-grade dysplasia from early adenocarcinoma in Barrett’s esophagus . (comment) Gastroenterology . 1993;105:40–50
- . Predictors of progression to cancer in Barrett’s esophagus (baseline histology and flow cytometry identify low- and high-risk patient subsets) . Am J Gastroenterol . 2000;95:1669–1676
- . DNA/protein flow cytometry as a predictive marker of malignancy in dysplasia-free Barrett’s esophagus (thirteen-year follow-up study on a cohort of patients) . Cytometry . 1998;34:257–263
- . Prospective multivariate analysis of clinical, endoscopic, and histological factors predictive of the development of Barrett’s multifocal high-grade dysplasia or adenocarcinoma . Am J Gastroenterol . 1999;94:3413–3419
- . The diagnosis of low-grade dysplasia in Barrett’s esophagus and its implications for disease progression . Am J Gastroenterol . 2000;95:3383–3387
- . Long-term nonsurgical management of Barrett’s esophagus with high-grade dysplasia . Gastroenterology . 2001;120:1607–1619
- . Extent of high-grade dysplasia in Barrett’s esophagus correlates with risk of adenocarcinoma . Gastroenterology . 2001;120:1630–1639
- . Value of endoscopic surveillance in the detection of neoplastic change in Barrett’s oesophagus . Br J Surg . 1988;75:760–763
- . The incidence of adenocarcinoma and dysplasia in Barrett’s esophagus (report on the Cleveland Clinic Barrett’s Esophagus Registry) . Am J Gastroenterol . 1999;94:2037–2042
- Observer variation in the diagnosis of dysplasia in Barrett’s esophagus . Hum Pathol . 1988;19:166–178
- . Dysplasia as a predictive marker for invasive carcinoma in Barrett esophagus (a follow-up study based on 138 cases from a diagnostic variability study) . Hum Pathol . 2001;32:379–388
- . Screening and surveillance for Barrett esophagus in high-risk groups (a cost-utility analysis) . (comment) Ann Intern Med . 2003;138:176–186
- . Surgical treatment of Barrett’s carcinoma. Correlations between morphologic findings and prognosis . J Thorac Cardiovasc Surg . 1994;107:1059–1065 discussion 1065–1066
- . Surgical pathology of adenocarcinoma arising in Barrett’s esophagus. Analysis of 67 cases . Am J Surg Pathol . 1995;19:183–191
- . Determinants of survival following the diagnosis of esophageal adenocarcinoma (United States) . Cancer Causes Control . 1996;7:322–327
- . Impact of endoscopic biopsy surveillance of Barrett’s oesophagus on pathological stage and clinical outcome of Barrett’s carcinoma . Gut . 1998;43:216–222
- . Cost effectiveness of detecting Barrett’s cancer . Gut . 1996;39:574–579
- . Barrett’s oesophagus (results from a 13-year surveillance programme) . Eur J Gastroenterol Hepatol . 2000;12:649–654
- . Oesophageal cancer is an uncommon cause of death in patients with Barrett’s oesophagus . Gut . 1996;39:5–8
- . Final results from 10 year cohort of patients undergoing surveillance for Barrett’s oesophagus (observational study) . BMJ . 2000;321:1252–1255
- . Surveillance and survival in Barrett’s adenocarcinomas (a population-based study) . Gastroenterology . 2002;122:633–640
- . Quality of life in patients with Barrett’s esophagus undergoing surveillance . Am J Gastroenterol . 2002;97:2193–2200
- . Updated guidelines for the diagnosis, surveillance, and therapy of Barrett’s esophagus . Am J Gastroenterol . 2002;97:1888–1895
- . Optimizing endoscopic biopsy detection of early cancers in Barrett’s high-grade dysplasia . Am J Gastroenterol . 2000;95:3089–3096
- . Endoscopic biopsy technique for acquiring larger mucosal samples . Gastrointest Endosc . 1991;37:332–337
- . Jumbo biopsy forceps protocol still misses unsuspected cancer in Barrett’s esophagus with high-grade dysplasia . Gastrointest Endosc . 1999;49:170–176
- . Endoscopic mucosal resection for lesions with endoscopic features suggestive of malignancy and high-grade dysplasia within Barrett’s esophagus . Gastrointest Endosc . 2000;52:328–332
- . Diagnostic value of cytopathology in Barrett esophagus and associated carcinoma . Am J Clin Pathol . 1988;89:493–498
- . A comparative cytopathologic and histologic study of atypia, dysplasia, and adenocarcinoma in Barrett’s esophagus . Cancer . 1992;69:8–16
- . Endoscopic biopsies and cytologic brushings of the esophagus are diagnostically complementary . Am J Clin Pathol . 1995;103:295–299
- . Digital image analysis . Mayo Clin Proc . 1995;70:81–82
- Surveillance of Barrett’s esophagus using brush cytology and digital image analysis (a randomized prospective trial) . (abstr) Gastrointest Endosc . 2003;57:AB91
- . Quantitative fluorescence image analysis of DNA content and nuclear morphology on esophageal balloon cytology smears and subsequent development of esophageal and gastric cardia cancer in Linxian, China . Cancer Epidemiol Biomarkers Prev . 1998;7:59–64
- . Studies of esophageal balloon cytology in Linxian, China . Cancer Epidemiol Biomarkers Prev . 1997;6:121–130
- . Chromoendoscopy and magnification endoscopy in Barrett’s esophagus . Gastrointest Endosc Clin North Am . 2003;13:269–277
- . Mucosal iodine staining improves endoscopic visualization of squamous dysplasia and squamous cell carcinoma of the esophagus in Linxian, China . Cancer . 1998;83:220–231
- . Association of multiple Lugol-voiding lesions with synchronous and metachronous esophageal squamous cell carcinoma in patients with head and neck cancer . Gastrointest Endosc . 2002;56:517–521
- . Diagnosis of superficial esophageal cancer and dysplasia using endoscopic screening with a 2% lugol dye solution in patients with head and neck cancer . Head Neck . 2000;22:170–174
- . Esophageal dysplasias are detected by endoscopy with Lugol in patients at risk for squamous cell carcinoma in southern Brazil . Dis Esophagus . 1999;12:191–195
