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Prospective randomized controlled trial of argon plasma coagulation ablation vs. endoscopic surveillance of patients with Barrett's esophagus after antireflux surgery
Prospective randomized controlled trial of argon plasma coagulation ablation vs. endoscopic surveillance of patients with Barrett’s esophagus after antireflux surgery Roger Ackroyd, MBChB, MD (Dist), FRCS, FRCSEd, FRCS (Gen Surg), William Tam, MBBS, FRACP, Mark Schoeman, MBBS, PhD, FRACP, Peter G. Devitt, MBBS, MS, FRCS, FRACS, David I. Watson, MBBS, MD, FRACS Adelaide, South Australia
Background: Argon plasma coagulation is one of several techniques used to ablate Barrett’s esophagus. This study assessed the efficacy and safety of argon plasma coagulation in the ablation of Barrett’s esophagus in patients who have undergone antireflux surgery. Methods: A total of 40 patients with Barrett’s esophagus who had undergone a fundoplication were entered into a prospective, randomized, unblinded study comparing argon plasma coagulation with endoscopic surveillance. Treatment was repeated until either no Barrett’s epithelium remained or a maximum of 6 treatment sessions. Results: One month after the final treatment, complete ablation was achieved in 12 patients. In the remaining 8, a reduction of over 95% was observed. One patient died at 9 months of an unrelated cause. At 1 year, one patient with residual Barrett’s epithelium regressed completely, while relapse of Barrett’s esophagus was seen in another because of fundoplication failure. Buried glands were observed in 35% patients at 1 month, but only 5% at 1 year. Dysplasia was never seen. In the surveillance group, partial regression was observed in 11 patients, and, in 3 with short-segment Barrett’s esophagus, regression was complete. The length of Barrett’s esophagus increased in two patients. Two had low-grade dysplasia initially, but this was not evident at 1 year. Overall, complete ablation was achieved in 12 of 19 (63%) patients in the ablation group and 3 of 20 (15%) in the surveillance group (p < 0.01). Conclusions: Argon plasma coagulation of Barrett’s esophagus is safe and effective. The effects are durable, and buried glands may resolve with time. Long-term follow-up is required to assess the impact of argon plasma coagulation on cancer risk. (Gastrointest Endosc 2004;59:1-7.)
The incidence of esophageal adenocarcinoma is increasing rapidly,1 and the major risk factor associated with this increase is Barrett’s esophagus. In an attempt to reduce this risk, various treatments have been proposed. Most involve a combination of endoscopic surveillance and reduction of esophageal acid exposure by either pharmacologic or surgical means. There is no consensus as to the optimal surveillance interval for patients with Barrett’s esophagus2
Received April 23, 2003. For revision July 22, 2003. Accepted October 2, 2003. Current affiliations: University of Adelaide, Department of Surgery and Gastroenterology Unit, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia. This work was presented to the Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland, September 26-27, 2002, Manchester, United Kingdom, (Br J Surg 2003;90:377). Reprint requests: Mr. R. Ackroyd MD FRCS, Consultant Surgeon, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, United Kingdom. Copyright Ó 2004 by the American Society for Gastrointestinal Endoscopy 0016-5107/$30.00 PII: S0016-5107(03)02528-8 VOLUME 59, NO. 1, 2004
or the cost effectiveness of surveillance.3 Although some studies have shown a better outcome after surgery for patients with an early surveillance detected cancer,4 others have suggested little benefit.3 Furthermore, a minority of patients presenting with esophageal cancer are known to have Barrett’s esophagus, and most have not been under surveillance.4 Evidence that reduction of esophageal acid exposure produces significant regression of Barrett’s esophagus is sparse. Some regression has been reported in response to treatment with H2-receptor antagonists5 and proton pump inhibitors (PPI),6,7 although this is disputed.8-10 After antireflux surgery, regression was noted in 40% of patients in one study,11 and, in another study, squamous islands appeared within the columnar mucosa.12 Others have not demonstrated regression.13,14 A recently reported study demonstrated regression in 36.4% of patients after antireflux surgery, as compared with only 7.1% of those treated with a PPI.15 There also was evidence of regression from low-grade dysplasia (LGD) to no dysplasia in 68% and from intestinal metaplasia to no metaplasia in 21.2% of surgically GASTROINTESTINAL ENDOSCOPY
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treated patients, especially those with short-segment Barrett’s esophagus. However, some patients with long-segment Barrett’s actually had progression to a higher degree of dysplasia. Because of the controversies surrounding endoscopic surveillance and the disappointing outcomes after pharmacologic and surgical therapy, other therapies for Barrett’s esophagus have been considered. It has been shown that if Barrett’s epithelium is ablated and allowed to heal in an anacid environment, there may be preferential repopulation by normal squamous epithelium.16 Several ablation techniques have been used, including thermal laser photoablation,17-19 multipolar electrocoagulation,20,21 EMR,22,23 photodynamic therapy (PDT),24-26 and argon plasma coagulation (APC).27-30 Argon plasma coagulation is a non-contact thermal