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Esophageal Adenocarcinoma in Barrett’s Esophagus After Endoscopic Ablative Therapy: A Meta-Analysis and Systematic Review Sachin Wani, MD1,2, Srinivas R. Puli, MD1,2, Nicholas J. Shaheen, MD, MPH1,2, Brenda Westhoff, MD1,2, Sanjeev Slehria, MD1,2, Ajay Bansal, MD1,2, Amit Rastogi, MD1,2, Hari Sayana, MD1,2 and Prateek Sharma, MD1,2
OBJECTIVES:
The extent of reduction of esophageal adenocarcinoma (EAC) incidence in Barrett’s esophagus (BE) patients after endoscopic ablation is not known. The objective of this study was to determine the cancer incidence in BE patients after ablative therapy and compare these rates to cohort studies of BE patients not undergoing ablation.
METHODS:
A MEDLINE search of the literature on the natural history and ablative modalities in BE patients was performed. Patients with nondysplastic BE (NDBE), low-grade dysplasia (LGD), or high-grade dysplasia (HGD) and follow-up of at least 6 months were included. The rate of cancer in patients undergoing ablation and from the natural history data was calculated using weighted-average incidence rates (WIR).
RESULTS:
A total of 53 articles met the inclusion criteria for the natural history data. Pooled natural history data showed cancer incidence of 5.98/1,000 patient-years (95% CI 5.05–6.91) in NDBE; 16.98/1,000 patient-years (95% CI 13.1–20.85) in LGD; and 65.8/1,000 patient-years (95% CI 49.7–81.8) in HGD patients. A total of 65 articles met the inclusion criteria for BE patients undergoing ablation (1,457 patients, NDBE; 239 patients, LGD; and 611 patients, HGD). The WIR for cancer was 1.63/1,000 patient-years (95% CI 0.07–3.34) for NDBE; 1.58/1,000 patient-years (95% CI 0.66–3.84) for LGD; and 16.76/1,000 patient-years (95% CI 10.6–22.9) for HGD patients.
CONCLUSIONS: Compared to historical reports of the natural history of BE, ablation may be associated with a
reduction in cancer incidence, although such a comparison is limited by likely heterogeneity between treatment and natural history studies. The greatest benefit of ablation was observed in BE patients with HGD. Am J Gastroenterol 2009; 104:502–513; doi:10.1038/ajg.2008.31; published online 6 January 2009
INTRODUCTION Barrett’s esophagus (BE) is an acquired condition resulting from chronic gastroesophageal reflux disease and is a wellrecognized premalignant condition for the development of esophageal adenocarcinoma (EAC) (1,2). It is characterized by a metaplastic transformation of the squamous epithelium to a columnar type identified by the typical salmon-colored cephalad displacement of the squamocolumnar junction into the tubular esophagus, accompanied by the presence of goblet
cells on histologic evaluation (3). The condition entails a 30- to 50-fold greater risk of developing EAC and has an incidence of development of adenocarcinoma that approaches 0.5% annually (4–6). EAC is a highly lethal cancer and is the most rapidly increasing cancer in the United States and Western Europe with an incremental increase of 4–10% per year (7–9). Clinical strategies for preventing deaths from this cancer focus on techniques for identification of esophageal neoplasms in an asymptomatic, early, and curable stage. Screening for
1
Division of Gastroenterology and Hepatology, Veterans Affairs Medical Center, University of Kansas School of Medicine, Kansas City, Missouri, USA; 2Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina, USA. Correspondence: Prateek Sharma, MD, Division of Gastroenterology (111), Veterans Affairs Medical Center, University of Kansas School of Medicine, 4801 E. Linwood Blvd., Kansas City, Missouri, USA. E-mail:
[email protected] Received 15 August 2008; accepted 2 September 2008 The American Journal of GASTROENTEROLOGY
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BE in the general population cannot be recommended at the present time and screening in selective high-risk population has yet to be established (10). Despite the lack of clinical evidence, patients with BE are then routinely enrolled in surveillance programs in an attempt to identify those who might benefit from treatment at a preinvasive stage of EAC with an ultimate aim of reducing cancer-related deaths (10–12). Esophageal carcinogenesis is a multistep process that may progress along the histological sequence of intestinal metaplasia, low-grade dysplasia (LGD), high-grade dysplasia (HGD), and invasive adenocarcinoma. The degree of dysplasia has been shown to correlate with the risk of developing cancer, and HGD is associated with the greatest risk (13). The cancer incidence in patients with LGD appears to be 0.6% per year whereas HGD patients may have in excess of a 5% risk per year (6,14,15). Unfortunately, neither medical (profound acid inhibition) (16,17) nor surgical (fundoplication) (18,19) therapies appear to achieve complete regression of BE and elimination of its cancer risk and the incidence of cancer in patients treated with either surgical antireflux procedures or medical therapy appears to be similar (20). Because of the morbidity and mortality associated with surgical esophagectomy, there has been interest in ablative therapies for BE which offers a less invasive treatment option (21). Several ablative therapies have been developed in attempts to reverse BE and reduce cancer risk. Modalities include argon plasma coagulation (APC), multipolar electrocoagulation (MPEC), lasers (neodymium–yttrium aluminum garnet, potassium titanium phosphate), photodynamic therapy (PDT), and radiofrequency energy (22–26). These techniques are based on the hypothesis that injury of the metaplastic epithelium combined with vigorous acid suppression would lead to reversion of the BE to squamous epithelium and reduce the risk of progression to cancer (23). It is not known if ablative therapies eliminate or significantly reduce cancer incidence in the long term. The goals of this systematic review and meta-analysis were: (i) to determine the incidence of EAC in patients with nondysplastic BE (ND BE), LGD, and HGD undergoing routine surveillance and (ii) to determine the incidence of EAC in patients with ND BE, LGD, and HGD that underwent endoscopic ablation therapy.