- . Endoscopic detection of early esophageal cancer in a high-risk population (does Lugol staining improve videoendoscopy?) . Gastrointest Endosc . 1997;45:480–484
- . Methylene blue chromoendoscopy for detection of short-segment Barrett’s esophagus . Gastrointest Endosc . 2001;54:289–293
- . Methylene blue chromoendoscopy for Barrett’s esophagus (coming soon to your GI unit?) . (letter; comment) Gastrointest Endosc . 2001;54:403–409
- . Methylene blue staining of dysplastic and nondysplastic Barrett’s esophagus (an in vivo and ex vivo study) . Endoscopy . 2001;33:391–400
- . Methylene blue-directed biopsies improve detection of intestinal metaplasia and dysplasia in Barrett’s esophagus . Gastrointest Endosc . 2000;51:560–568
- . Sky blue or murky waters (the diagnostic utility of methylene blue) . Gastrointest Endosc . 2001;54:409–413
- . Comparison of methylene blue-directed biopsies and conventional biopsies in the detection of intestinal metaplasia and dysplasia in Barrett’s esophagus (a preliminary study) . Gastrointest Endosc . 2001;54:294–301
- . Biopsy surveillance is still necessary in patients with Barrett’s oesophagus despite new endoscopic imaging techniques . Gut . 2003;52:18–23
- . Chromoendoscopy with methylene blue and associated DNA damage in Barrett’s oesophagus . Lancet . 2003;362:373–374
- . Combined magnification endoscopy with chromoendoscopy for the evaluation of Barrett’s esophagus . Gastrointest Endosc . 1994;40:747–749
- . Enhanced magnification endoscopy (a new technique to identify specialized intestinal metaplasia in Barrett’s esophagus) . Gastrointest Endosc . 2001;53:559–565
- . Classification of Barrett’s epithelium by magnifying endoscopy . Gastrointest Endosc . 2002;55:641–647
- . Magnification chromoendoscopy for the detection of intestinal metaplasia and dysplasia in Barrett’s oesophagus . (comment) Gut . 2003;52:24–27
- . Endoscopic fluorescence detection of high-grade dysplasia in Barrett’s esophagus . (comment) Gastroenterology . 1996;111:93–101
- . Endoscopic ultraviolet-induced autofluorescence spectroscopy of the esophagus (tissue characterization and potential for early cancer diagnosis) . Endoscopy . 2000;32:756–765
- . The use of an optical biopsy system in Barrett’s esophagus . (abstr) Gastroenterology . 2001;120:A413
- . Light-induced autofluorescence spectroscopy for the endoscopic detection of esophageal cancer . Gastrointest Endosc . 2001;54:195–201
- . Temporally and spectrally resolved fluorescence spectroscopy for the detection of high grade dysplasia in Barrett’s esophagus . Lasers Surg Med . 2003;32:10–16
- . Detection of adenocarcinoma in Barrett’s oesophagus by means of laser induced fluorescence . Gut . 1996;39:711–716
- . Detection of high-grade dysplasia in Barrett’s esophagus by spectroscopy measurement of 5-aminolevulinic acid-induced protoporphyrin IX fluorescence . Gastrointest Endosc . 2002;56:479–487
- . Time gated fluorescence spectroscopy in Barrett’s oesophagus . Gut . 2003;52:28–33
- . Enhanced gastrointestinal diagnosis (light-scattering spectroscopy and optical coherence tomography) . Gastrointest Endosc Clin North Am . 2000;10:71–80 vi
- . Fluorescence and Raman spectroscopy . Gastrointest Endosc Clin North Am . 2003;13:279–296
- . Fluorescence, reflectance, and light-scattering spectroscopy for evaluating dysplasia in patients with Barrett’s esophagus . Gastroenterology . 2001;120:1620–1629
- . A randomized cross-over study comparing light-induced fluorescence endoscopy (LIFE) with standard endoscopy for detection of early neoplasia in Barrett’s esophagus . (abstr) Gastroenterology . 2003;124:A49
- . In vivo endoscopic OCT imaging of precancer and cancer of human mucosa . Opt Exp . 1997;1:432–440
- . High-resolution imaging of the human esophagus and stomach in vivo using optical coherence tomography . Gastrointest Endosc . 2000;51:467–474
- . High-resolution endoscopic imaging of the GI tract using optical coherence tomography . Gastrointest Endosc . 2000;51:474–479
- . In vivo endoscopic optical coherence tomography of esophagitis, Barrett’s esophagus, and adenocarcinoma of the esophagus . Endoscopy . 2000;32:750–755
- . Diagnosis of Barrett’s esophagus using optical coherence tomography . Gastrointest Endosc Clin North Am . 2003;13:309–323
- . Barrett’s esophagus . Gastroenterology . 2002;122:1569–1591
- . Intramucosal adenocarcinoma arising under squamous re-epithelialisation of Barrett’s oesophagus . Gut . 2000;46:574–577
- . Persistent genetic abnormalities in Barrett’s esophagus after photodynamic therapy . Gastroenterology . 2000;119:624–630
- . Lack of impact of therapy on extent of Barrett’s esophagus in 67 patients . Dig Dis Sci . 1990;35:93–96
- . Long-term results of classic antireflux surgery in 152 patients with Barrett’s esophagus (clinical, radiologic, endoscopic, manometric, and acid reflux test analysis before and late after operation) . Surgery . 1998;126:645–657
- . Endoscopic regression of Barrett’s oesophagus during omeprazole treatment; a randomised double blind study . Gut . 1999;45:489–494
- . Laparoscopic antireflux surgery in the treatment of gastroesophageal reflux in patients with Barrett esophagus . Arch Surg . 2000;135:801–805
- . Complete elimination of reflux symptoms does not guarantee normalization of intraesophageal acid reflux in patients with Barrett’s esophagus . Am J Gastroenterol . 1998;93:711–716
- . Failure of oesophageal acid control in candidates for Barrett’s oesophagus reversal on a very high dose of proton pump inhibitor . Aliment Pharmacol Ther . 2000;14:597–602
- . Dynamic effects of acid on Barrett’s esophagus. An ex vivo proliferation and differentiation model . J Clin Invest . 1996;98:2120–2128
- . Bile salts induce or blunt cell proliferation in Barrett’s esophagus in an acid-dependent fashion . Am J Physiol Gastrointest Liver Physiol . 2000;278:G1000–G1009
