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Incidence of esophageal adenocarcinoma in patients with Barrett's esophagus and high-grade dysplasia: a meta-analysis
ORIGINAL ARTICLE: Clinical Endoscopy
Incidence of esophageal adenocarcinoma in patients with Barrett’s esophagus and high-grade dysplasia: a meta-analysis Amit Rastogi, MD, Srinivas Puli, MD, Hashem B. El-Serag, MD, MPH, Ajay Bansal, MD, Sachin Wani, MD, Prateek Sharma, MD Kansas City, Missouri, USA
Background: Patients with Barrett’s esophagus (BE) and high-grade dysplasia (HGD) are at a high risk for developing esophageal adenocarcinoma. However, the reported rate of cancer development in patients with HGD who were undergoing surveillance has varied among published studies. Objective: To determine an overall precise estimate of cancer incidence in patients with HGD who were undergoing surveillance endoscopy. Design: Systematic review and meta-analysis. Methods: We conducted a systematic search of the published literature and selected original articles that examined patients with histologically proven BE and HGD, patients who had not undergone endoscopic ablation or surgical therapy, patients with 6 months’ follow-up, no esophageal cancer at the time of enrollment or within 6 months, and studies in which follow-up was reported in person-time. Two investigators independently conducted the search and abstraction. Main Outcome Measurement: The weighted mean event rate was calculated and expressed as the weighted incidence rate, and its CIs were calculated. Results: The search yielded 4 articles that met the inclusion criteria, and these were analyzed. A total of 236 patients with HGD were followed for 1241 patient-years, and esophageal adenocarcinoma was reported in 69 patients, providing a crude incidence rate of 5.57 per 100 patient-years. The weighted incidence rate was 6.58 per 100 patient-years (95% CI, 4.97-8.19). Limitations: A small number of studies that met inclusion criteria. Conclusions: In patients with BE and with HGD who were undergoing surveillance, esophageal adenocarcinoma develops in approximately 6 per 100 patient-years during the first few years of follow-up. These data may better inform physicians and patients in management decisions. (Gastrointest Endosc 2008;67:394-8.)
Barrett’s esophagus (BE) is a metaplastic transformation of the esophageal epithelium from the native squamous epithelium to columnar epithelium. BE is a premalignant condition that predisposes to esophageal adenocarcinoma1,2 and increases the risk of cancer development by more than 40-fold.3,4 Histologically, patients with BE are stratified as those with no dysplasia, low-grade dysplasia, and high-grade dysplasia (HGD).5,6 It has been
Copyright ª 2008 by the American Society for Gastrointestinal Endoscopy 0016-5107/$32.00 doi:10.1016/j.gie.2007.07.019
suggested that BE progresses from low-grade dysplasia to HGD and then to esophageal adenocarcinoma.7,8 Patients with BE and HGD are at the highest risk for development of esophageal adenocarcinoma. However, the reported rate of cancer development in HGD in the patients undergoing surveillance has varied in published literature from 5% to 20%, making management of these patients very controversial, ie, surgery versus endoscopic ablation versus observation as the 3 major treatment strategies. Surgical therapy suggested for HGD is esophagectomy,9 which is associated with considerable mortality (4%-19%)10 and morbidity (20%-47%),11 and is highly dependent on surgical value and expectation. Endoscopic therapies for HGD that include different ablative
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Abbreviations: BE, Barrett’s esophagus; HGD, high-grade dysplasia; SD, standard deviation.
Rastogi et al
techniques and mucosal resection are less invasive than esophagectomy, and, although initial results appear promising, the efficacy in reducing the incidence of cancer long term is not clear.12 Although aggressive follow-up and observation alone has been suggested as a strategy, it has no effect on cancer development. Moreover, none of these treatment strategies has been directly compared. There has been a significant rise in the incidence of esophageal adenocarcinoma in the Western countries.13 More frequent use of endoscopy, both for screening and for surveillance of BE, has resulted in an increased rate of detection of BE and HGD.14 There is no clear consensus regarding the optimal management strategy for HGD in BE. We performed a systematic review and meta-analysis of existing studies to determine the cancer incidence in patients with HGD in BE undergoing surveillance endoscopy. This is desirable, not only to assist both physicians and patients in making management decisions but also to evaluate the efficacy of different treatment modalities for HGD.
Esophageal adenocarcinoma in patients with BE and HGD
Capsule Summary What is already known on this topic d
Patients with high-grade dysplasia in Barrett’s esophagus (HGD-BE) have a high risk for developing esophageal adenocarcinoma, but the reported cancer rate has varied.
What this study adds to our knowledge d
In a meta-analysis of 236 patients with HGD-BE followed for 1241 patient-years, esophageal adenocarcinoma was reported in 69 patients, providing a weighted incidence rate of 6.58 per 100 patient-years.
surveillance biopsy protocol, study design, and incidence of cancer development. Two investigators independently performed the search and abstracted data. Areas of differences and inconsistencies between the data abstractors were resolved by consensus.