METHODS Search strategy
A systematic review of all published articles that provided information about the number or percentage of patients that developed EAC in the setting of BE was performed. Similarly, a systematic review of the medical literature for published articles and abstracts on ablative therapies in BE patients that provided information about the number or percentage of patients that developed EAC after ablation, and length of follow-up was performed. All English language articles were searched in MEDLINE (through PubMed, an electronic search engine for published articles and Ovid) for the years 1966 to January 2008, ACP Journal club, cumulative index to nursing and allied health literature, International pharmaceutical abstracts, © 2009 by the American College of Gastroenterology
old MEDLINE, MEDLINE nonindexed citations, Biosis previews, FDA databases (medical devices), and Cochrane Central Register of Controlled Trials (CENTRAL). Proceedings from the annual meetings of the American Gastroenterological Association and the American College of Gastroenterology were hand searched to identify relevant abstracts. Medical subject headings or keywords used for the search included Barrett’s esophagus, Barrett’s oesophagus, BE, dysplasia, low-grade dysplasia, LGD, high-grade dysplasia, HGD, surveillance, esophageal adenocarcinoma, esophageal cancer, cancer, carcinoma, dysplasia–carcinoma sequence, gastroesophageal reflux disease, recurrence AND ablation, laser, NdYAG, KTP, argon plasma coagulation, photodynamic therapy, multipolar electrocoagulation, and radiofrequency ablation (RFA). The bibliographies from each article were then scanned to identify additional articles for inclusion. A manual search of expert opinion review articles was performed and bibliographies from subject experts were reviewed. Each abstract was screened for eligibility. All the references at the end of each selected article were explored to retrieve additional studies. This process was repeated by a second independent assessor, and discrepancies resolved by consensus. Our process and reporting conform to the standards proposed by the Meta-Analysis of Observational Studies in Epidemiology study group (27). Study selection
Criteria for study selection were defined a priori. Studies in the natural history group were included if they met the following inclusion criteria: (i) patients with histologically proven BE with or without dysplasia at cohort inception; (ii) patients not having undergone endoscopic ablation or surgical therapy, (iii) no esophageal cancer at the time of enrollment or within 6 months; and (iv) follow-up reported in person-time. All studies with an average follow-up duration of less than 6 months were excluded because cancers detected within 6 months may be prevalent rather than incident cancers. Studies in the ablative group were included if they met the following inclusion criteria: (i) study included patients with ND BE and/or LGD and/or HGD; (ii) subjects had undergone ablative endoscopic therapy (APC, MPEC, PDT, laser, radiofrequency ablation); (iii) histological confirmation of BE with or without dysplasia at cohort inception; (iv) histological confirmation of any EAC during the follow-up period; (v) mean or median follow-up postablative therapy was reported, and was of at least 6 months’ duration. Studies were excluded if: (i) patients had a prior history of EAC; (ii) patients had documented EAC at initiation of ablative therapy; (iii) patients underwent endoscopic mucosal resection (EMR); (iv) patients had partial ablation of BE. The inclusion criteria were not restricted by study size and uncontrolled trials were not excluded from the analysis. Data Abstraction and validity assessment
Variables assessed in the data abstraction processes included number of patients, study design, type of ablation, type of analysis (per protocol or intent to treat), treatment arms, preablation The American Journal of GASTROENTEROLOGY
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histology (ND BE, LGD, HGD), mean or median follow-up after ablation, histology at the end of follow-up, number of EAC developed during the follow-up period, and time to the development of cancer. BE patients reported in this analysis met the standardized definition—the presence of endoscopically visible columnar mucosa in the distal esophagus of any length with intestinal metaplasia documented on histology. In situations when a single study reported follow-up of subjects with differing degrees of dysplasia, study outcomes and follow-up time were apportioned as appropriate between the various dysplasia categories. When studies reported multiple methods of ablative therapy, study outcomes, and follow-up time were similarly apportioned between appropriate treatment groups. Studies were scored for quality by using the criteria established by Jadad et al. (controlled trials—scale: 0–5) (28) and by Wells et al. (Newcastle–Ottawa scale (uncontrolled observational studies—scale: 0–9)) (29). The full text of selected articles was reviewed independently by two investigators (SW, SP) and any disagreement in the data abstracted was resolved by consensus. If serial publications reported cancer risk in the same cohort of patients, only the most recent report was included in the analysis. Study authors were contacted when the province of the patients in serial reports could not be determined from the publications. The primary outcome assessment was the incidence rate of EAC after ablation in BE patients for varying degrees of dysplasia, expressed as cancers per patient-year. This was compared to “control rates”—rate of cancer development in patients with BE from the natural history data. Statistical analysis
Because most studies do not present patient-level data on cancer rates by age, gender, or years from diagnosis, only crude rates could be derived from these studies. Patient-years were calculated as: number of patients×mean duration of follow-up. Incidence rates were calculated as number of cases of EAC/ patient-years. The incidence of EAC after ablative therapy was weighted for the sample size and duration of follow-up to obtain a summary weighted-average incidence rate. This summary incidence rate of esophageal cancer in each ablative treatment modality was expressed as weighted-average incidence rate (WIR). Similarly, weighted EAC incidence rates were obtained from the natural history data to give a WIR for controls. Further, in order to test for study homogeneity, tests of heterogeneity were performed using the DerSimonian– Laird random effects analysis (30). If P value is >0.10, the null hypothesis that studies are heterogeneous is rejected. Confidence intervals for WIR were calculated by Chiang’s normal approximation to Poisson rate sums (Poisson model) (31) and by an improved approximation adjusted for the total number of observed events (binomial model) (32). The estimated size of difference between groups was calculated with the 95% confidence interval (95% CI). Because almost all the reported data in this analysis originated from cohort, rather than comparative studies, we were unable to generate true estimates of the number needed to treat (NNT) to avoid one cancer. Use of a The American Journal of GASTROENTEROLOGY
weighted incidence rate was chosen for our analysis over more traditional methods of meta-analysis, such as Mantel–Haensel or Peto methodology, because the time-dependent nature of the data did not allow categorization into 2×2 tables. Publication bias was tested using the Egger’s test and funnel plot diagrams (33). If the P value is >0.05, the null hypothesis that there is publication bias is rejected. Role of funding sources
No funding source had any role in the design, performance, analsis or reporting of this systematic review and meta-analysis.