- . Duodenal reflux induces cyclooxygenase-2 in the esophageal mucosa of rats (evidence for involvement of bile acids) . Gastroenterology . 2001;121:1391–1399
- . Chemoprevention of esophageal adenocarcinoma by COX-2 inhibitors in an animal model of Barrett’s esophagus . Gastroenterology . 2002;122:1101–1112
- . Differentiation and proliferation in Barrett’s esophagus and the effects of acid suppression . Gastroenterology . 1999;117:327–335
- . Long-term outcome of medical and surgical therapies for gastroesophageal reflux disease (follow-up of a randomized controlled trial) . (comment) JAMA . 2001;285:2331–2338
- . Risk of adenocarcinomas of the esophagus and gastric cardia in patients with gastroesophageal reflux diseases and after antireflux surgery . Gastroenterology . 2001;121:1286–1293
- . Mucosal ablation therapy of barrett esophagus . Mayo Clin Proc . 2001;76:433–437
- . Role of mucosal ablative therapy in the treatment of the columnar-lined esophagus . Chest Surg Clin North Am . 2002;12:185–203
- . Restoration of squamous mucosa after ablation of Barrett’s esophageal epithelium . Gastroenterology . 1993;104:1686–1691
- . Effective and safe endoscopic reversal of nondysplastic Barrett’s esophagus with thermal electrocoagulation combined with high-dose acid inhibition (a multicenter study) . Gastrointest Endosc . 2001;53:554–558
- . Prospective randomized controlled trial of argon plasma coagulation ablation vs. endoscopic surveillance of patients with Barrett’s esophagus after antireflux surgery . (comment) Gastrointest Endosc . 2004;59:1–7
- . Barrett’s esophagus (combined treatment using argon plasma coagulation and laparoscopic antireflux surgery) . Dis Esophagus . 2003;16:279–283
- . Eradication of Barrett’s mucosa with argon plasma coagulation and acid suppression (immediate and mid term results) . (comment) Gut . 1998;43:747–751
- . High power setting argon plasma coagulation for the eradication of Barrett’s esophagus . (comment) Am J Gastroenterol . 2000;95:1661–1668
- . Prevention of the neoplastic progression of Barrett’s oesophagus by endoscopic argon beam plasma ablation . (comment) Br J Surg . 2001;88:1357–1362
- . Efficacy and one year follow up of argon plasma coagulation therapy for ablation of Barrett’s oesophagus (factors determining persistence and recurrence of Barrett’s epithelium) . (comment) Gut . 2002;51:776–780
- . Local endoscopic therapy for intraepithelial high-grade neoplasia and early adenocarcinoma in Barrett’s oesophagus (acute-phase and intermediate results of a new treatment approach) . (comment) Eur J Gastroenterol Hepatol . 2002;14:1085–1091
- . Argon plasma coagulation in the treatment of Barrett’s high-grade dysplasia and in situ adenocarcinoma . Endoscopy . 2001;33:257–261
- . Ablation of Barrett’s epithelium by endoscopic argon plasma coagulation in combination with high-dose omeprazole . Gastrointest Endosc . 2000;51:659–663
- . Photodynamic therapy for Barrett’s esophagus (follow-up in 100 patients) . Gastrointest Endosc . 1999;49:1–7
- . 5-aminolevulinic acid photodynamic therapy versus argon plasma coagulation for ablation of Barrett’s oesophagus (a randomised trial) . Gut . 2004;53:785–790
- . The effect of selective cyclooxygenase-2 inhibition in Barrett’s esophagus epithelium (an in vitro study) . J Natl Cancer Inst . 2002;94:422–429
- . Acid- and bile-induced PGE(2) release and hyperproliferation in Barrett’s esophagus are COX-2 and PKC-epsilon dependent . Am J Physiol Gastrointest Liver Physiol . 2002;283:G327–G334
- . Increased expression of inducible nitric oxide synthase and cyclooxygenase-2 in Barrett’s esophagus and associated adenocarcinomas . Cancer Res . 1998;58:2929–2934
- . Aspirin use and risk of fatal cancer . (comment) Cancer Res . 1993;53:1322–1327
- . Aspirin and reduced risk of esophageal carcinoma . Cancer . 1995;76:1116–1119
- . Use of aspirin and other nonsteroidal anti-inflammatory drugs and risk of esophageal and gastric cancer . Cancer Epidemiol Biomarkers Prev . 1998;7:97–102
- . Effect of anti-inflammatory drugs on overall risk of common cancer (case-control study in general practice research database) . (comment) BMJ . 2000;320:1642–1646
- . Nonsteroidal anti-inflammatory drugs and risk of digestive cancers at sites other than the large bowel . Cancer Epidemiol Biomarkers Prev . 2000;9:119–123
- . Medical decision analysis of chemoprevention against esophageal adenocarcinoma . Gastroenterology . 2003;124:1758–1766
- . Lifestyle factors and Barrett’s esophagus . Am J Gastroenterol . 2002;97:1328–1331
- . Population attributable risks of esophageal and gastric cancers . J Natl Cancer Inst . 2003;95:1404–1413
- . Clinical presentation of carcinoma of the oesophagus . J Roy Coll Surg Edinbh . 1986;31:199–206
- . Management of malignant esophagorespiratory fistula . Chest Surg Clin North Am . 1996;6:765–776
- . Double-contrast barium meal and upper gastrointestinal endoscopy. A comparative study . Ann Intern Med . 1984;101:538–545
- . Dysphagia (a cost analysis of the diagnostic approach) . Am J Gastroenterol . 2002;97:2733–2737
- . AGA technical review on treatment of patients with dysphagia caused by benign disorders of the distal esophagus . (comment) Gastroenterology . 1999;117:233–254
- . Ultrathin endoscopy in the assessment and treatment of upper and lower gastrointestinal tract strictures . Gastrointest Endosc . 1998;48:618–620
- . Prospective evaluation of biopsy number in the diagnosis of esophageal and gastric carcinoma . Gastroenterology . 1982;82:228–231
- . Optimal number of biopsy specimens in the diagnosis of carcinoma of the oesophagus . Gut . 1992;33:724–726
- . The role of endoscopy in the assessment and treatment of esophageal cancer . Gastrointest Endosc . 2003;57:817–822