MATERIALS AND METHODS Search criteria Studies were systematically searched independently by 2 investigators in MEDLINE (1966 to January 2006), PubMed, Ovid journals, the Database of Abstracts of Reviews of Effect, ACP Journal Club, the Cumulative Index to Nursing and Allied Health Literature, International Pharmaceutical Abstracts, old MEDLINE, MEDLINE Nonindexed Citations, BIOSIS Previews, the Food and Drug Administration database, and Cochrane Control Trial Registry. The key words used to search were Barrett’s esophagus, BE, high grade dysplasia, dysplasia, surveillance, esophageal adenocarcinoma, esophageal cancer, cancer, carcinoma, dysplasia-carcinoma sequence, gastroesophageal reflux disease, and HGD. Each abstract and title was screened for eligibility. All the references at the end of each selected article were explored to retrieve additional studies.
Study selection Studies in the English language that met all of the following inclusion criteria were selected: (1) patients with histologically proven BE and HGD, (2) patients not having undergone endoscopic ablation or surgical therapy, (3) no esophageal cancer at the time of enrollment or within 6 months, and (4) follow-up reported in persontime. All studies with an average follow-up duration of less than 6 months were excluded because cancers detected within 6 months may be prevalence rather than incidence cancers.
Statistical method A meta-analysis was conducted by combining the cancerevent rate (incidence) in each study by using weighted incidence rates. The mean event rate for each study weighted by its patient-year was used to obtain a weighted incidence rate. Approximate 95% CIs for the weighted incidence rates were calculated by Chiang’s normal approximation to Poisson rate sums (Poisson model)15-17 and by an improved approximation adjusted for the total number of observed events (binomial model). A random effects model was performed by using the Laird and DerSimonian methods, and the effect size was estimated.18 The point estimates for each study as the summary estimate and their corresponding 95% CIs were presented in a forest plot. Because of the small number of studies, the test of heterogeneity is unreliable in this case but was performed nonetheless. Publication bias was tested with the funnel plot and the Egger test.
Role of funding sources No funding sources had any role in the design, performance, analysis, or reporting of this systematic review and meta-analysis.
RESULTS Search findings
The abstracted data included the following: number of patients with HGD in BE, follow-up in person-years,
Our initial search yielded 3843 citations. Of these, 196 articles were relevant, and these were retrieved and reviewed. Finally, 4 of 196 articles were selected, because they met all the inclusion and exclusion criteria. The rest were excluded because they did not meet the inclusion criteria. There was complete agreement between the investigators on selection of these studies.
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Volume 67, No. 3 : 2008 GASTROINTESTINAL ENDOSCOPY 395
Data abstraction
Esophageal adenocarcinoma in patients with BE and HGD
Rastogi et al
TABLE 1. Study characteristics
Study, year, country 20
Reid et al,
2000, USA
Patient count (n)
Mean follow-up (y)
Histologically proven HGD
Type of biopsy forceps
Biopsy protocol, frequency
327
4
Yes
Jumbo forceps
4-Quadrant biopsies every 1 or 2 cm, and every 4.6 mo
Weston et al,21 2000, USA
19
3
Yes
Jumbo forceps
4-Quadrant biopsies every 1 cm and every 3-6 mo
Schnell et al,19 2001, USA
79
7.3
Yes
Standard 28-mm forceps
If BE !1 cm, then 2 biopsies; if BE O2 cm, then 4-quadrant biopsies; every 3 mo initially
Overholt et al,22 2005, USA, Canada
70
1.5
Yes
Jumbo forceps
4-Quadrant biopsies every 2 cm, every 3 mo
Study characteristics Three of the studies were conducted in a single center,19-21 and 1 was a multicenter study by Overholt et al.22 The latter was also the only study that was a partially blinded randomized trial of endoscopic treatment with photodynamic therapy vs observation in patients with BE and with HGD; the remaining 3 were observational case series. All patients enrolled in these studies had no history of esophageal adenocarcinoma, and a baseline and at least 1 follow-up endoscopic examination within 6 months did not reveal esophageal malignancy. All patients had histologic-proven HGD. The selected characteristics of each study is shown in Table 1. The study by Overholt et al22 included 70 patients, with a mean age of 67 years; 84% men, 97% white. Thirty-five patients had a BE length !6 cm, and 35 had a BE length of R6 cm. Adenocarcinoma developed in 20 patients during follow-up. Schnell et al19 followed 75 patients with HGD; mean age was 74 years, 98% were men, and 98% were white. The mean (standard deviation [SD]) length of BE was 3.8 3.8 cm. Adenocarcinoma developed in 12 patients during follow-up. Weston et al21 reported on 15 patients with a mean age of 61 years, all men and all white. The mean (SD) BE length was 6.8 4 cm. Adenocarcinoma developed in 4 patients during follow-up. The study by Reid et al20 did not elaborate on age, sex, or BE length. Data regarding the distribution of dysplasia (multifocal vs unifocal) or the presence of gross lesions were not reported uniformly in these studies, although, in the study by Weston et al,21 all patients had unifocal HGD.