electrocoagulation technique that involves the flow of electrical current through a beam of ionized argon gas. It produces a shallow depth of necrosis (2-3 mm) and is of potential value in the ablation of conditions that involve the superficial layers of the mucosa, such as Barrett’s epithelium, with an epithelial depth of 0.5 to 0.6 mm.31 Several studies have demonstrated the feasibility of APC ablation of Barrett’s epithelium.27-30 Byrne et al.27 treated 30 patients with Barrett’s esophagus, 27 of whom completed treatment. There was macroscopic replacement of the columnar lining by squamous epithelium, but, in 30%, there was histopathologic evidence of persistent intestinal metaplasia underneath the squamous epithelium. In this series, there were two perforations, one of which resulted in the death of the patient. Tigges et al.28 studied the efficacy of APC followed by fundoplication in 30 patients with Barrett’s esophagus. There was complete squamous re-epithelialization after a median of two treatments in all patients. Of 22 patients evaluated by endoscopy at 1 year, all were free of Barrett’s epithelium except two in whom the fundoplication had failed. Basu et al.30 treated 50 patients with Barrett’s esophagus by using APC and PPI therapy. Greater than 90% ablation was achieved after a median of 4 treatments in 68% of patients. Persistent Barrett’s epithelium was associated with a longer length of Barrett’s esophagus, and buried glands (intestinal metaplasia) were observed in 44% of patients. At 1 year, only 32% of patients in whom ablation initially was successful had not had a recurrence of Barrett’s epithelium. Although the results of these studies are encouraging, there are no prospective randomized controlled evaluations of APC in patients with Barrett’s esophagus. The aim of this study was to evaluate the safety and efficacy of APC ablation of Barrett’s 2
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esophagus in patients who had previously undergone fundoplication, by means of a prospective randomized controlled trial. PATIENTS AND METHODS Patients with Barrett’s esophagus who had undergone laparoscopic fundoplication for symptoms of gastroesophageal reflux were identified from our computerized database. All patients between 18 and 75 years of age were invited to participate in the study. All had proven Barrett’s esophagus with or without LGD at the commencement of the trial. Patients with high-grade dysplasia (HGD) or ulcerative esophagitis were excluded. Barrett’s esophagus was diagnosed only when specialized columnar epithelium (with intestinal metaplasia) was demonstrated.1 Dysplasia was defined as neoplastic epithelium superficial to the basement membrane (with inflammation absent)1,32 present in at least one biopsy specimen. All patients gave full written informed consent for participation in the study. This study protocol was approved by the human clinical research ethics committee of our hospital. All procedures were performed on an out-patient basis. Patients were randomized to receive either annual endoscopic surveillance or APC ablation. The randomization was performed in the endoscopy suite by opening one of 40 sealed opaque envelopes; half contained the instruction for surveillance and the other half specified treatment by APC. All patients were sedated for the procedures by intravenous administration of midazolam (5 mg), and those undergoing ablation therapy also were given fentanyl intravenously (50 mcg) for analgesia. Endoscopy was performed by using a standard upper endoscope (GIF-Q140; Olympus Optical Co. Ltd., Tokyo, Japan). The length and percentage of the circumference of the esophagus covered by columnar epithelium was recorded and from these, the area of involvement was calculated. All longitudinal measurements were made by using the upper incisor teeth (or gum) as a reference, and photographic or videotape documentation was obtained for all procedures. At the initial endoscopy, multiple biopsy specimens were taken from the columnar epithelium to confirm the diagnosis of Barrett’s esophagus (per modified ‘‘Seattle’’ protocol with 4-quadrant biopsy specimens at 2 cm intervals by using large cup disposable biopsy forceps). All biopsy specimens were analyzed by one of 3 independent GI pathologists, all of whom were blinded to the randomization group of the patient. All patients randomized to surveillance were simply advised of this fact and underwent no further therapy. They were recalled for surveillance endoscopy 1 year later. At that time, the endoscopic findings were noted, and biopsy specimens were taken and analyzed as before. In patients randomized to ablation treatment, APC was performed by using a high-frequency electrosurgical generator coupled to an argon delivery unit (ERBE ICC 200/APC 300; MedTech Systems, Adelaide, South Australia). Gas delivery was via a flexible Teflon-coated 2.3-mm-diameter catheter with a heat resistant ceramic VOLUME 59, NO. 1, 2004