- . Prospective comparison of the value of brushings before and after biopsy in the endoscopic diagnosis of gastroesophageal malignancy . Acta Cytol . 1991;35:549–552
- . Biopsy-negative malignant esophageal stricture (diagnosis by endoscopic ultrasound) . Am J Gastroenterol . 1998;93:2257–2260
- . Intraepithelial high-grade neoplasia and early adenocarcinoma in short-segment Barrett’s esophagus (SSBE) (curative treatment using local endoscopic treatment techniques) . Endoscopy . 2002;34:604–610
- . Esophageal cancer (patient evaluation and pre-treatment staging) . Surg Oncol . 2001;10:103–111
- . N1 esophageal carcinoma (the importance of staging and downstaging) . J Thorac Cardiovasc Surg . 2001;121:454–462
- . Endoscopic classification of esophageal cancer (correlation with the T stage) . Gastrointest Endosc . 1992;38:662–668
- . Esophageal cancer. Radiologic staging . Radiol Clin North Am . 1997;35:281–294
- . Incidence and distribution of distant metastases from newly diagnosed esophageal carcinoma . Cancer . 1995;76:1120–1125
- . Preoperative staging of esophageal cancer (comparison of endoscopic US and dynamic CT) . (comment) Radiology . 1991;181:419–425
- . CALGB 9380 (a prospective trial of the feasibility of thoracoscopy/laparoscopy in staging esophageal cancer) . Ann Thorac Surg . 2001;71:1073–1079
- . Improved detection of individual nodal involvement in squamous cell carcinoma of the esophagus by FDG PET . J Nucl Med . 2000;41:808–815
- . Clinical staging of esophageal carcinoma. CT, EUS, and PET . Chest Surg Clin North Am . 2000;10:471–485
- . Endoscopic ultrasound-guided fine needle aspiration in esophageal cancer . Min Chir . 2002;57:811–818
- . Esophageal cancer staging (improved accuracy by endoscopic ultrasound of celiac lymph nodes) . Ann Thorac Surg . 1999;67:319–321 discussion 322
- . The utility of EUS and EUS-guided fine needle aspiration in detecting celiac lymph node metastasis in patients with esophageal cancer (a single-center experience) . Gastrointest Endosc . 2001;54:714–719
- . Endoscopic ultrasound for staging esophageal cancer, with or without dilation, is clinically important and safe . (comment) Gastrointest Endosc . 1995;41:540–546
- . Clinical impact of endoscopic ultrasound-guided fine needle aspiration biopsy in patients with upper gastrointestinal tract malignancies. A prospective study . Endoscopy . 2001;33:478–483
- . Preoperative TN staging of esophageal cancer (comparison of miniprobe ultrasonography, spiral CT and MRI) . World J Gastroenterol . 2003;9:219–224
- . CT or EUS for the initial staging of esophageal cancer? A cost minimization analysis . (comment) Gastrointest Endosc . 2000;52:715–720
- . Potential impact of preoperative EUS on esophageal cancer management and cost . Gastrointest Endosc . 2002;56:391–396
- . Staging of esophageal cancer with 18F-fluorodeoxyglucose positron emission tomography . Am J Roentgenol . 1997;168:417–424
- . Pitfalls of positive findings in staging esophageal cancer with F-18-fluorodeoxyglucose positron emission tomography . Ann Surg Oncol . 2003;10:1100–1105
- . Improvement in staging of esophageal cancer with the addition of positron emission tomography . Ann Thorac Surg . 1997;64:770–776 discussion 776–777
- . Role of positron emission tomography in staging esophageal cancer . Ann Thorac Surg . 1997;64:765–769
- . Whole-body FDG positron emission tomographic imaging for staging esophageal cancer comparison with computed tomography . Clin Nucl Med . 2000;25:882–887
- . Utility of positron emission tomography for the staging of patients with potentially operable esophageal carcinoma . J Clin Oncol . 2000;18:3202–3210
- . Positron emission tomography in the initial staging of esophageal cancer . Arch Surg . 2002;137:1001–1007
- . Prospective analysis of accuracy of positron emission tomography, computed tomography, and endoscopic ultrasonography in staging of adenocarcinoma of the esophagus and the esophagogastric junction . Ann Surg Oncol . 2003;10:954–960
- . Clinical value of diagnostic laparoscopy with laparoscopic ultrasound in patients with cancer of the esophagus or cardia . J Gastrointest Surg . 1997;1:167–173
- . Detection of occult lymph node metastases in esophageal cancer by minimally invasive staging combined with molecular diagnostic techniques . J Soc Laparoendosc Surg . 1998;2:331–336
- . The role of thoracoscopic staging of esophageal cancer patients . Eur J Cardiothorac Surg . 1999;16(Suppl 1):S31–S33
- . Staging laparoscopy and laparoscopic ultrasonography in more than 400 patients with upper gastrointestinal carcinoma . J Am Coll Surg . 1999;189:459–465
- . Thoracoscopic and laparoscopic staging for esophageal cancer . Semin Thorac Cardiovasc Surg . 2000;12:186–194
- . The role of laparoscopy in preoperative staging of esophageal cancer . (comment) Surg Endosc . 2000;14:495–499
- . Minimally invasive surgical staging for esophageal cancer . Surg Endosc . 2000;14:700–702
- . Thoracoscopy/laparoscopy in the staging of esophageal cancer (Maryland experience) . Surg Laparosc Endosc Percutan Tech . 2002;12:213–218
- . Preoperative bronchoscopic assessment of airway invasion by esophageal cancer (a prospective study) . Chest . 1998;113:687–695
- . MR endoscopy (preliminary experience in human trials) . (erratum appears in Radiology 1997;203:580) Radiology . 1997;202:868–870
- . Local staging of esophageal cancer using endoscopic magnetic resonance imaging (prospective comparison with endoscopic ultrasound) . Endoscopy . 1998;30:745–749
- . An analysis of multiple staging management strategies for carcinoma of the esophagus (computed tomography, endoscopic ultrasound, positron emission tomography, and thoracoscopy/laparoscopy) . Ann Thorac Surg . 2002;74:1026–1032