RESULTS The initial search identified 4,327 reference articles of which 457 relevant articles were selected and reviewed. A total of 65 original articles that met the inclusion and exclusion criteria provided sufficient information to determine the number and proportion of patients with EAC postablative therapy (Appendix). These studies included 1,457 patients with ND BE, 239 with LGD, and 611 with HGD. This analysis included 28 studies in which APC was the treatment modality; 9 studies with laser treatment; 11 with MPEC; 22 studies with PDT or PDT-ALA (5-aminolevulinic acid) and one study with RFA as the treatment modality. Six studies reported more than one type of treatment modality in the study. A total of 53 original articles that met the inclusion and exclusion criteria provided sufficient information to determine the number and proportion of patients with EAC during surveillance endoscopy (i.e. natural history). These studies included 6,847 patients with ND BE (Table 1), 1,512 with LGD (Table 2), and 236 with HGD (Table 3). This analysis included 45 studies (5,6,15,34–74) that provided information on the incidence of EAC in patients with ND BE, 16 studies (6,14,15,42,45,54,69,70,72,73,75–80) in LGD patients and 4 studies (14,15,26,81) in patients with HGD. Barrett’s esophagus without dysplasia
The incidence of EAC (WIR) in ND BE patients undergoing surveillance was 5.98 per 1,000 patients-years (95% CI: 5.05– 6.91); test of heterogeneity, P = 0.96. The cancer incidence (WIR) in this group of patients undergoing ablative treatment by all methodologies was 1.63 per 1,000 patient-years (95% CI 0.07–3.34); test of heterogeneity, P = 0.99 (Table 4A). Barrett’s esophagus with low-grade dysplasia
In the control group of BE patients with LGD undergoing surveillance, the incidence of EAC (WIR) was 16.98/1,000 patient-years (95% CI 13.1–20.85); test of heterogeneity, P = 0.99 whereas the WIR in patients after ablative treatment was 1.58/1,000 patient-years (95% CI 0.66–3.84); test of heterogeneity, P = 0.99 (Table 4B). Barrett’s with high-grade dysplasia
The incidence (WIR) after ablative treatment in BE patients with HGD was 16.76/1,000 patient-years (95% CI 10.6–22.9); VOLUME 104 | FEBRUARY 2009 www.amjgastro.com
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Author
Year
No. of patients
Years in follow-up
Patient years in follow-up
No. of incident cancers
Spechler et al. (34)
1984
105
3.3
350
2
Savary et al. (35)
1984
402
3.8
1,528
5
Cameron et al. (36)
1985
104
8.4
882
2
Cooper and Barbezat (37)
1987
52
0.8
45
0
Robertson et al. (38)
1988
56
3
168
3
Achkar and Carey (39)
1988
62
2.6
166
1
Skinner (40)
1989
45
3.2
145
3
Ovaska et al. (41)
1989
32
5.1
166
3
Hameeteman et al. (42)
1989
50
5.2
260
5
Williamson et al. (43)
1991
176
2.8
497
5
Watson et al. (44)
1991
45
3.5
158
1
Miros et al. (45)
1991
81
3.6
290
3
Iftikhar et al. (46)
1992
102
4.5
462
4
Bartelsman et al. (47)
1992
50
5.2
260
5
Reid et al. (48)
1992
62
2.8
176
5
Moghissi et al. (49)
1993
26
11.5
299
4
van der Burgh et al. (50)
1996
155
9.2
1,440
8
McDonald et al. (51)
1996
112
6.5
728
3
Ortiz et al. (52)
1996
59
4.8
287
2
Drewitz et al. (53)
1997
170
4.9
834
4
3
562
3
94
2
Ferraris et al. (54)
1997
187
Weston et al. (55)
1997
55
1.7
Streitz et al. (56)
1998
149
3.4
510
7
Csendes et al. (57)
1998
151
7.5
1,147
4
Katz et al. (58)
1998
102
Teodori et al. (59)
1998
30
O’Connor et al. (5)
1999
125
Sharma et al. (60)
2000
78
Bani-Hani et al. (61)
2000
307
3.58
5.5
563
3
390
4
4.2
525
1
2.58
201
1
1,099
12
13
MacDonald et al. (62)
2000
143
4.4
629
5
Rana and Johnston (63)
2000
44
9.5
418
2
Reid et al. (15)
2000
129
Conio et al. (64)
2001
79
Oberg et al. (65)
2001
Basu et al. (66)
2001
Spechler et al. (67)
2001
108
Parilla et al. (68)
2003
40
Conio et al. (69)
2003
150
6.6
990
4
Murray et al. (70)
2003
1300
3.9
5,070
21
Meining et al. (71)
2004
26
2.5
65
0
Basu et al. (66)
2004
112
2.9
405
2
Hage et al. (72)
2004
64
12.7
812
6
Dulai et al. (73)
2005
441
3.44
1,517
2
Sharma et al. (6)
2006
618
4.12
2,546
12
Gladman et al. (74)
2006
195
5.5
1,068
4
© 2009 by the American College of Gastroenterology
3.9
503
5
5
395
4
140
5.8
812
3
128
2.9
371
0
9.6
1,037
4
200
2
5