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tip (ERBE APC probe 2200 A; ERBE Elektromedizin GmbH, Tubingen, Germany). The power and gas flow settings were, respectively, 60 W and 2.0 L/min. The columnar epithelium was ablated by APC in linear lengthwise strips. Any gaps in electrocoagulation were filled in by additional localized application of APC. Ablation of isolated columnar ‘‘islands’’ was achieved by local application of APC, taking care to avoid damage to adjacent squamous mucosa. To reduce the risk of stricture formation, treatment was limited in any single procedure to 50% of the circumference, up to a maximum length of 5 cm. In patients with short-segment Barrett’s esophagus (<3 cm), the whole area of Barrett’s epithelium was treated in one session. After ablative treatment, patients were treated with analgesic and/or anti-emetic medications as required and were allowed to eat and drink as they wished. All patients were discharged home the same day and told to take analgesic medication orally as needed. A contact telephone number was provided for the patient to use should any problem be encountered. Endoscopy was repeated 4 weeks later. If Barrett’s epithelium remained, ablation therapy was repeated at 4 weekly intervals until either no Barrett’s epithelium was visible or until a maximum of 6 treatments had been performed, whichever occurred first. Four weeks after the last treatment, endoscopy was performed and a final assessment of the treatment effects was made. The macroscopic findings were noted, and multiple biopsy specimens were taken and examined, as previously mentioned. Further endoscopy was performed at 1 year after the start of treatment. The endoscopist performing the 1-year follow-up endoscopies in the surveillance APC groups was blinded to the original intervention. At all stages, the pathologist examining the biopsy specimens was blinded to the randomization group. Statistical analysis Before patient recruitment, a power calculation was performed by using a commercially available software package (In Stat, Version 2.01; Graph Pub Software, San Diego, Calif.). It was calculated that to show a 30% difference in complete ablation of Barrett’s esophagus between the treatment and surveillance groups, which was thought to represent a clinically significant improvement, at a significance level (two-sided) of p < 0.05 and a power of 90%, 16 patients would be required in each group. To allow for a possible drop out rate of 20%, 20 patients were recruited in each group. Data are presented as median (interquartile range) (range). Patient demographics and pre- and post-treatment findings were analyzed by using a 2-tailed Mann-Whitney U test for continuous variables and the Fisher exact test for 2 3 2 contingency table data. Comparison of histopathology data was performed by using the chi-square test. The issue of multiple statistical tests of hypotheses being performed on outcome data arising from individual patients was addressed by claiming statistical significance only if, for a single test, the nominal p value was <0.01. VOLUME 59, NO. 1, 2004
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Table 1. Demographic data for the two patient groups
Age (y) Gender (M:F) Alcohol (Y:N)y Smoker (Y:N)y Time since surgery (mo)
Ablation group (n = 20)
Surveillance group (n = 20)
47 (41-57) (range: 36-69) 15:5 16:4 2:18 26.5 (20-36) (range: 4-71)
51 (38-59) (range: 31-73) 17:3 15:5 2:18 31.5 (20-50) (range: 5-65)
p Value NS* NSz NSz NSz NS*
Quantitative data are summarized as median (interquartile range) and the range. NS, Not significant. *Mann-Whitney U test. yAlcohol use and smoking are defined as any amount of use of alcohol or smoking currently or in the past. zFisher exact test.
RESULTS Eighty patients with Barrett’s esophagus who had previously undergone laparoscopic fundoplication were identified. Of these, 40 agreed to participate in this study. Thirty-nine had undergone a Nissen (3608) fundoplication, and one had an anterior partial (1808) wrap.33 All operations had been successful, with all patients having no further symptoms because of reflux and no need of acid-suppressant medication. Six patients had undergone postoperative 24-hour pH monitoring as part of another study. This demonstrated a median esophageal acid exposure (pH < 4) of 0.4% of the 24-hour study period. Patient demographics were comparable for the two groups (Table 1), and there was no significant difference between the groups in the initial endoscopic findings (Table 2). Histopathologic evaluation of biopsy specimens confirmed the presence of intestinal metaplasia in all cases. Two patients in the surveillance group had LGD. The median number of treatment sessions in the ablation group was 3 (2-4) (range 2-6). All patients in this group underwent endoscopy 1 month after the last treatment. Complete macroscopic ablation was achieved in 12 of 20 patients (60%), all of whom initially had segments of Barrett’s epithelium no more than 4 cm in length. The 8 patients in whom ablation was incomplete all had significantly longer segments of Barrett’s esophagus, but, even in this group, a greater than 95% area reduction was achieved in all cases, with small columnar islands present in only 3 patients. Overall, the median post-treatment length of Barrett’s esophagus was 0 cm (0-0.1; range 0-0.5), as compared with 4.0 cm (3-8; range 2-13) pretreatment (p < 0.05), and the median reduction GASTROINTESTINAL ENDOSCOPY
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Table 2. Initial endoscopic findings in the two patient groups
Length of circumferential Barrett’s esophagus (cm) Total length of Barrett’s esophagus (cm) Hiatal hernia (Y:N) Initial histology SIM? (LGD?)
Ablation group (n = 20)
Surveillance group (n = 20)
3.5 (2-7) (range: 0-11)
2.0 (2-4.5) (range: 0-16)
NS*
4.0 (3-8) (range: 2-13)
4.0 (2-5) (range: 2-19)
NS*
1:19
1:19
NSy
20 (0)
20 (2)
NSy
p Value
Quantitative data are summarized as median (interquartile range) and the range. SIM, Specialized intestinal metaplasia; LGD, low-grade dysplasia. *Mann-Whitney U test. yFisher exact test.