- . Endoscopic evaluation of the depth of invasion in cases of superficial esophageal cancer in determining indications for endoscopic mucosal resection . (in Japanese) Nippon Geka Gakkai Zasshi . 2002;103:337–342
- . Differences in diagnostic criteria for esophageal squamous cell carcinoma between Japanese and Western pathologists . (comment) Cancer . 2000;88:996–1006
- . The European experience with esophageal cancer limited to the mucosa and submucosa . Gastrointest Endosc . 1986;32:88–90
- . Early oesophageal cancer: results of a European multicentre survey. Group Europeen pour l’Etude des Maladies de l’Oesophage . Br J Surg . 1995;82:98–101
- . Oesophagectomy for early adenocarcinoma and dysplasia arising in Barrett’s oesophagus . Aust N Z J Surg . 2003;73:121–124
- . Long-term survival after esophagectomy for Barrett’s adenocarcinoma in endoscopically surveyed and nonsurveyed patients . J Gastrointest Surg . 2002;6:29–36
- . Limited resection for early adenocarcinoma in Barrett’s esophagus . Ann Surg . 2000;232:733–742
- . Early adenocarcinoma in Barrett’s oesophagus . Br J Surg . 1997;84:1470–1473
- . Adenocarcinoma in Barrett’s esophagus. A clinicopathologic study of 65 cases . Ann Surg . 1991;213:122–125
- . Curative resection for esophageal adenocarcinoma (analysis of 100 en bloc esophagectomies) . Ann Surg . 2001;234:520–530 discussion 530–531
- . Barrett’s esophagus with high grade dysplasia (surgical results and long-term outcome—an update) . J Gastrointest Surg . 2003;7:164–170 discussion 170–171
- . Surgical management of high-grade dysplasia in Barrett’s esophagus . (comment) Am J Gastroenterol . 1993;88:1832–1836
- . Controversy in the treatment of superficial esophageal carcinoma—indications and problems of the procedures . (in Japanese) Nippon Geka Gakkai Zasshi . 1992;93:1059–1062
- . Endoscopic mucosal resection of esophageal cancer . (in Japanese) Gan To Kagaku Ryoho . 1995;22:192–195
- . Treatment of superficial cancer of the esophagus (a summary of responses to a questionnaire on superficial cancer of the esophagus in Japan) . Surgery . 1998;123:432–439
- . Esophageal stenosis after endoscopic mucosal resection of superficial esophageal lesions . Gastrointest Endosc . 2003;57:165–169
- . Endoscopic esophageal mucosal resection using a transparent tube . Surg Endosc . 1990;4:198–201
- . Endoscopic mucosal resection for early esophageal cancer . (in Japanese) Nippon Rinsho . 1996;54:1286–1291
- . A new technique for endoscopic mucosal resection with an insulated-tip electrosurgical knife improves the completeness of resection of intramucosal gastric neoplasms . Gastrointest Endosc . 2002;55:576–581
- . Endoscopic snare mucosectomy in the esophagus without any additional equipment (a simple technique for resection of flat early cancer) . Endoscopy . 1997;29:380–383
- . A prospective randomized trial of two different endoscopic resection techniques for early stage cancer of the esophagus . Gastrointest Endosc . 2003;58:167–175
- . Endoscopic mucosal resection of early cancer and high-grade dysplasia in Barrett’s esophagus . Gastroenterology . 2000;118:670–677
- . Combined endoscopic mucosal resection and photodynamic therapy for esophageal neoplasia within Barrett’s esophagus . Gastrointest Endosc . 2001;54:682–688
- . Circumferential EMR and complete removal of Barrett’s epithelium (a new approach to management of Barrett’s esophagus containing high-grade intraepithelial neoplasia and intramucosal carcinoma) . Gastrointest Endosc . 2003;57:854–859
- . Circumferential EMR of carcinoma arising in Barrett’s esophagus (case report) . Gastrointest Endosc . 2003;58:288–292
- . Laser and multipolar electrocoagulation ablation of early Barrett’s adenocarcinoma (long-term follow-up) . Gastrointest Endosc . 1999;49:442–446
- . KTP laser destruction of dysplasia and early cancer in columnar-lined Barrett’s esophagus . Gastrointest Endosc . 1999;49:8–12
- . Photodynamic ablation of high-grade dysplasia and early cancer in Barrett’s esophagus by means of 5-aminolevulinic acid . (comment) Gastroenterology . 1998;114:448–455
- . Photodynamic ablation of early cancers of the stomach by means of mTHPC and laser irradiation (preliminary clinical experience) . (comment) Gut . 1998;43:345–349
- . Local treatment of early cancer in short Barrett’s esophagus by means of argon plasma coagulation (initial experience) . Endoscopy . 1999;31:497–500
- . Photodynamic therapy in Barrett’s esophagus (reduction of specialized mucosa, ablation of dysplasia, and treatment of superficial esophageal cancer) . Semin Surg Oncol . 1995;11:372–376
- . Neodymium:yttrium-aluminum garnet contact laser ablation of Barrett’s high grade dysplasia and early adenocarcinoma . Am J Gastroenterol . 2002;97:2998–3006
- . Treatment of superficial esophageal cancer by external radiation therapy alone (results of a multi-institutional experience) . Int J Radiat Oncol Biol Phys . 2000;46:921–925
- Superficial esophageal cancer (multicenter analysis of results of definitive radiation therapy in Japan) . Radiology . 1995;196:271–274
- . High dose rate brachytherapy for superficial cancer of the esophagus . Int J Radiat Oncol Biol Phys . 2000;46:71–76
- . Precise clinical staging allows treatment modification of patients with esophageal carcinoma . Oncology . 1997;11:58–62
- . Prognostic factors in T1 and T2 squamous cell carcinoma of the thoracic esophagus . Arch Surg . 1999;134:50–54
- . Selection of operation for esophageal cancer based on staging . Ann Surg . 1986;204:391–401
- . Long-term results of transhiatal esophagectomy for esophageal carcinoma. A multivariate analysis of prognostic factors . Cancer . 1993;72:2312–2319
- . Extended esophagectomy with 3-field lymph node dissection for esophageal cancer . Arch Surg . 2003;138:1383–1389 discussion 1390