incidence rate was 5.57 per 100 patient-years, whereas the weighted incidence rate calculated in the random effects model was 6.58 per 100 patient-years. When using the Poisson’s model, the 95% CIs for the weighted incidence rate were calculated as 4.99 to 8.46. By the binomial model, the 95% CI was 4.97 to 8.18. The forest plot is shown in Figure 1, and the size of the dark squares on the CIs indicates the weight of the study. The weight of each study is a direct indicator of the magnitude of the esophageal cancer incidence rate in that study. Statistically significant heterogeneity was present (P Z .02), suggesting significant differences among the studies. Because of this heterogeneity, each study was systematically eliminated in estimating heterogeneity, and the study by Weston et al21 was determined to be the outlier. Without the Weston et al21 study, the crude incidence rate of esophageal adenocarcinoma was 5.44 per 100 patientyears, and the weighted incidence rate was 6.45 per 100 patient-years (95% CI 4.81–8.06) (Fig. 2). The P value for the test of heterogeneity was .1. The Egger test and the funnel plot were not suggestive of publication bias.
DISCUSSION
Data from the 4 studies that met the inclusion and exclusion criteria were analyzed for cancer incidence. The 4 studies contained a total of 236 patients followed for 1241 patient-years, during which time a total of 69 esophageal adenocarcinomas were reported. The crude
Despite the lack of high-level evidence for a survival advantage, endoscopic screening of patients with longstanding reflux and surveillance of patients with BE have been proposed.23,24 With increasing numbers of screening upper endoscopies being performed, there has been a rise in the detection and recognition of BE as well as HGD.14 Circumstantial evidence indicates the sequential histologic alteration from BE with no dysplasia to low-grade dysplasia followed by HGD and finally adenocarcinoma. Patients with HGD have the highest risk of progression to esophageal adenocarcinoma, with rates varying from 5% to 20% over a short time period. Furthermore, esophagectomy specimens in small studies of patients with HGD in
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Incidence of esophageal adenocarcinoma
Rastogi et al
Esophageal adenocarcinoma in patients with BE and HGD
BE have revealed up to a 30% to 40% prevalence of invasive cancer.25 The considerable variation in the risk of progression of HGD to cancer in different studies19,20,26,27 has contributed to the unresolved debate regarding multiple management strategies for patients with HGD. These include esophagectomy, endoscopic ablative therapies, EMR, and intensive surveillance. The risks and benefits of each of these strategies are beyond the scope of this discussion. A precise estimate of the progression of HGD to cancer will provide insight to the patient and the physician, and will help decide upon the further management tailored to the needs and expectations of the patient. This analysis was aimed to determine the precise cancer incidence in patients with BE and with HGD who were undergoing surveillance. By using strict inclusion criteria, we determined only 4 studies could be included in the meta-analysis. The overall weighted incidence rate for the development of cancer was estimated to be 6.58 per 100 patient-years (95% CI 4.99-8.46) during the initial 1.5 to 7 years after HGD diagnosis. These figures can assist patients and physicians in making important management decisions. For example, a 55-year-old healthy patient with HGD may opt for aggressive management, such as esophagectomy, given that his cancer risk over the next 5 years may be 30% to 35%. However, a patient with a life
expectancy of less than 5 years may choose a less aggressive approach. There are several inherent problems in using the diagnosis of dysplasia as a cancer-risk marker in patients with BE. Histologic changes from reflux esophagitis can mimic those of low-grade dysplasia. Although generally low for any dysplasia, interobserver agreement among pathologists is best for HGD.28,29 In a multicenter study,30 the kappa score for HGD/carcinoma was 0.65 (substantial), for BE without dysplasia it was 0.58 (moderate–substantial), but for low-grade dysplasia it was 0.32 (fair). Apart from this, there is the issue of sampling error on biopsy specimens obtained during endoscopy. Because dysplasia in BE is usually flat and patchy, random 4-quadrant biopsies can miss areas of dysplasia or early cancer. For instance, if adenocarcinoma is detected in patients with a previous endoscopy that shows no dysplasia or lowgrade dysplasia only, then the potential explanations would be rapid progression of dysplasia to cancer between surveillance endoscopies, sampling error, or development of cancer directly from metaplastic epithelium without dysplasia.31 However, despite these challenges associated with the diagnosis of dysplasia, it still remains the risk marker routinely used in clinical practice. One of the limitations of this meta-analysis is the small number of studies that could be included and the relatively small number of patients and events in these studies. The small number of studies has prevented robust assessment of heterogeneity and publication bias. In addition, all 4 studies that met the inclusion criteria were conducted in North America, thus limiting the generalizability of these results. The calculated pooled estimate for the incidence of esophageal adenocarcinoma assumes a linear increase in the incidence over time; the validity of this assumption is unknown. Further, the information pertains predominantly to the first few years after HGD diagnosis, and whether similar risk exists in the long term is unknown. There are also limitations related to the information available in the individual studies. Patients with all lengths of BE with HGD were included, and, hence, this analysis does not differentiate between the risk of progression to cancer in short versus long-segment BE. Also, differentiating between the rates of progression of unifocal versus multifocal HGD and flat versus nodular HGD was not possible from these studies. This review also does not identify the risk or confounding factors for progression of HGD to cancer, including the presence of hiatus hernia or the use of aspirin, nonsteroidal anti-inflammatory drugs, or proton pump inhibitors. In conclusion, this meta-analysis is an attempt to synthesize the information from different studies and provide a more precise estimate of cancer risk in patients with BE and with HGD. These data may help better inform physicians and patients in management decisions and also help in future studies to compare the extent of any reduction in cancer incidence after intervention therapy for HGD.