in area of Barrett’s epithelium was 100% (99%-100%; range 95%-100%). A good correlation (r = 0.80) was seen between the length of Barrett’s esophagus and the number of treatments necessary to achieve complete ablation (Fig. 1). Biopsy specimens taken from the neosquamous epithelium confirmed the presence of normal squamous epithelium in all cases, although in 7 patients (35%), there was evidence of buried columnar glands (with intestinal metaplasia) beneath the squamous epithelium. One patient in the ablation group died at 9 months because of cardiac disease. Follow-up data at 12 months were, therefore, available for 39 patients (19 ablation, 20 surveillance) (Table 3). After 1 year, 11 of 19 (58%) patients in the ablation group had no macroscopic evidence of Barrett’s esophagus. Ten of these were the same patients in whom complete ablation was observed at the 1-month post-final treatment endoscopy. In one of the patients in whom ablation previously had been complete, there was evidence of relapse in the form of columnar islands. This patient had symptoms of recurrent reflux, and endoscopy at 12 months confirmed that the fundoplication had come undone. In another patient, there was further regression of Barrett’s epithelium with the disappearance of the previously noted columnar islands. The median length of Barrett’s epithelium at 1 year in the ablation group was 0 cm (0-0; range 0-3). In 3 patients, residual Barrett’s epithelium took the form of small columnar islands alone. No change was seen at 1 year in the length of columnar epithelium in 4
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Figure 1. Correlation between length of Barrett’s esophagus and number of treatment sessions (r = 0.80; p < 0.0001).
Table 3. Endoscopic findings at 1 year in the two patient groups Ablation group (n = 19)
Surveillance group (n = 20)
Patients with 8:11 macroscopic residual Barrett’s esophagus (Y:N) Length of Barrett’s 0 (0-0) esophagus (cm) (range: 0-3) Histopathology 11 squamous 6 SIM 2 fundic Buried Barrett’s 1:18 glands (Y:N) Dysplasia (Y:N) 0:19
17:3
p Value <0.01*
2 (1-3) <0.001y (range: 0-13) 3 squamous <0.001z 10 SIM 7 fundic 0:20 NS* 0:20
NS*
Quantitative data are summarized as median (interquartile range) and the range. NS, Not significant. *Fisher exact test. yMann-Whitney U test. zChi-square test.
patients who had incomplete ablation at 1 month. Histopathologic evaluation of biopsy specimens from the neosquamous epithelium again confirmed the presence of normal squamous mucosa in all cases, but buried columnar glands now were seen in only one patient (5%). Biopsy specimens from the residual columnar epithelium contained specialized intestinal metaplasia (SIM) in all but two patients, in whom the biopsy specimens revealed fundic-type epithelium. At no stage was dysplasia or malignancy identified in any patient in the APC group. VOLUME 59, NO. 1, 2004
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Barrett’s esophagus was present in 17 of 20 patients in the surveillance group at 1 year. Partial regression was observed in 11 patients. Complete regression was noted in 3 patients with a diagnosis of short-segment Barrett’s esophagus at randomization. However, in two patients, there was an increase in length of the columnar epithelium. Overall, the median length of Barrett’s epithelium in this group was 2 cm (1-3; range 0-13). Biopsy specimens from the neosquamous epithelium in the 3 patients with complete regression revealed normal squamous epithelium. In patients with residual columnar epithelium, biopsy specimens contained SIM in all but 7 in whom there was fundic-type epithelium. In the two patients with LGD in initial biopsy specimens, biopsy specimens at 1 year confirmed the presence of SIM, but there was no evidence of dysplasia or malignancy. Overall, at 1 year, complete ablation of Barrett’s epithelium was achieved in 11 of 19 patients (58%) in the ablation group, compared with 3 of 20 (15%) in the surveillance group (p < 0.01). In the ablation group, some patients experienced minor side effects, but there was no serious complication. Several patients reported mild retrosternal discomfort and odynophagia immediately after treatment, but this was shortlived (up to 3 days) and responded to treatment with orally administered analgesics. One patient stayed in the hospital for 1 day after the first treatment, but none were re-admitted. There was no post-treatment hemorrhage, stricture, or perforation. DISCUSSION Data to show that either pharmacologic or surgical therapy lead to significant regression of Barrett’s esophagus are sparse, hence, there is considerable interest in ablation therapy. However, there are few rigorous evaluations of ablation therapies, and few of these include patients with previous fundoplication.19,27,34,35 In a non-randomized trial, Salo et al.19 compared patients treated by endoscopic Nd-YAG laser photoablation combined with fundoplication to control patients who declined therapy. Grade et al.36 studied APC ablation in 9 patients with Barrett’s esophagus in whom half of the esophageal circumference was ablated, with the nonablated mucosa serving as the control. The results of one randomized controlled study of PDT ablation of Barrett’s esophagus have been published,26 but there is no similar study of APC ablation therapy. In the present trial, up to 6 APC treatments were performed. Complete ablation was achieved in 12 of 20 patients (60%), and greater than 95% ablation was achieved in all patients. There was a relationship between the length of Barrett’s esophagus and the VOLUME 59, NO. 1, 2004