- . Node status in transmural esophageal adenocarcinoma and outcome after en bloc esophagectomy . J Thorac Cardiovasc Surg . 1999;117:960–968
- Operable squamous esophageal cancer (current results from the East) . World J Surg . 1994;18:347–354
- . Operable esophageal cancer (current results from the West) . World J Surg . 1994;18:361–366
- . Technique and role of minimally invasive esophagectomy for premalignant and malignant diseases of the esophagus . Surg Oncol Clin North Am . 2002;11:337–350
- . Minimally invasive esophagectomy . Ann Thorac Surg . 2000;70:906–911 discussion 911–912
- . Downstaging of esophageal cancer after preoperative radiation and chemotherapy . Ann Surg . 1995;221:685–693 discussion 693–695
- Pre-operative radiotherapy prolongs survival in operable esophageal carcinoma: a randomized, multicenter study of pre-operative radiotherapy and chemotherapy. The second Scandinavian trial in esophageal cancer . World J Surg . 1992;16:1104–1109 discussion 1110
- . A randomized study of chemotherapy, radiation therapy, and surgery versus surgery for localized squamous cell carcinoma of the esophagus . Cancer . 1994;73:1779–1784
- . A prospective study of combined therapy in esophageal cancer . Hepatogastroenterology . 1994;41:391–393
- . A comparison of multimodal therapy and surgery for esophageal adenocarcinoma . (comment) N Engl J Med . 1996;335:462–467
- . Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus . N Engl J Med . 1997;337:161–167
- . Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer . (comment) N Engl J Med . 1998;339:1979–1984
- . Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma . J Clin Oncol . 2001;12:305–313
- . A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer . Am J Surg . 2003;185:538–543
- . Survival of patients with carcinoma of the esophagus treated with combined-modality therapy . J Thorac Cardiovasc Surg . 1993;105:749–755 discussion 755–756
- . INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer (high-dose versus standard-dose radiation therapy) . J Clin Oncol . 2002;20:1167–1174
- . Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group . JAMA . 1999;281:1623–1627
- . Methods of palliation of esophageal and gastric cancer . Surg Oncol Clin North Am . 2002;11:459–483
- . Palliative dilation of esophageal carcinoma . Gastrointest Endosc . 1985;31:61–63
- . Esophageal dilation in malignant dysphagia . Cancer . 1985;56:2713–2715
- . Palliative endoscopic dilatation in carcinoma of the esophagus and esophagogastric junciton . Acta Chir Scand . 1989;155:179–184
- . Comparison among the perforation rates of Maloney, balloon, and savary dilation of esophageal strictures . Gastrointest Endosc . 2000;51:460–462
- . A randomized comparison of dilatation alone versus dilatation plus laser in patients receiving chemotherapy and external beam radiation for esophageal carcinoma . Dig Dis Sci . 1998;43:2255–2260
- . Improving results of esophageal stenting (a study on 160 consecutive unselected patients) . Endoscopy . 1997;29:701–709
- . Expandable metal stents for the treatment of cancerous obstruction of the gastrointestinal tract . N Engl J Med . 2001;344:1681–1687
- . Expandable versus conventional esophageal prostheses (easier insertion may not preclude subsequent stent-related problems) . Gastrointest Endosc . 1996;43:204–208
- . Esophageal self-expandable metallic stents–indications, practice, techniques, and complications (results of a national survey) . Gastrointest Endosc . 1997;45:360–364
- . Palliative treatment of oesophageal carcinoma—efficacy of plastic versus self-expandable stents . South Afr Med J . 1999;89:640–643
- . A controlled trial of an expansile metal stent for palliation of esophageal obstruction due to inoperable cancer . N Engl J Med . 1993;329:1302–1307
- . Plastic prosthesis versus expandable metal stents for palliation of inoperable esophageal thoracic carcinoma (a controlled prospective study) . Gastrointest Endosc . 1996;43:478–482
- . Coated self-expanding metal stents versus latex prostheses for esophagogastric cancer with special reference to prior radiation and chemotherapy (a controlled, prospective study) . Gastrointest Endosc . 1998;47:113–120
- . Metal stents improve dysphagia, nutrition and survival in malignant oesophageal stenosis (a randomized controlled trial comparing modified Gianturco Z-stents with plastic Atkinson tubes) . Eur J Gastroenterol Hepatol . 1998;10:653–657
- . Randomized clinical trial comparing self-expanding metallic stents with plastic endoprostheses in the palliation of oesophageal cancer . Br J Surg . 2002;89:985–992
- . A prospective trial of a new self-expanding plastic stent for malignant esophageal obstruction . Am J Gastroenterol . 2001;96:1350–1354
- . Use of the Polyflex stent in the palliative therapy of esophageal carcinoma (results in 14 cases and review of the literature) . Surg Endosc . 2001;15:1444–1447
- . Palliation of esophageal carcinoma with a new self-expanding plastic stent . Endoscopy . 2003;35:207–211
- . Prospective evaluation of a new self-expanding plastic stent for inoperable esophageal strictures . Surg Endosc . 2003;17:891–895
- . Esophageal stent placement without fluoroscopy . Gastrointest Endosc . 2001;53:348–351
- . Placement of esophageal self-expanding metallic stents without fluoroscopy . Gastrointest Endosc . 2001;54:357–359
- . A prospective, randomized, controlled trial of covered expandable metal stents in the palliation of malignant esophageal obstruction at the gastroesophageal junction . Am J Gastroenterol . 2001;96:1791–1796
- . Palliation of inoperable esophageal carcinoma (a prospective randomized trial of laser therapy and stent placement) . Radiology . 1997;202:344–348
- . A new design metal stent (Flamingo stent) for palliation of malignant dysphagia (a prospective study) . Gastrointest Endosc . 2000;51:139–145