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Table 1. Publications reporting the incidence of esophageal adenocarcinoma in nondysplastic Barrett’s esophagus
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Table 2. Publications reporting the incidence of esophageal adenocarcinoma in Barrett’s esophagus patients with low-grade dysplasia Author
Year
No. of patients with LGD
Years in follow-up
Patient-years in follow-up
Hameeteman et al. (42)
1989
6
5.2
31
3
Miros et al. (45)
1991
10
3.6
36
1
Ferraris et al. (54)
1997
5
3
15
1
Reid et al. (15)
2000
43
168
3
3.9 2
No. of incident cancers
Montgomery et al. (75)
2001
26
52
4
Schnell et al. (14)
2001
738
7.3
5,387
10
Weston et al. (76)
2001
48
3.4
163
1
Skacel et al. (77)
2002
16
1.9
30
2
Murray et al. (70)
2003
171
3.7
633
7
Conio et al. (69)
2003
16
5.5
88
1
12.7
Hage et al. (72)
2004
11
140
1
Dulai et al. (73)
2005
134
3.21
430
1
Sharma et al. (6)
2006
156
5
780
5
Srivastava et al. (78)
2007
31
3.1
96
14
Lim et al. (79)
2007
34
8
272
9
Vieth (80)
2007
67
2.33
156
23
LGD, low-grade dysplasia.
Table 3. Publications reporting the incidence of esophageal adenocarcinoma in Barrett’s esophagus patients with high-grade dysplasia Author
Year
No. of patients with HGD
Years in follow-up
Patient-years in follow-up
No. of incident cancers
Overholt et al. (26)
2005
70
1.5
105
20
Reid et al. (15)
2000
76
4
304
42
Schnell et al. (14)
2001
75
7.3
547.5
12
Weston et al. (81)
2000
15
3
45
4
HGD, high-grade dysplasia.
test of heterogeneity, P = 0.47 whereas BE patients with HGD undergoing surveillance showed a WIR of 65.8 cancers per 1,000 patient-years (95% CI 49.7–81.9); test of heterogeneity, P = 0.02 of follow-up (Table 4C). There was no evidence of publication bias for studies that evaluated the effect of ablative therapies on ND BE and HGD patients whereas publication bias was identified in LGD patients. The Egger bias test gave a value of 0.06 (95% CI: − 0.009 to 0.143, P = 0.08) for ND BE and 0.316 (95% CI: − 0.08 to 0.71, P = 0.11) for HGD patients. A value of − 0.066 (95% CI: − 0.125 to − 0.007, P = 0.02) was obtained for LGD patients suggestive of publication bias. In addition, there was no evidence The American Journal of GASTROENTEROLOGY
of publication bias for studies that reported incidence of EAC in BE patients (ND BE (Egger bias test 0.2, 95% CI: − 0.03 to 0.44, P = 0.09) and HGD (Egger bias test 2.41, 95% CI: − 10.5 to 15.4, P = 0.5)) undergoing surveillance. However, publication bias was identified in LGD patients undergoing follow-up (Egger bias test 2.07, 95% CI: 1.06–3.07, P = 0.0006). The possibility that this is related to small study effects cannot be excluded. As majority of the studies that met inclusion criteria in this meta-analysis and systematic review were observational uncontrolled trials, an analysis of results based on study quality was performed. The median score for study quality using the Newcastle–Ottawa scoring system was 5.5. As a VOLUME 104 | FEBRUARY 2009 www.amjgastro.com
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Treatment modality
No. of studies
No. of patients
Direct WIR per 1,000 patient-years
95% confidence interval
(A) Nondysplastic BE APC
27
773
1.76
− 0.3
15.26
− 14.65
3.816
LASER
6
71
MPEC
11
399
0
0
0
PDT
1
15
0
0
0
PDT-ALA
3
57
0
0
0
PDT+PDT-ALA
4
72
0
0
0
0
0
0
1.632
0.072
3.348
RFA
45.12
1
70
49
1457
APC
9
103
0
0
0
LASER
4
19
0
0
0
MPEC
2
10
0
0
0
PDT
2
53
2.85
− 2.74
PDT-ALA
4
54
4.22
− 4.05
PDT+PDT-ALA
6
107
3.55
− 1.46
8.56
21
239
1.58
0.66
3.84
APC
6
46
42.7
LASER
4
16
32.14
MPEC
0
0
10
479
10.83
6.62
15.03
8
70
47.7
4.15
91.23
PDT+PDT-ALA
18
549
15.54
8.88
22.18
All modalities
28
611
16.76
10.62
22.9
All modalities (B) BE with LGD
All modalities
8.46 12.5
(C) BE with HGD
PDT PDT-ALA
0
4.32 − 30.4 0
81.1 94.69 0
ALA, aminolevulinic acid; APC, argon plasma coagulation; BE, Barrett’s esophagus; HGD, high-grade dysplasia; LGD, low-grade dysplasia; MPEC, multipolar electrocoagulation; PDT, photodynamic therapy; PDT-ALA, PDT-5-aminolevulinic acid; RFA, radiofrequency ablation; WIR, weighted-average incidence rate.
subgroup analysis, when divided at the median, studies with scores either above or below the median did not report significantly different WIRs.