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Figure 1. Forest (meta-analysis) plot for the weighted incidence rate of esophageal adenocarcinoma in 4 studies of patients with BE and HGD.
Figure 2. Forest (meta-analysis) plot for the weighted incidence rate without the Weston et al21 study.
Esophageal adenocarcinoma in patients with BE and HGD
ACKNOWLEDGMENT This study was supported by the Veterans’ Affairs Medical Center, Kansas City, Missouri.
DISCLOSURES The following authors report that they have no disclosures relevant to this publication: S. Puli, H. B. El-Serag, A. Bansal, S. Wani. The following authors have disclosed actual or potential conflicts: P. Sharma has received grants from Olympus and Barrx. A. Rastogi has received a grant from Procter and Gamble.
REFERENCES 1. Winters C Jr, Spurling TJ, Chobanian SJ, et al. Barrett’s esophagus. A prevalent, occult complication of gastroesophageal reflux disease. Gastroenterology 1987;92:118-24. 2. Spechler SJ, Robbins AH, Rubins HB, et al. Adenocarcinoma and Barrett’s esophagus. An overrated risk? Gastroenterology 1984;87:927-33. 3. Hamilton SR, Smith RRL, Cameron JL. Prevalence and characteristics of Barrett esophagus in patients with adenocarcinoma of the esophagus or esophagogastric junction. Hum Pathol 1988;19:942-8. 4. MacDonald WC, MacDonald JB. Adenocarcinoma of the esophagus and/or gastric cardia. Cancer 1987;60:1094-8. 5. Paull A, Trier JS, Dalton MD, et al. The histologic spectrum of Barrett’s esophagus. N Engl J Med 1976;295:476-80. 6. Thompson JJ, Zinsser KR, Enterline HT. Barrett’s metaplasia and adenocarcinoma of the esophagus and gastroesophageal junction. Hum Pathol 1983;14:42-61. 7. Reid BJ, Sa´nchez CA, Blount PL, et al. Barrett’s esophagus: cell cycle abnormalities in advancing stages of neoplastic progression. Gastroenterology 1993;105:119-29. 8. Stein HJ, Siewert JR. Barrett’s esophagus: pathogenesis, epidemiology, functional abnormalities, malignant degeneration and surgical management. Dysphagia 1993;8:276-88. 9. Stein HJ. Esophageal cancer: screening and surveillance. Results of a consensus conference held at the VIth World Congress of the International Society for Diseases of the Esophagus. Dis Esophagus 1996;9: S3-19. 10. Swisher SG, DeFord L, Merriman KW, et al. Effects of operative volume on morbidity, mortality, and hospital use after esophagectomy for cancer. J Thorac Cardiovasc Surg 2000;119:1126-34. 11. Begg CB, Cramer LD, Hoskins WJ, et al. Impact of hospital volume on operative mortality for major cancer surgery. JAMA 1998;280:1747-51. 12. Ell C, May A, Pech O, et al. Curative endoscopic resection of early esophageal adenocarcinomas (Barrett’s cancer). Gastrointest Endosc 2007;65:3-10. 13. Pohl H, Welch HG. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J Natl Cancer Inst 2005;97:142-6. 14. Conio M, Cameron AJ, Romero Y, et al. Secular trends in the epidemiology and outcome of Barrett’s esophagus in Olmsted County, Minnesota. Gut 2001;48:304-9.