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ability to achieve complete ablation, a finding consistent with those of other studies.29,35 Similar results have been achieved by using other ablation therapies in patients with Barrett’s esophagus without fundoplication. In a study of 16 patients with Barrett’s esophagus treated with potassiumtitanyl-phosphate laser photoablation and acid suppression, squamous re-epithelialization was achieved in all cases.18 In a study of aminolevulinic acidinduced PDT, ablation of Barrett’s epithelium was noted in 33 of 40 patients,37 with a median area reduction of 30% (range 0%-90%). All patients initially had LGD, and, after treatment, dysplasia was noted in only one patient. Argon plasma coagulation may have advantages over other ablative modalities. The equipment is inexpensive, easy to use, and does not require a laser. In contrast to PDT, there is no need to administer a photosensitizing drug, and systemic photosensitization is avoided. However, adverse effects have been reported with APC, including hemorrhage, stricture,29,34 and perforation,27,35 which can be fatal.27 Argon plasma coagulation produces a shallow depth of damage compared with other treatment modalities, and complications usually are associated with high power settings. The APC power setting used in this study was adequate to achieve the desired effect but not so high as to increase the risk of complications. A drawback of all forms of ablative therapy is the persistence of columnar glands beneath the neosquamous epithelium, which occurs in 6% to 69% of cases.17,18,29,38 In the present study, buried glands were seen in 35% of patients at 1 month and 5% at 1 year. The reason for these apparently better results is unknown. It may be related to the anacid esophageal environment after fundoplication, or it may simply be because of sampling error in this relatively small group of patients. The clinical relevance of buried glands is unknown. Although there are reports of adenocarcinoma developing in patients with buried glands,39,40 the risk is difficult to quantify.41 Studies have demonstrated the ability to ablate Barrett’s epithelium and induce squamous reepithelialization, but the durability of the new epithelium is unknown. In the current study, all but one of the patients in whom complete ablation was observed 1 month after treatment remained free of Barrett’s epithelium at 1 year. In the patient in whom Barrett’s epithelium recurred, the fundoplication had come undone, and the patient had a relapse of reflux-related symptoms. In the present study, some patients with incomplete ablation had further regression of the Barrett’s epithelium over time. The reason is unclear, GASTROINTESTINAL ENDOSCOPY
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although it may be that much of the residual Barrett’s epithelium was in the form of isolated columnar islands, which may be more likely to regress than larger areas. The observation that Barrett’s epithelium regressed in the surveillance group was unexpected. In 3 patients with an initial diagnosis of shortsegment Barrett’s esophagus, no residual epithelium was present at 1 year. These findings are consistent with those of other studies. Brand et al.11 noted complete regression in 4 of 10 patients. Among 14 patients, Low et al.42 observed partial regression in 10 with long-segment Barrett’s esophagus and complete regression in two with short-segment Barrett’s esophagus. However, in a review of 11 series, incorporating 340 surgical patients, only 4% had complete regression, and 12% had partial regression.43 Conversely, in a study of 152 patients undergoing open fundoplication with long-term follow-up, there was no regression of Barrett’s esophagus. Furthermore, LGD developed in 15 and adenocarcinoma in 4.44 The results of the present study differ from those of Basu et al.30 In the latter study, 44% of patients had buried glands and 68% had a recurrence of Barrett’s epithelium at 1 year. However, there are significant methodologic differences between the two studies, which may account for these differences: use of different forceps (‘‘jumbo’’ vs. standard), APC power settings (30 vs. 60 W), and definitions of complete ablation. Although all patients in the present study initially had Barrett’s esophagus with SIM, in some patients, residual columnar epithelium at 1 year no longer included SIM. The reason(s) for this is unclear. It may be because of sampling error, although this is unlikely, because a rigid biopsy protocol was followed. Apparent regression of SIM has been noted in patients with short-segment Barrett’s esophagus after fundoplication.45 In the present series, most patients without SIM at 1 year had short-segment Barrett’s esophagus at the time of inclusion in the study. Equally, two patients in the surveillance group, who had LGD at randomization, had no dysplasia at 1 year. Again, it is impossible to know whether this represents true regression or sampling error. In conclusion, APC ablation after fundoplication is safe and effective in almost 60% of patients with Barrett’s esophagus. Whether this leads to a reduction in cancer risk is unknown. REFERENCES 1. Haggitt RC. Barrett’s esophagus, dysplasia and adenocarcinoma. Hum Pathol 1994;25:982-93. 6