DISCUSSION BE is a common condition present in 10–15% of individuals with chronic gastroesophageal reflux disease (82). Increased interest in BE has paralleled the rising risk of EAC, the cancer with the most rapidly increasing per capita risk in the Western world (7,8). A wide variety of endoscopic mucosal ablative techniques have been evaluated in an effort to define the role of ablative therapies in patients with BE with or without dysplasia. However, the degree of long-term control of neoplasia is not known and most of the reports are in © 2009 by the American College of Gastroenterology
the form of case series with a dearth of randomized controlled trials. This meta-analysis and systematic review demonstrates that for BE patients that underwent ablative therapies, the WIR for cancer was 1.63/1,000 patient-years (95% CI − 0.07 to 3.34) for NDBE; 1.58/1,000 patient-years (95% CI − 0.66 to 3.84) for LGD; and 16.76/1,000 patient-years (95% CI 10.6–22.9) for HGD patients. Interestingly, the WIR for cancer was higher for ND BE than for LGD patients undergoing ablation. This most likely represents a statistical aberrancy due to smaller sample sizes in the LGD studies. On the other hand, the natural history pooled data in BE patients undergoing surveillance showed considerably higher cancer incidence rates of 5.98/1,000 patientyears (95% CI 5.05–6.91) in ND BE; 16.98/1,000 patient-years (95% CI 13.1–20.85) in LGD; and 65.8/1,000 patient-years The American Journal of GASTROENTEROLOGY
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Table 4. WIR of esophageal adenocarcinoma in Barrett’s esophagus patients undergoing ablative therapy
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(95% CI 49.7–81.8) in HGD patients. As noted above, given the differences in the patient characteristics and the inability to adjust for the various confounding variables, a direct comparison between the two groups (patients undergoing surveillance, i.e. natural history and those that underwent ablative therapies) was not possible. If we were to calculate approximate NNTs (despite the limitations stated above), when comparing the WIR of ablative groups to those of historical surveillance controls, the NNT with ablative therapies to prevent one case of EAC in a given year for ND BE was 250 and for HGD patients it was 20. The WIR for EAC appears to be approximately four times lower in the ablation group for both ND BE and HGD patients. As the baseline risk of EAC is increased approximately 10-fold in HGD patients, the NNT is likely to be much lower for this highrisk group of patients. These findings suggest that endoscopic ablation of BE may be associated with a reduction in cancer incidence with the greatest benefit observed in HGD patients. These data have important ramifications regarding the application of ablative therapy in patients with no dysplasia or lesser degrees of dysplasia. In such patients, the risks and costs associated with any proposed ablative therapy must be low enough to compensate for the low rate of malignant progression in these groups. Innovations in endoscopic therapy have allowed for the development of various ablative therapies which offer minimally invasive treatment options for patients with BE with or without dysplasia. This study provides insight into the risks of development of EAC postablative therapies. The results of this study serve another important purpose. It has been shown that patients with prevalent BE participating in an endoscopic surveillance program overestimated their chances of developing EAC (83). Intuitively, BE patients may have a poor understanding of the cancer risk after ablation as well. These data allow gastroenterologists to better inform patients with BE of their risk of EAC after ablation which in turn could decrease healthrelated anxiety, improve quality of life, and avoid overuse of health care resources. At present, it appears that improved efforts to educate patients regarding true risk of cancer in the setting of BE are warranted. Persistence of underlying intestinal metaplasia (superficial and buried under the neosquamous epithelium) after ablation is a problem that cannot be ignored. This has been reported in 0–44% of cases and long-term follow-up of successfully treated patients show recurrence of intestinal metaplasia ranging from 0% to 68% (84). This is not specific for the type of ablative therapy and a number of investigators using various modes of ablative therapy have reported this finding (22,85–88). Residual intestinal metaplasia carries with it the potential to progress to dysplasia and/or adenocarcinoma although the magnitude of this risk is not well characterized (89,90). Regardless of the magnitude of malignant progression after ablative therapy, it is clear that cancer risk is only reduced and not abolished. Treatment may need to be repeated and surveillance endoscopy with procurement The American Journal of GASTROENTEROLOGY