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Rastogi et al 15. Chiang CL. Standard error of the age-adjusted death rate. US Department of Health, Education and Welfare: Vital Statistics Special Reports 1961;47:271-85. 16. Keyfitz N. Sampling variance of standardized mortality rates. Hum Biol 1966;38:309-17. 17. Dobson AJ, Kuulasmaa K, Eberle E, et al. Confidence intervals for weighted sums of Poisson parameters. Stat Med 1991;10:457-62. 18. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88. 19. Schnell TG, Sontag SJ, Chejfec G, et al. Long-term nonsurgical management of Barrett’s esophagus with high-grade dysplasia. Gastroenterology 2001;120:1607-19. 20. Reid BJ, Levine DS, Longton G, et al. 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;95:1669-76. 21. Weston AP, Sharma P, Topalovski M, et al. Long-term follow-up of Barrett’s high-grade dysplasia. Am J Gastroenterol 2000;95:1888-93. 22. Overholt BF, Lightdale CJ, Wang KK, et al. Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Barrett’s esophagus: international, partially blinded, randomized phase III trial. Gastrointest Endosc 2005;62:488-98. 23. Sampliner RE. Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines for the diagnosis, surveillance, and therapy of Barrett’s esophagus. Am J Gastroenterol 2002;97:1888-95. 24. Sharma P, McQuaid K, Dent J, et al. A critical review of the diagnosis and management of Barrett’s esophagus: the AGA Chicago Workshop. Gastroenterology 2004;127:310-30. 25. Collard JM. High-grade dysplasia in Barrett’s esophagus. The case for esophagectomy. Chest Surg Clinic 2002;12:77-92. 26. Hameeteman W, Tytgat GN, Houthoff HJ, et al. Barrett’s esophagus: development of dysplasia and adenocarcinoma. Gastroenterology 1989;96:1249-56. 27. Buttar NS, Wang KK, Sebo TJ, et al. Extent of high grade dysplasia in Barrett’s esophagus correlates with risk of adenocarcinoma. Gastroenterology 2001;120:1630-9. 28. Reid BJ, Haggitt RC, Rubin CE. Observer variation in the diagnosis of dysplasia in Barrett’s esophagus. Hum Pathol 1988;19:166-78. 29. Skacel M, Petras RE, Gramlich TL, et al. The diagnosis of low-grade dysplasia in Barrett’s esophagus and its implications for disease progression. Am J Gastroenterol 2000;95:3383-7. 30. Montgomery E, Bronner MP, Goldblum JR, et al. Reproducibility of the diagnosis of dysplasia in Barrett’s esophagus: a reaffirmation. Hum Pathol 2001;32:368-78. 31. Spechler SJ. Dysplasia in Barrett’s esophagus: limitations of current management strategies. Am J Gastroenterol 2005;100:927-35.
Received March 21, 2007. Accepted July 9, 2007. Current affiliations: Division of Gastroenterology and Hepatology (A.R., A.B., S.W., P.S.), University of Kansas School of Medicine and Veteran’s Affairs Medical Center, Department of Internal Medicine (S.P.), University of Kansas School of Medicine, Kansas City, Kansas, Sections of Gastroenterology and Health Services Research (H.B.E.-S.), Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, Texas, USA. Reprint requests: Prateek Sharma, MD, Gastroenterology Section-111, University of Kansas School, VA Medical Center, 4801 E. Linwood Blvd, Kansas City, MO 64128.
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Incidence of esophageal adenocarcinoma in patients with Barrett’s esophagus and high-grade dysplasia: a meta-analysis Amit Rastogi, MD, Srinivas Puli, MD, Hashem B. El-Serag, MD, MPH, Ajay Bansal, MD, Sachin Wani, MD, Prateek Sharma, MD Kansas City, Missouri, USA
Background: Patients with Barrett’s esophagus (BE) and high-grade dysplasia (HGD) are at a high risk for developing esophageal adenocarcinoma. However, the reported rate of cancer development in patients with HGD who were undergoing surveillance has varied among published studies. Objective: To determine an overall precise estimate of cancer incidence in patients with HGD who were undergoing surveillance endoscopy. Design: Systematic review and meta-analysis. Methods: We conducted a systematic search of the published literature and selected original articles that examined patients with histologically proven BE and HGD, patients who had not undergone endoscopic ablation or surgical therapy, patients with 6 months’ follow-up, no esophageal cancer at the time of enrollment or within 6 months, and studies in which follow-up was reported in person-time. Two investigators independently conducted the search and abstraction. Main Outcome Measurement: The weighted mean event rate was calculated and expressed as the weighted incidence rate, and its CIs were calculated. Results: The search yielded 4 articles that met the inclusion criteria, and these were analyzed. A total of 236 patients with HGD were followed for 1241 patient-years, and esophageal adenocarcinoma was reported in 69 patients, providing a crude incidence rate of 5.57 per 100 patient-years. The weighted incidence rate was 6.58 per 100 patient-years (95% CI, 4.97-8.19). Limitations: A small number of studies that met inclusion criteria. Conclusions: In patients with BE and with HGD who were undergoing surveillance, esophageal adenocarcinoma develops in approximately 6 per 100 patient-years during the first few years of follow-up. These data may better inform physicians and patients in management decisions. (Gastrointest Endosc 2008;67:394-8.)