- . A randomised prospective comparison of the Flamingo Wallstent and Ultraflex stent for palliation of dysphagia associated with lower third oesophageal carcinoma . Gut . 2003;52:922–926
- . A comparison of 3 types of covered metal stents for the palliation of patients with dysphagia caused by esophagogastric carcinoma (a prospective, randomized study) . Gastrointest Endosc . 2001;54:145–153
- . A practical guide for choosing an expandable metal stent for GI malignancies (is a stent by any other name still a stent?) . Gastrointest Endosc . 2001;54:269–272
- . Gianturco-Z stents in the palliative treatment of malignant esophageal obstruction and esophagotracheal fistulas . Endoscopy . 1995;27:495–500
- . Restenting malignant oesophageal strictures . Br J Surg . 1998;85:261–263
- . Endoscopic Nd:YAG laser therapy for esophageal wallstent occlusion due to tumor ingrowth . Endoscopy . 1996;28:400
- . Photodynamic therapy for the treatment of tumor ingrowth in expandable esophageal stents . Endoscopy . 1997;29:271–274
- . Prior radiation and chemotherapy increase the risk of life-threatening complications after insertion of metallic stents for esophagogastric malignancy . Gastrointest Endosc . 1996;43:196–203
- . A prospective trial of self-expanding metal stents in the palliation of malignant esophageal strictures near the upper esophageal sphincter . Gastrointest Endosc . 1997;45:300–303
- . Morbidity and mortality after self-expandable metallic stent placement in patients with progressive or recurrent esophageal cancer after chemoradiotherapy . Gastrointest Endoscopy . 2003;57:882–885
- . Does chemoradiation therapy increase the incidence of complications with self-expanding coated stents in the management of malignant esophageal strictures . Am J Gastroenterol . 1997;92:2192–2196
- . Palliation of malignant dysphagia and fistulae with coated expandable metal stents (experience with 101 patients) . Gastrointest Endosc . 1998;48:172–179
- . Treatment of unresectable carcinoma of the esophagus or the gastroesophageal junction by mesh stents with or without radiochemotherapy . Int J Oncol . 1998;13:583–588
- . Severe complications in advanced esophageal cancer treated with radiotherapy after intubation of esophageal stents (a questionnaire survey of the Japanese Society for Esophageal Diseases) . Int J Radiat Oncol Biol Phys . 2003;56:1327–1332
- . Self-expanding metal esophageal stent with anti-reflux mechanism . Gastrointest Endosc . 2001;53:603–613
- . Effectiveness of open versus antireflux stents for palliation of distal esophageal carcinoma and prevention of symptomatic gastroesophageal reflux . Radiology . 2002;225:359–365
- . Management of unresectable oesophageal cancer (a review of 537 patients) . Eur J Cardiothorac Surg . 1994;8:113–116
- . Self-expanding metal stents for complicated and recurrent esophagogastric cancer . Gastrointest Endosc . 2001;54:579–586
- . Malignant esophageal fistulas and perforations (management with plastic-covered metallic endoprostheses) . Radiology . 1997;204:527–532
- . Management of malignant esophagotracheal fistulas with airway stenting and double stenting . Chest . 1996;110:1155–1160
- . Comparison of conventional and wire mesh expandable prostheses and surgical bypass in patients with malignant esophagorespiratory fistulas . Ann Thorac Surg . 1998;65:919–923
- . Plastic-covered metallic endoprostheses in the management of oesophageal perforation in patients with oesophageal carcinoma . Clin Radiol . 1995;50:304–309
- . Use of ethanol-induced tumor necrosis to palliate dysphagia in patients with esophagogastric cancer . Gastrointest Endosc . 1990;36:43–46
- . Palliation of malignant dysphagia by ethanol induced tumour necrosis . Gut . 1994;35: 299-203
- . Palliation of malignant oesophageal obstruction by endoscopic alcohol injection . Endoscopy . 1994;26:275–277
- . The use of ethanol injection under endoscopic control to palliate dysphagia caused by esophagogastric cancer . Endoscopy . 1994;26:311–314
- . Palliative treatment of esophageal cancer with transendoscopic injection of alcohol . (in Spanish) Rev Gastroenterol Mex . 1996;61:208–211
- . Intratumoral therapy of cisplatin/epinephrine injectable gel for palliation in patients with obstructive esophageal cancer . Am J Clin Oncol . 2000;23:386–392
- . Palliation of patients with dysphagia due to advanced esophageal cancer by endoscopic injection of cisplatin/epinephrine injectable gel . Gastrointest Endosc . 2002;56:644–651
- . Palliative bipolar electrocoagulation therapy of obstruction of esophageal cancer . Gastrointest Endosc . 1987;33:349–353
- . Comparison of low-power YAG laser and BICAP tumor probe for palliation of esophageal cancer strictures . Gastroenterology . 1988;94:1263–1270
- . Palliative therapy of malignant esophageal stricture with the bipolar tumor probe and prosthetic tube . Gastrointest Endosc . 1989;35:531–535
- . Endoscopic palliation of inoperable cancer of the oesophagus or cardia by argon electrocoagulation . Scand J Gastroenterol . 1998;33:21–23
- . One-stage retrograde approach to Nd:YAG laser palliation of esophageal carcinoma . Endoscopy . 1996;28:350–355
- . A prospective comparison of laser therapy and intubation in endoscopic palliation for malignant dysphagia . Gastroenterology . 1991;100:1303–1310
- . Outpatient management of esophageal cancer with endoscopic Nd:YAG laser . Am J Gastroenterol . 1987;82:46–50
- . Endoscopic Nd-YAG laser therapy as palliative treatment for esophageal and cardial cancer. Parameters affecting long-term outcome . Dig Dis Sci . 1990;35:294–301
- . Laser palliation of inoperable malignant dysphagia (initial and at death) . Gastrointest Endosc . 1996;43:29–32