of biopsies from the area of former Barrett’s is currently recommended. This systematic review and meta-analysis has several limitations. This meta-analysis includes cohort studies in which patients were not randomly assigned to an intervention and there was no control/sham group in the majority of the studies. This precluded comparing the results between patients that underwent ablative therapies and those that were undergoing routine surveillance. Hence, accurate calculations of relative risk reduction after ablation along with numbers needed to treat were not possible. The true lifetime cancer risk for a patient with BE is unknown. It is also not clear that the EAC incidence rate in BE remains constant over time, or that the rate is the same for patients in all age groups. Although survival analysis techniques would most ideally address the time-dependent nature of the relationships explored in this study, the vast majority of reports do not report censoring events from time zero and only give cumulative crude incidence data over a set period of time. Hence performance of survival analysis is not possible with the available data but unrealistically simplified a complex biological process allowing us to make at least some estimate of frequency of outcomes of interest. The control cancer incidence rates were obtained by pooling patients from published studies reporting the natural history of BE. This may be a source of bias as surveillance after ablation may be more rigorous than routine surveillance, and healthier patients may preferentially be enrolled. However, we would expect more rigorous biopsy protocols to bias to work against the efficacy of ablative therapy, as more intensive surveillance decreases the likelihood of a missed cancer. Surveillance intervals were not standardized throughout the studies. Another concern about the interpretation of these results is the potential for publication bias in the reported studies. Recent data demonstrate that the cancer risk in BE may be overestimated in the literature and it is possible that “negative” ablation studies have not been reported (91). There was heterogeneity in acid suppressive therapies (proton pump inhibitors/antireflux surgery) throughout the studies, which could not be factored into the final analysis. These analyses could not account for the effect of confounding variables such as age, length of BE segment, smoking, etc., on the overall cancer incidence rates in the patients undergoing ablation or surveillance and no sensitivity analyses were able to be performed. Also, the authors did not seek to identify unpublished data and although rigorous attempts were made to locate all studies that conformed to the defined criteria, it is possible that some studies escaped the notice of the authors. As abstracts were included in this analysis, the data appearing solely in abstracts may be of poorer quality than those published in journals. Another limitation is that the incidence of complications (esophageal strictures, perforations, etc.) was not assessed (overall or for individual modalities). In a systematic review and meta-analysis that assessed the incidence of strictures following ablative therapy, Wei et al. reported that the highest risk of esophageal stricture formation postablative therapy was associated with PDT with porfimer VOLUME 104 | FEBRUARY 2009 www.amjgastro.com
sodium (35%) followed by laser ablation (4.5%), APC (3.2%), and MPEC (0.9%) (92). EMR was not included in this analysis. The majority of the studies involving EMR have used this technique also as a diagnostic tool and hence it is difficult to ascertain if complete EMR was performed. Also, EMR was usually used with other therapies. This technique shows much promise but is an inherently different kind of therapy that allows the complete removal of mucosal lesions by resecting through the middle or deep layers of the submucosa. Future prospective studies should explore the incidence rate reduction of EAC treated with EMR with or without other ablation techniques in patients with BE. Studies were included in the final analysis only if patients were followed up for at least 6 months after ablation. Although the appropriate duration for such studies is debatable, it is unlikely that evaluating cancer risk for 6 months or less is sufficient. To elucidate the true cancer risk, data on patients followed-up for a longer duration (>5 years) would be ideal. Such studies are rare in the literature. Several important questions should be addressed in future studies. Large randomized prospective studies should evaluate if ablation therapy reduces/eliminates cancer risk. Studies should focus on whether ablative therapies eliminate the necessity of further endoscopic surveillance, whether they are cost effective, and whether the risks of ablation are less than the risk of progression of BE. Better risk stratification of BE patients is required given that only a minority will develop HGD and/or cancer and also that patients can progress to cancer from nondysplastic tissue. High-risk patient groups with BE should be identified and surveillance strategies should be focused on this patient group, saving health care dollars. Advances in understanding the biology of BE are necessary to select candidates appropriately. Validation of biomarkers (ploidy studies, cytogenic techniques) in combination with risk factors of gender, ethnicity, obesity, etc., that would improve the ability of select the high-risk patient groups would represent a major biologic breakthrough. In summary, this systematic review suggests that endoscopic ablation of BE (ND BE, LGD, and HGD) is associated with low rates of progression to cancer. When compared to historical cohorts undergoing endoscopic surveillance, there may be a reduction in cancer incidence rates; the higher the grade of dysplasia, the greater the absolute reduction in the cancer risk. Treatment for BE with the various ablative therapies should be guided by the “primum nil nocere” principle. These procedures are not without risk for complications (strictures, perforation, bleeding, and ulceration) that could potentially impact the patient’s life. Although the relative risk for EAC in the setting of BE is high compared to those without BE, the absolute risk is still low (0.5% per person-year for ND BE) (5,6). Therefore, ablation of ND BE awaits evidence demonstrating that the costs and risks associated with the procedure are outweighed by the benefits before widespread use of this is adopted in clinical practice. Similarly, spontaneous regression © 2009 by the American College of Gastroenterology