Barrett’s esophagus (BE) is a metaplastic transformation of the esophageal epithelium from the native squamous epithelium to columnar epithelium. BE is a premalignant condition that predisposes to esophageal adenocarcinoma1,2 and increases the risk of cancer development by more than 40-fold.3,4 Histologically, patients with BE are stratified as those with no dysplasia, low-grade dysplasia, and high-grade dysplasia (HGD).5,6 It has been
Copyright ª 2008 by the American Society for Gastrointestinal Endoscopy 0016-5107/$32.00 doi:10.1016/j.gie.2007.07.019
suggested that BE progresses from low-grade dysplasia to HGD and then to esophageal adenocarcinoma.7,8 Patients with BE and HGD are at the highest risk for development of esophageal adenocarcinoma. However, the reported rate of cancer development in HGD in the patients undergoing surveillance has varied in published literature from 5% to 20%, making management of these patients very controversial, ie, surgery versus endoscopic ablation versus observation as the 3 major treatment strategies. Surgical therapy suggested for HGD is esophagectomy,9 which is associated with considerable mortality (4%-19%)10 and morbidity (20%-47%),11 and is highly dependent on surgical value and expectation. Endoscopic therapies for HGD that include different ablative
394 GASTROINTESTINAL ENDOSCOPY Volume 67, No. 3 : 2008
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Abbreviations: BE, Barrett’s esophagus; HGD, high-grade dysplasia; SD, standard deviation.
Rastogi et al
techniques and mucosal resection are less invasive than esophagectomy, and, although initial results appear promising, the efficacy in reducing the incidence of cancer long term is not clear.12 Although aggressive follow-up and observation alone has been suggested as a strategy, it has no effect on cancer development. Moreover, none of these treatment strategies has been directly compared. There has been a significant rise in the incidence of esophageal adenocarcinoma in the Western countries.13 More frequent use of endoscopy, both for screening and for surveillance of BE, has resulted in an increased rate of detection of BE and HGD.14 There is no clear consensus regarding the optimal management strategy for HGD in BE. We performed a systematic review and meta-analysis of existing studies to determine the cancer incidence in patients with HGD in BE undergoing surveillance endoscopy. This is desirable, not only to assist both physicians and patients in making management decisions but also to evaluate the efficacy of different treatment modalities for HGD.
Esophageal adenocarcinoma in patients with BE and HGD
Capsule Summary What is already known on this topic d
Patients with high-grade dysplasia in Barrett’s esophagus (HGD-BE) have a high risk for developing esophageal adenocarcinoma, but the reported cancer rate has varied.
What this study adds to our knowledge d
In a meta-analysis of 236 patients with HGD-BE followed for 1241 patient-years, esophageal adenocarcinoma was reported in 69 patients, providing a weighted incidence rate of 6.58 per 100 patient-years.
surveillance biopsy protocol, study design, and incidence of cancer development. Two investigators independently performed the search and abstracted data. Areas of differences and inconsistencies between the data abstractors were resolved by consensus.
MATERIALS AND METHODS Search criteria Studies were systematically searched independently by 2 investigators in MEDLINE (1966 to January 2006), PubMed, Ovid journals, the Database of Abstracts of Reviews of Effect, ACP Journal Club, the Cumulative Index to Nursing and Allied Health Literature, International Pharmaceutical Abstracts, old MEDLINE, MEDLINE Nonindexed Citations, BIOSIS Previews, the Food and Drug Administration database, and Cochrane Control Trial Registry. The key words used to search were Barrett’s esophagus, BE, high grade dysplasia, dysplasia, surveillance, esophageal adenocarcinoma, esophageal cancer, cancer, carcinoma, dysplasia-carcinoma sequence, gastroesophageal reflux disease, and HGD. Each abstract and title was screened for eligibility. All the references at the end of each selected article were explored to retrieve additional studies.
Study selection Studies in the English language that met all of the following inclusion criteria were selected: (1) patients with histologically proven BE and HGD, (2) patients not having undergone endoscopic ablation or surgical therapy, (3) no esophageal cancer at the time of enrollment or within 6 months, and (4) follow-up reported in persontime. All studies with an average follow-up duration of less than 6 months were excluded because cancers detected within 6 months may be prevalence rather than incidence cancers.
Statistical method A meta-analysis was conducted by combining the cancerevent rate (incidence) in each study by using weighted incidence rates. The mean event rate for each study weighted by its patient-year was used to obtain a weighted incidence rate. Approximate 95% CIs for the weighted incidence rates were calculated by Chiang’s normal approximation to Poisson rate sums (Poisson model)15-17 and by an improved approximation adjusted for the total number of observed events (binomial model). A random effects model was performed by using the Laird and DerSimonian methods, and the effect size was estimated.18 The point estimates for each study as the summary estimate and their corresponding 95% CIs were presented in a forest plot. Because of the small number of studies, the test of heterogeneity is unreliable in this case but was performed nonetheless. Publication bias was tested with the funnel plot and the Egger test.
Role of funding sources No funding sources had any role in the design, performance, analysis, or reporting of this systematic review and meta-analysis.