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with provisional clinical implications. Hum Pathol 1983;14: 931-68. Watson DI, Jamieson GG, Pike GK, Davies N, Richardson M, Devitt PG. Prospective randomized double blind trial between laparoscopic Nissen fundoplication and anterior partial fundoplication. Br J Surg 1999;86:123-30. Pereira-Lima JC, Busnello JV, Saul C, Toneloto EB, Lopes CV, Rynkowski CB, et al. High power setting argon plasma coagulation for the eradication of Barrett’s esophagus. Am J Gastroenterol 2000;95:1661-8. Morris CD, Byrne JP, Armstrong GR, Attwood SE. Prevention of the neoplastic progression of Barrett’s oeosphagus by endoscopic argon beam plasma ablation. Br J Surg 2001;88:1357-62. Grade AJ, Shah IA, Medlin SM, Ramirez FC. The efficacy and safety of argon plasma coagulation therapy in Barrett’s esophagus. Gastrointest Endosc 1999;50:18-22. Ackroyd R, Brown NJ, Davis MF, Stephenson TJ, Stoddard CJ, Reed MWR. Aminolevulinic acid-induced photodynamic therapy: safe and effective ablation of dysplasia in Barrett’s esophagus. Dis Esophagus 2000;13:18-22. Mo¨rk H, Barth T, Kreipe HH, Kraus M, Al-Taie O, Jakob F, et al. Reconstitution of squamous epithelium in Barrett’s oesophagus with endoscopic argon plasma coagulation: a prospective study. Scand J Gastroenterol 1998;33:1130-4. Van Laethem JL, Peny MO, Salmon I, Cremer M, Deviere J. Intramucosal adenocarcinoma arising under squamous re-epithelialisation of Barrett’s oesophagus. Gut 2000;46: 574-7. Shand A, Dallal H, Palmer K, Ghosh S, MacIntyre M. Adenocarcinoma arising in columnar lined oesophagus following treatment with argon plasma coagulation. Gut 2001;48:580-1. Kelty C, Ackroyd R. Re-epithelialisation of Barrett’s oesophagus [letter]. Gut 2000;47:741. Low DE, Devine DS, Dail DH, Kozarek RA. Histological and anatomic changes in Barrett’s esophagus after antireflux surgery. Am J Gastroenterol 1999;94:80-5. DeMeester SR, DeMeester TR. Columnar mucosa and intestinal metaplasia of the esophagus: fifty years of controversy. Ann Surg 2000;231:303-21. Csendes A, Braghetto I, Burdiles P, Puente G, Korn O, Diaz JC, et al. Long-term results of classic anti-reflux surgery in 152 patients with Barrett’s esophagus: clinical, radiologic, endoscopic, manometric and acid reflux test analysis before and late after operation. Surgery 1998;123:645-57. DeMeester SR, Campos GMR, DeMeester TR, Bremner CG, Hagen JA, Peters JH, et al. The impact of an antireflux procedure on intestinal metaplasia of the cardia. Ann Surg 1998;228:547-56.
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Background: Argon plasma coagulation is one of several techniques used to ablate Barrett’s esophagus. This study assessed the efficacy and safety of argon plasma coagulation in the ablation of Barrett’s esophagus in patients who have undergone antireflux surgery. Methods: A total of 40 patients with Barrett’s esophagus who had undergone a fundoplication were entered into a prospective, randomized, unblinded study comparing argon plasma coagulation with endoscopic surveillance. Treatment was repeated until either no Barrett’s epithelium remained or a maximum of 6 treatment sessions. Results: One month after the final treatment, complete ablation was achieved in 12 patients. In the remaining 8, a reduction of over 95% was observed. One patient died at 9 months of an unrelated cause. At 1 year, one patient with residual Barrett’s epithelium regressed completely, while relapse of Barrett’s esophagus was seen in another because of fundoplication failure. Buried glands were observed in 35% patients at 1 month, but only 5% at 1 year. Dysplasia was never seen. In the surveillance group, partial regression was observed in 11 patients, and, in 3 with short-segment Barrett’s esophagus, regression was complete. The length of Barrett’s esophagus increased in two patients. Two had low-grade dysplasia initially, but this was not evident at 1 year. Overall, complete ablation was achieved in 12 of 19 (63%) patients in the ablation group and 3 of 20 (15%) in the surveillance group (p < 0.01). Conclusions: Argon plasma coagulation of Barrett’s esophagus is safe and effective. The effects are durable, and buried glands may resolve with time. Long-term follow-up is required to assess the impact of argon plasma coagulation on cancer risk. (Gastrointest Endosc 2004;59:1-7.)