of LGD has been demonstrated in the majority of BE patients, and the vast majority of subjects with ND BE and LGD will not benefit from ablative therapy. The greatest benefit appears to be in patients with HGD and these data support the current practice offering ablation to such patients. These data will help better inform physicians and patients contemplating endoscopic ablation therapy. ACKNOWLEDGMENTS
This research was supported by the Veterans Affairs Medical Center, Kansas City, Missouri. CONFLICT OF INTEREST
Guarantor of the article: Sachin Wani, MD and Prateek Sharma, MD. Specific author contributions: All authors participated in the design, conductance, analysis, and in writing the paper. All authors have approved the final draft submitted. Financial support: None. Potential competing interest: None. REFERENCES 1. Winters C, Spurling TC, Chobanian SJ et al. Barrett’s esophagus: a prevalent occult complication of gastroesophageal reflux disease. Gastroenterology 1987;92:118–24. 2. Hamilton SR, Smith R, Cameron JL. Prevalence and characteristics of Barrett’s esophagus in patients with adenocarcinoma of the esophagus or esophagogastric junction. Hum Pathol 1988;19:942–8. 3. Spechler SJ. Clinical practice. Barrett’s esophagus. N Engl J Med 2002;346:836–42. 4. Drewitz DJ, Sampliner RE, Garewal HS. The incidence of adenocarcinoma in Barrett’s esophagus: a prospective study of 170 patients followed 4.8 years. Am J Gastroenterol 1997;92:212–5. 5. O’Connor JB, Falk GW, Richter JE. The incidence of adenocarcinoma and dysplasia in Barrett’s esophagus: report on the Cleveland Clinic Barrett’s Esophagus Registry. Am J Gastroenterol 1999;94:2037–42. 6. Sharma P, Falk GW, Weston AP et al. Dysplasia and cancer in a large multicenter cohort of patients with Barrett’s esophagus. Clin Gastroenterol Hepatol 2006;4:566–72. 7. Blot WJ, McLaughlin JK. The changing epidemiology of esophageal cancer. Semin Oncol 1999;26:2–8. 8. Brown LM, Devesa SS. Epidemiologic trends in esophageal and gastric cancer in the United States. Surg Oncol Clin N Am 2002;11:235–56. 9. Eloubeide MA, Mason AC, Desmond RA et al. Temporal trends (1973–1997) in survival of patients with esophageal adenocarcinoma in the United States: a glimmer of hope? Am J Gastroenterol 2003;98: 1627–33. 10. Wang KK, Sampliner RE. Updated guidelines 2008 for the diagnosis, surveillance and therapy of Barrett’s esophagus. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 2008;103:788–97. 11. Falk GW, Ours TM, Richter JE. Practice patterns for surveillance of Barrett’s esophagus in the United States. Gastrointest Endosc 2000;52:197–203. 12. Corley DA, Levin TR, Habel LA et al. Surveillance and survival in Barrett’s adenocarcinoma: a population based study. Gastroenterology 2002;122:633–40. 13. Rastogi A, Puli S, El-Serag HB et al. Incidence of esophageal adenocarcinoma in patients with Barrett’s esophagus and high-grade dysplasia: a meta analysis. Gastrointest Endosc 2008;67:394–9. 14. 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. 15. Reid BJ, Levine DS, Longton G et al. Predictors of progression of cancer in Barrett’s esophagus: Baseline histology and flow cytometry identify lowand high-risk patient subsets. Am J Gastroenterol 2000;95:1669–76.
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APPENDIX List of studies with the follow up periods Author
Type of Rx
No. of patients
Grade of dysplasia
Follow-up period
Time to development of cancer
Study quality
Bright et al.
APC
20
BE 19 LGD 1
Mean 68 m
No CA
2a
Sharma et al.
APC MPEC
19 16
BE 35
Mean 24 m
No CA
3a
Ferraris et al.
APC
96
BE 96
Mean 36 m
No CA
6
Overholt et al.
PDT
138
HGD 138
Mean 60 m
21 CA
2a
Sharma et al.
RFA
70
BE 70
Mean 12 m
No CA
5
APC
60
BE 60
Mean 14 m
No CA
6
APC MPEC
24 24
BE 24 BE 23 LGD 1
Mean 24 m, median 25 m (12–40), mean 24 m, median 25 m (12–40)
No CA No CA
3a
PDT-ALA APC
25 14
BE 20 LGD 5 BE 11 LGD 3
Mean 12 m (6–24), mean 12 m (9–21)
No CA No CA
1a
2007
2006 Manner et al. 2005 Dulai et al.
2004 Hage et al.
© 2009 by the American College of Gastroenterology
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List of studies with the follow up periods Author
Type of Rx
No. of patients
Grade of dysplasia
Follow-up period
Time to development of cancer
Study quality
Norberto et al.
Nd:YAG laser
15
BE 11 LGD 2 HGD 2
Mean 28 m (7–61)
No CA
6
Wang et al.
PDT
127
BE 15 LGD 40 HGD 72
Mean 80 m (24–134)
4 CA 3-baseline HGD: 71, 71, 44 m to CA 1-baseline LGD: 28 m to CA
6
Kelty et al.
PDT-ALA APC
34 34
BE 34 BE 34
Median 24 m (1–24)
No CA
1a
Rahmani et al.
APC
97
BE 75 LGD 22
Mean 36 m (4–70 )
No CA
5
Rahmani et al.
PDT
63
HGD 63
Mean 30 m (6–72)
No CA
6
Wolfsen et al.
PDT
60
HGD 60
Median 19 m (6–78)
No CA
6
Haringsma et al.
PDT (5-ALA)
11
HGD 11
Mean 10.6 m (3–25)
No CA
4
Macrae et al.
PDT (5-ALA)
8
HGD 8
R: 5–98
1 CA
6
Ackroyd et al.
PDT-ALA
40
LGD 40
Median 53 m (18–68)
1 CA: 36 m to CA
6
Overholt et al.
PDT
78
LGD 13 HGD 65
Mean 58.5 m (41–122)
1 CA: 6 m to CA
6
Lowe et al.
MPEC APC
46 2
BE 46 BE 2
Mean 32 m (24–84)
No CA
6
Bowers et al.
KTP
9
BE 8 LGD 1
Mean 81.6 m (72–90)
No CA
4
Morino et al.
APC
23
BE 23
Mean 31.9 m (16–45)
No CA
6
Zoepf et al.
PDT-ALA APC
10 10
LGD 4 HGD 6 BE 5 LGD 5
Median 27 m (12–42), median 24 m (4–46)
No CA No CA
1a
Madisch et al.
APC
62
BE 62
Median 46 m (9–85)
No CA
5
Tam et al.