RESULTS Search findings
The abstracted data included the following: number of patients with HGD in BE, follow-up in person-years,
Our initial search yielded 3843 citations. Of these, 196 articles were relevant, and these were retrieved and reviewed. Finally, 4 of 196 articles were selected, because they met all the inclusion and exclusion criteria. The rest were excluded because they did not meet the inclusion criteria. There was complete agreement between the investigators on selection of these studies.
www.giejournal.org
Volume 67, No. 3 : 2008 GASTROINTESTINAL ENDOSCOPY 395
Data abstraction
Esophageal adenocarcinoma in patients with BE and HGD
Rastogi et al
TABLE 1. Study characteristics
Study, year, country 20
Reid et al,
2000, USA
Patient count (n)
Mean follow-up (y)
Histologically proven HGD
Type of biopsy forceps
Biopsy protocol, frequency
327
4
Yes
Jumbo forceps
4-Quadrant biopsies every 1 or 2 cm, and every 4.6 mo
Weston et al,21 2000, USA
19
3
Yes
Jumbo forceps
4-Quadrant biopsies every 1 cm and every 3-6 mo
Schnell et al,19 2001, USA
79
7.3
Yes
Standard 28-mm forceps
If BE !1 cm, then 2 biopsies; if BE O2 cm, then 4-quadrant biopsies; every 3 mo initially
Overholt et al,22 2005, USA, Canada
70
1.5
Yes
Jumbo forceps
4-Quadrant biopsies every 2 cm, every 3 mo
Study characteristics Three of the studies were conducted in a single center,19-21 and 1 was a multicenter study by Overholt et al.22 The latter was also the only study that was a partially blinded randomized trial of endoscopic treatment with photodynamic therapy vs observation in patients with BE and with HGD; the remaining 3 were observational case series. All patients enrolled in these studies had no history of esophageal adenocarcinoma, and a baseline and at least 1 follow-up endoscopic examination within 6 months did not reveal esophageal malignancy. All patients had histologic-proven HGD. The selected characteristics of each study is shown in Table 1. The study by Overholt et al22 included 70 patients, with a mean age of 67 years; 84% men, 97% white. Thirty-five patients had a BE length !6 cm, and 35 had a BE length of R6 cm. Adenocarcinoma developed in 20 patients during follow-up. Schnell et al19 followed 75 patients with HGD; mean age was 74 years, 98% were men, and 98% were white. The mean (standard deviation [SD]) length of BE was 3.8 3.8 cm. Adenocarcinoma developed in 12 patients during follow-up. Weston et al21 reported on 15 patients with a mean age of 61 years, all men and all white. The mean (SD) BE length was 6.8 4 cm. Adenocarcinoma developed in 4 patients during follow-up. The study by Reid et al20 did not elaborate on age, sex, or BE length. Data regarding the distribution of dysplasia (multifocal vs unifocal) or the presence of gross lesions were not reported uniformly in these studies, although, in the study by Weston et al,21 all patients had unifocal HGD.
incidence rate was 5.57 per 100 patient-years, whereas the weighted incidence rate calculated in the random effects model was 6.58 per 100 patient-years. When using the Poisson’s model, the 95% CIs for the weighted incidence rate were calculated as 4.99 to 8.46. By the binomial model, the 95% CI was 4.97 to 8.18. The forest plot is shown in Figure 1, and the size of the dark squares on the CIs indicates the weight of the study. The weight of each study is a direct indicator of the magnitude of the esophageal cancer incidence rate in that study. Statistically significant heterogeneity was present (P Z .02), suggesting significant differences among the studies. Because of this heterogeneity, each study was systematically eliminated in estimating heterogeneity, and the study by Weston et al21 was determined to be the outlier. Without the Weston et al21 study, the crude incidence rate of esophageal adenocarcinoma was 5.44 per 100 patientyears, and the weighted incidence rate was 6.45 per 100 patient-years (95% CI 4.81–8.06) (Fig. 2). The P value for the test of heterogeneity was .1. The Egger test and the funnel plot were not suggestive of publication bias.