The incidence of esophageal adenocarcinoma is increasing rapidly,1 and the major risk factor associated with this increase is Barrett’s esophagus. In an attempt to reduce this risk, various treatments have been proposed. Most involve a combination of endoscopic surveillance and reduction of esophageal acid exposure by either pharmacologic or surgical means. There is no consensus as to the optimal surveillance interval for patients with Barrett’s esophagus2
Received April 23, 2003. For revision July 22, 2003. Accepted October 2, 2003. Current affiliations: University of Adelaide, Department of Surgery and Gastroenterology Unit, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia. This work was presented to the Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland, September 26-27, 2002, Manchester, United Kingdom, (Br J Surg 2003;90:377). Reprint requests: Mr. R. Ackroyd MD FRCS, Consultant Surgeon, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, United Kingdom. Copyright Ó 2004 by the American Society for Gastrointestinal Endoscopy 0016-5107/$30.00 PII: S0016-5107(03)02528-8 VOLUME 59, NO. 1, 2004
or the cost effectiveness of surveillance.3 Although some studies have shown a better outcome after surgery for patients with an early surveillance detected cancer,4 others have suggested little benefit.3 Furthermore, a minority of patients presenting with esophageal cancer are known to have Barrett’s esophagus, and most have not been under surveillance.4 Evidence that reduction of esophageal acid exposure produces significant regression of Barrett’s esophagus is sparse. Some regression has been reported in response to treatment with H2-receptor antagonists5 and proton pump inhibitors (PPI),6,7 although this is disputed.8-10 After antireflux surgery, regression was noted in 40% of patients in one study,11 and, in another study, squamous islands appeared within the columnar mucosa.12 Others have not demonstrated regression.13,14 A recently reported study demonstrated regression in 36.4% of patients after antireflux surgery, as compared with only 7.1% of those treated with a PPI.15 There also was evidence of regression from low-grade dysplasia (LGD) to no dysplasia in 68% and from intestinal metaplasia to no metaplasia in 21.2% of surgically GASTROINTESTINAL ENDOSCOPY
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treated patients, especially those with short-segment Barrett’s esophagus. However, some patients with long-segment Barrett’s actually had progression to a higher degree of dysplasia. Because of the controversies surrounding endoscopic surveillance and the disappointing outcomes after pharmacologic and surgical therapy, other therapies for Barrett’s esophagus have been considered. It has been shown that if Barrett’s epithelium is ablated and allowed to heal in an anacid environment, there may be preferential repopulation by normal squamous epithelium.16 Several ablation techniques have been used, including thermal laser photoablation,17-19 multipolar electrocoagulation,20,21 EMR,22,23 photodynamic therapy (PDT),24-26 and argon plasma coagulation (APC).27-30 Argon plasma coagulation is a non-contact thermal electrocoagulation technique that involves the flow of electrical current through a beam of ionized argon gas. It produces a shallow depth of necrosis (2-3 mm) and is of potential value in the ablation of conditions that involve the superficial layers of the mucosa, such as Barrett’s epithelium, with an epithelial depth of 0.5 to 0.6 mm.31 Several studies have demonstrated the feasibility of APC ablation of Barrett’s epithelium.27-30 Byrne et al.27 treated 30 patients with Barrett’s esophagus, 27 of whom completed treatment. There was macroscopic replacement of the columnar lining by squamous epithelium, but, in 30%, there was histopathologic evidence of persistent intestinal metaplasia underneath the squamous epithelium. In this series, there were two perforations, one of which resulted in the death of the patient. Tigges et al.28 studied the efficacy of APC followed by fundoplication in 30 patients with Barrett’s esophagus. There was complete squamous re-epithelialization after a median of two treatments in all patients. Of 22 patients evaluated by endoscopy at 1 year, all were free of Barrett’s epithelium except two in whom the fundoplication had failed. Basu et al.30 treated 50 patients with Barrett’s esophagus by using APC and PPI therapy. Greater than 90% ablation was achieved after a median of 4 treatments in 68% of patients. Persistent Barrett’s epithelium was associated with a longer length of Barrett’s esophagus, and buried glands (intestinal metaplasia) were observed in 44% of patients. At 1 year, only 32% of patients in whom ablation initially was successful had not had a recurrence of Barrett’s epithelium. Although the results of these studies are encouraging, there are no prospective randomized controlled evaluations of APC in patients with Barrett’s esophagus. The aim of this study was to evaluate the safety and efficacy of APC ablation of Barrett’s 2
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esophagus in patients who had previously undergone fundoplication, by means of a prospective randomized controlled trial. PATIENTS AND METHODS Patients with Barrett’s esophagus who had undergone laparoscopic fundoplication for symptoms of gastroesophageal reflux were identified from our computerized database. All patients between 18 and 75 years of age were invited to participate in the study. All had proven Barrett’s esophagus with or without LGD at the commencement of the trial. Patients with high-grade dysplasia (HGD) or ulcerative esophagitis were excluded. Barrett’s esophagus was diagnosed only when specialized columnar epithelium (with intestinal metaplasia) was demonstrated.1 Dysplasia was defined as neoplastic epithelium superficial to the basement membrane (with inflammation absent)1,32 present in at least one biopsy specimen. All patients gave full written informed consent for participation in the study. This study protocol was approved by the human clinical research ethics committee of our hospital. All procedures were performed on an out-patient basis. Patients were randomized to receive either annual endoscopic surveillance or APC ablation. The randomization was performed in the endoscopy suite by opening one of 40 sealed opaque envelopes; half contained the instruction for surveillance and the other half specified treatment by APC. All patients were sedated for the procedures by intravenous administration of midazolam (5 mg), and those undergoing ablation therapy also