- . Laser and brachytherapy in the palliation of adenocarcinoma of the oesophagus and cardia . Gut . 1996;39:726–731
- . Radiotherapy enhances laser palliation of malignant dysphagia (a randomised study) . Gut . 1997;40:362–369
- . Laser therapy combined with brachytherapy for the palliation of malignant dysphagia . Singapore Med J . 1998;39:202–207
- . Photodynamic therapy with porfimer sodium versus thermal ablation therapy with Nd:YAG laser for palliation of esophageal cancer (a multicenter randomized trial) . Gastrointest Endosc . 1995;42:507–512
- . Photodynamic therapy for obstructing esophageal cancer (light dosimetry and randomized comparison with Nd:YAG laser therapy) . Gastroenterology . 1995;109:63–72
- . Comparison of 5-aminolaevulinic acid and porphyrin photosensitization for photodynamic therapy of malignant bronchial stenosis (a clinical pilot study) . Lasers Surg Med . 2002;30:12–17
- . A comparison of laser therapy, plastic stents, and expandable metal stents for palliation of malignant dysphagia in patients without a fistula . Gastrointest Endosc . 1998;48:383–388
- . Inoperable adenocarcinoma of the oesophagogastric junction (a comparative clinical study of laser coagulation versus self-expanding metallic stents with special reference to cost analysis) . Eur J Surg Oncol . 2002;28:711–715
- . Expandable metal stents versus laser combined with radiotherapy for palliation of unresectable esophageal cancer (a prospective randomized trial) . Hepatogastroenterology . 2000;47:724–727
- . A randomized trial of thermal ablative therapy versus expandable metal stents in the palliative treatment of patients with esophageal carcinoma . Gastrointest Endosc . 2001;54:549–557
- . Nd:YAG laser versus polidocanol injection for palliation of esophageal malignancy (a prospective, randomized study) . Gastrointest Endosc . 1991;37:607–610
- . Endoscopic palliation of oesophageal cancer (results of a prospective comparison of Nd:YAG laser and ethanol injection) . Eur J Surg . 1999;165:351–356
- . Enteral nutritional support of the patient with cancer (route and role) . J Clin Gastroenterol . 2003;36:297–302
- . Early postoperative enteral nutrition improves gut oxygenation and reduces costs compared with total parenteral nutrition . see comment Crit Care Med . 2001;29:242–248
- . Quality of life and home enteral tube feeding (a French prospective study in patients with head and neck or oesophageal cancer) . Br J Cancer . 2000;82:263–269
- . Percutaneous endoscopic gastrostomy for nutrition in patients with oesophageal cancer . Eur J Surg . 2001;167:839–844
- . Stomal metastases complicating percutaneous endoscopic gastrostomy (CT findings and the argument for radiologic tube placement) . Am J Roentgenol . 2002;179:735–739
- . Assessment of health state utilities and quality of life in patients with malignant esophageal dysphagia . Am J Gastroenterol . 2004;99:1044–1049
- . Life expectancy and cancer risk in patients with Barrett’s esophagus (a prospective controlled investigation) . Am J Med . 2001;111:33–37
- . Conservative treatment versus antireflux surgery in Barrett’s oesophagus (long-term results of a prospective study) . Br J Surg . 1996;83:274–278
- . The incidence of adenocarcinoma in columnar-lined esophagus . N Engl J Med . 1985;313:857–859
- . The development of dysplasia and adenocarcinoma during endoscopic surveillance of Barrett’s esophagus . Am J Gastroenterol . 1998;93:536–541
- . Adenocarcinoma and Barrett’s oesophagus. A clinico-pathological study . Eur J Cardiothorac Surg . 1993;7:126–131
- . Adenocarcinoma arising in Barrett’s esophagus . Dig Dis Sci . 1989;34:1336–1339
- . Barretts’s esophagus (does an antireflux procedure reduce the need for endoscopic surveillance?) . J Thorac Cardiovasc Surg . 1996;111:1135–1138 discussion 1139–1140
- . Length of Barrett’s oesophagus (an important factor in the development of dysplasia and adenocarcinoma) . (see comments) Gut . 1992;33:1155–1158
- . Incidence of adenocarcinoma and mortality in patients with Barrett’s oesophagus diagnosed between 1976 and 1986 (implications for endoscopic surveillance) . Dis Esophagus . 2000;13:28–31
- . Barrett’s esophagus (development of dysplasia and adenocarcinoma) . Gastroenterology . 1989;96:1249–1256 (see comments)
- . Endoscopic surveillance of Barrett’s esophagus (a cost-effectiveness comparison with mammographic surveillance for breast cancer) . Am J Gastroenterol . 1998;93:911–915
- . The incidence of adenocarcinoma in Barrett’s esophagus (a prospective study of 170 patients followed 4.8 years) . Am J Gastroenterol . 1997;92:212–215 (see comments)
- . Incidence of Barrett’s adenocarcinoma in an Italian population: an endoscopic surveillance programme. Gruppo Operativo per lo Studio delle Precancerosi Esofagee (GOSPE) . Eur J Gastroenterol Hepatol . 1997;9:881–885
- . p53 protein overexpression in low grade dysplasia (L.G.D.) in Barrett’s esophagus (immunohistochemical marker predictive of progression) . Am J Gastroenterol . 2001;96:1355–1362
- . Barrett’s esophagus with high-grade dysplasia. An indication for prophylactic esophagectomy . Ann Surg . 1996;224:66–71
- . The rationale for esophagectomy as the optimal therapy for Barrett’s esophagus with high-grade dysplasia . Ann Surg . 1996;223:585–589 discussion 589–591
- . Long-term follow-up of Barrett’s high-grade dysplasia . Am J Gastroenterol . 2000;95:1888–1893
This literature review and the recommendations herein were prepared for the American Gastroenterological Association Clinical Practice and Economics Committee. The paper was approved by the Committee on January 31, 2005, and by the AGA Governing Board on March 20, 2005.
PII: S0016-5085(05)00606-2
doi:10.1053/j.gastro.2005.03.077
© 2005 American Gastroenterological Association. Published by Elsevier Inc. All rights reserved.