APC
34
BE 34
12 m
No CA
1a
Jamieson et al.
PDT-ALA
22
HGD 22
Median 18 m
CA4: 1, 3, 3, and 8 m to CA
6
Fisher et al.
Nd:YAG
21
BE 6 LGD 12 HGD 3
Mean 32.4 m (1–78)
CA 1: 6 m to CA
6
Attwood et al.
APC
29
HGD 29
Mean 37 m (7–78)
CA 4
5
Basu et al.
APC
50
BE
Mean 14 m
No CA
6
Ortner et al.
PDT –ALA
8
BE:3 LGD:5
Mean 32.6 m (12–48)
No CA
6
Weston et al.
Nd:YAG
7
HGD 7
Mean 12.8 m (2–36)
No CA
5
Wolfson et al.
PDT
34
HGD 34
Median 18.5 m (1–56)
No CA
6
Kahaleh et al.
APC
37
BE 31 LGD 6
Median 36 m (12–48)
2 CA: 12 and 18 m to CA
2a
Javaid et al.
PDT
6
HGD 6
Mean 12.8 m (4–27)
No CA
5
Hage et al.
APC
6
HGD 6
Mean 10.7 m (4–12)
No CA
4
Michopoulos et al.
MPEC(Heaterprobe)
10
BE 10
Mean 45.1 m (32–67)
No CA
6
Pinotti et al.
APC
19
BE 19
Mean 18 m (6–27)
No CA
5
Beejay et al.
PDT
15
HGD 15 (5 Ca)
Mean 38 m (11–82)
1 CA squamous cell CA
5
Schembre et al.
PDT
15
HGD 15
Mean 12 m (3–24)
No CA
6
2003
2002
The American Journal of GASTROENTEROLOGY
VOLUME 104 | FEBRUARY 2009 www.amjgastro.com
Esophageal Cancer in Barrett’s After Ablation
513
Author
Type of Rx
No. of patients
Grade of dysplasia
Follow-up period
Time to development of cancer
Study quality
Sampliner et al.
MPEC
20
BE 20
6m
Na CA
5
Jamieson et al.
PDT
11
HGD 11
Median 10 m (2–29)
No CA
5
Morris et al.
APC
45
BE 37 LGD 8
Mean 38.5 m, median 37 m (12–72)
No CA
6
Van Laethem et al.
APC
7
HGD 7
Median 24 m (12–36)
1 CA: 3 m to CA
5
Weston et al.
MPEC
20
BE 11 LGD 9
Mean 14.4 m (6–24)
No CA
5
Familiari et al.
APC
20
BE 8 LGD 12
Mean 28 m (6–36)
No CA
5
Fusaroli et al.
APC
17
BE 17
Mean 14.4 m (12–20)
No CA
6
2001
Sampliner et al.
MPEC
58
BE 58
6m
No CA
5
Pereira-Lima et al.
APC
63
BE 33 LGD 29 HGD 1
Mean 16.5 m (1–24)
No CA
6
Guelrud et al.
MPEC
178
BE 178
Mean 37 m (24–60)
No CA
5
Van Lethem et al.
APC
1
BE 1
18 m
1 CA: 18 m to CA
0
Pereira-Lima et al.
APC
33
BE 18 LGD 14 HGD 1
Mean 10.6 m (6–18)
No CA
5
Gossner et al.
PDT-ALA
9
HGD 9
Mean 16.9 m (3–37)
No CA
5
Gossner et al.
KTP Laser
8
LGD 4 HGD 4
Mean 10.6 m (6–15)
No CA
4
2000
1999
Salo et al.
Nd-YAG
11
BE 11
Mean 26 m (6–52)
No CA
7
Gossner et al.
PDT-ALA
2
HGD 2
Mean 12 m (10–15)
No CA
5
Montes et al.
MPEC
14
BE 14
Mean 21.6 m (18–30)
No CA
5
Sharma et al.
MPEC
11
BE 11
Mean 36 m (19–53)
No CA
6
Bonavina et al.
Nd-YAG
18
BE 18
Mean 14 m (4–32)
1 CA: 6 m to CA
6
Michopoulos et al.
MPEC (heat probe)
13
BE 13
Mean 15.92±8.89 (6–36)
No CA
5
APC
17
BE 17
12 m
No CA
6
1998 Van Laethem et al. Gossner et al.
PDT-ALA
7
HGD 7
Mean 7 m (5–11)
No CA
4
Mork et al.
APC
15
BE 15
Mean 9 m (6–13)
No CA
5
Byrne et al.
APC
27
BE 21 LGD 4 HGD 2
Median 9 m (6–18)
No CA
5
KTP
13
BE 13
R: 3–18 m
No CA
5
Barr et al.
PDT-ALA
5
HGD 5
Mean 38 m (26–44)
No CA
6
Luman et al.
Nd:YAG
4
BE 4
6m
No CA
1a
1997 Barham et al. 1996
APC, argon plasma coagulation; BE, Barrett’s esophagus; CA, cancer; HGD, high-grade dysplasia; KTP, potassium titanium phosphate; LGD, low-grade dysplasia; MPEC, multipolar electrocoagulation; PDT, photodynamic therapy; RFA, radiofrequency ablation. a Randomized controlled trial—quality assessed using Jadad scoring system, others assessed using Newcastle–Ottawa scoring system for observational studies.
© 2009 by the American College of Gastroenterology
The American Journal of GASTROENTEROLOGY
REVIEW
List of studies with the follow up periods