DISCUSSION
Data from the 4 studies that met the inclusion and exclusion criteria were analyzed for cancer incidence. The 4 studies contained a total of 236 patients followed for 1241 patient-years, during which time a total of 69 esophageal adenocarcinomas were reported. The crude
Despite the lack of high-level evidence for a survival advantage, endoscopic screening of patients with longstanding reflux and surveillance of patients with BE have been proposed.23,24 With increasing numbers of screening upper endoscopies being performed, there has been a rise in the detection and recognition of BE as well as HGD.14 Circumstantial evidence indicates the sequential histologic alteration from BE with no dysplasia to low-grade dysplasia followed by HGD and finally adenocarcinoma. Patients with HGD have the highest risk of progression to esophageal adenocarcinoma, with rates varying from 5% to 20% over a short time period. Furthermore, esophagectomy specimens in small studies of patients with HGD in
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Incidence of esophageal adenocarcinoma
Rastogi et al
Esophageal adenocarcinoma in patients with BE and HGD
BE have revealed up to a 30% to 40% prevalence of invasive cancer.25 The considerable variation in the risk of progression of HGD to cancer in different studies19,20,26,27 has contributed to the unresolved debate regarding multiple management strategies for patients with HGD. These include esophagectomy, endoscopic ablative therapies, EMR, and intensive surveillance. The risks and benefits of each of these strategies are beyond the scope of this discussion. A precise estimate of the progression of HGD to cancer will provide insight to the patient and the physician, and will help decide upon the further management tailored to the needs and expectations of the patient. This analysis was aimed to determine the precise cancer incidence in patients with BE and with HGD who were undergoing surveillance. By using strict inclusion criteria, we determined only 4 studies could be included in the meta-analysis. The overall weighted incidence rate for the development of cancer was estimated to be 6.58 per 100 patient-years (95% CI 4.99-8.46) during the initial 1.5 to 7 years after HGD diagnosis. These figures can assist patients and physicians in making important management decisions. For example, a 55-year-old healthy patient with HGD may opt for aggressive management, such as esophagectomy, given that his cancer risk over the next 5 years may be 30% to 35%. However, a patient with a life
expectancy of less than 5 years may choose a less aggressive approach. There are several inherent problems in using the diagnosis of dysplasia as a cancer-risk marker in patients with BE. Histologic changes from reflux esophagitis can mimic those of low-grade dysplasia. Although generally low for any dysplasia, interobserver agreement among pathologists is best for HGD.28,29 In a multicenter study,30 the kappa score for HGD/carcinoma was 0.65 (substantial), for BE without dysplasia it was 0.58 (moderate–substantial), but for low-grade dysplasia it was 0.32 (fair). Apart from this, there is the issue of sampling error on biopsy specimens obtained during endoscopy. Because dysplasia in BE is usually flat and patchy, random 4-quadrant biopsies can miss areas of dysplasia or early cancer. For instance, if adenocarcinoma is detected in patients with a previous endoscopy that shows no dysplasia or lowgrade dysplasia only, then the potential explanations would be rapid progression of dysplasia to cancer between surveillance endoscopies, sampling error, or development of cancer directly from metaplastic epithelium without dysplasia.31 However, despite these challenges associated with the diagnosis of dysplasia, it still remains the risk marker routinely used in clinical practice. One of the limitations of this meta-analysis is the small number of studies that could be included and the relatively small number of patients and events in these studies. The small number of studies has prevented robust assessment of heterogeneity and publication bias. In addition, all 4 studies that met the inclusion criteria were conducted in North America, thus limiting the generalizability of these results. The calculated pooled estimate for the incidence of esophageal adenocarcinoma assumes a linear increase in the incidence over time; the validity of this assumption is unknown. Further, the information pertains predominantly to the first few years after HGD diagnosis, and whether similar risk exists in the long term is unknown. There are also limitations related to the information available in the individual studies. Patients with all lengths of BE with HGD were included, and, hence, this analysis does not differentiate between the risk of progression to cancer in short versus long-segment BE. Also, differentiating between the rates of progression of unifocal versus multifocal HGD and flat versus nodular HGD was not possible from these studies. This review also does not identify the risk or confounding factors for progression of HGD to cancer, including the presence of hiatus hernia or the use of aspirin, nonsteroidal anti-inflammatory drugs, or proton pump inhibitors. In conclusion, this meta-analysis is an attempt to synthesize the information from different studies and provide a more precise estimate of cancer risk in patients with BE and with HGD. These data may help better inform physicians and patients in management decisions and also help in future studies to compare the extent of any reduction in cancer incidence after intervention therapy for HGD.
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Figure 1. Forest (meta-analysis) plot for the weighted incidence rate of esophageal adenocarcinoma in 4 studies of patients with BE and HGD.
Figure 2. Forest (meta-analysis) plot for the weighted incidence rate without the Weston et al21 study.
Esophageal adenocarcinoma in patients with BE and HGD
ACKNOWLEDGMENT This study was supported by the Veterans’ Affairs Medical Center, Kansas City, Missouri.
DISCLOSURES The following authors report that they have no disclosures relevant to this publication: S. Puli, H. B. El-Serag, A. Bansal, S. Wani. The following authors have disclosed actual or potential conflicts: P. Sharma has received grants from Olympus and Barrx. A. Rastogi has received a grant from Procter and Gamble.
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Received March 21, 2007. Accepted July 9, 2007. Current affiliations: Division of Gastroenterology and Hepatology (A.R., A.B., S.W., P.S.), University of Kansas School of Medicine and Veteran’s Affairs Medical Center, Department of Internal Medicine (S.P.), University of Kansas School of Medicine, Kansas City, Kansas, Sections of Gastroenterology and Health Services Research (H.B.E.-S.), Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, Texas, USA. Reprint requests: Prateek Sharma, MD, Gastroenterology Section-111, University of Kansas School, VA Medical Center, 4801 E. Linwood Blvd, Kansas City, MO 64128.
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