were given fentanyl intravenously (50 mcg) for analgesia. Endoscopy was performed by using a standard upper endoscope (GIF-Q140; Olympus Optical Co. Ltd., Tokyo, Japan). The length and percentage of the circumference of the esophagus covered by columnar epithelium was recorded and from these, the area of involvement was calculated. All longitudinal measurements were made by using the upper incisor teeth (or gum) as a reference, and photographic or videotape documentation was obtained for all procedures. At the initial endoscopy, multiple biopsy specimens were taken from the columnar epithelium to confirm the diagnosis of Barrett’s esophagus (per modified ‘‘Seattle’’ protocol with 4-quadrant biopsy specimens at 2 cm intervals by using large cup disposable biopsy forceps). All biopsy specimens were analyzed by one of 3 independent GI pathologists, all of whom were blinded to the randomization group of the patient. All patients randomized to surveillance were simply advised of this fact and underwent no further therapy. They were recalled for surveillance endoscopy 1 year later. At that time, the endoscopic findings were noted, and biopsy specimens were taken and analyzed as before. In patients randomized to ablation treatment, APC was performed by using a high-frequency electrosurgical generator coupled to an argon delivery unit (ERBE ICC 200/APC 300; MedTech Systems, Adelaide, South Australia). Gas delivery was via a flexible Teflon-coated 2.3-mm-diameter catheter with a heat resistant ceramic VOLUME 59, NO. 1, 2004
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tip (ERBE APC probe 2200 A; ERBE Elektromedizin GmbH, Tubingen, Germany). The power and gas flow settings were, respectively, 60 W and 2.0 L/min. The columnar epithelium was ablated by APC in linear lengthwise strips. Any gaps in electrocoagulation were filled in by additional localized application of APC. Ablation of isolated columnar ‘‘islands’’ was achieved by local application of APC, taking care to avoid damage to adjacent squamous mucosa. To reduce the risk of stricture formation, treatment was limited in any single procedure to 50% of the circumference, up to a maximum length of 5 cm. In patients with short-segment Barrett’s esophagus (<3 cm), the whole area of Barrett’s epithelium was treated in one session. After ablative treatment, patients were treated with analgesic and/or anti-emetic medications as required and were allowed to eat and drink as they wished. All patients were discharged home the same day and told to take analgesic medication orally as needed. A contact telephone number was provided for the patient to use should any problem be encountered. Endoscopy was repeated 4 weeks later. If Barrett’s epithelium remained, ablation therapy was repeated at 4 weekly intervals until either no Barrett’s epithelium was visible or until a maximum of 6 treatments had been performed, whichever occurred first. Four weeks after the last treatment, endoscopy was performed and a final assessment of the treatment effects was made. The macroscopic findings were noted, and multiple biopsy specimens were taken and examined, as previously mentioned. Further endoscopy was performed at 1 year after the start of treatment. The endoscopist performing the 1-year follow-up endoscopies in the surveillance APC groups was blinded to the original intervention. At all stages, the pathologist examining the biopsy specimens was blinded to the randomization group. Statistical analysis Before patient recruitment, a power calculation was performed by using a commercially available software package (In Stat, Version 2.01; Graph Pub Software, San Diego, Calif.). It was calculated that to show a 30% difference in complete ablation of Barrett’s esophagus between the treatment and surveillance groups, which was thought to represent a clinically significant improvement, at a significance level (two-sided) of p < 0.05 and a power of 90%, 16 patients would be required in each group. To allow for a possible drop out rate of 20%, 20 patients were recruited in each group. Data are presented as median (interquartile range) (range). Patient demographics and pre- and post-treatment findings were analyzed by using a 2-tailed Mann-Whitney U test for continuous variables and the Fisher exact test for 2 3 2 contingency table data. Comparison of histopathology data was performed by using the chi-square test. The issue of multiple statistical tests of hypotheses being performed on outcome data arising from individual patients was addressed by claiming statistical significance only if, for a single test, the nominal p value was <0.01. VOLUME 59, NO. 1, 2004
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Table 1. Demographic data for the two patient groups
Age (y) Gender (M:F) Alcohol (Y:N)y Smoker (Y:N)y Time since surgery (mo)
Ablation group (n = 20)
Surveillance group (n = 20)
47 (41-57) (range: 36-69) 15:5 16:4 2:18 26.5 (20-36) (range: 4-71)
51 (38-59) (range: 31-73) 17:3 15:5 2:18 31.5 (20-50) (range: 5-65)
p Value NS* NSz NSz NSz NS*
Quantitative data are summarized as median (interquartile range) and the range. NS, Not significant. *Mann-Whitney U test. yAlcohol use and smoking are defined as any amount of use of alcohol or smoking currently or in the past. zFisher exact test.
RESULTS Eighty patients with Barrett’s esophagus who had previously undergone laparoscopic fundoplication were identified. Of these, 40 agreed to participate in this study. Thirty-nine had undergone a Nissen (3608) fundoplication, and one had an anterior partial (1808) wrap.33 All operations had been successful, with all patients having no further symptoms because of reflux and no need of acid-suppressant medication. Six patients had undergone postoperative 24-hour pH monitoring as part of another study. This demonstrated a median esophageal acid exposure (pH < 4) of 0.4% of the 24-hour study period. Patient demographics were comparable for the two groups (Table 1), and there was no significant difference between the groups in the initial endoscopic findings (Table 2). Histopathologic evaluation of biopsy specimens confirmed the presence of intestinal metaplasia in all cases. Two patients in the surveillance group had LGD. The median number of treatment sessions in the ablation group was 3 (2-4) (range 2-6). All patients in this group underwent endoscopy 1 month after the last treatment. Complete macroscopic ablation was achieved in 12 of 20 patients (60%), all of whom initially had segments of Barrett’s epithelium no more than 4 cm in length. The 8 patients in whom ablation was incomplete all had significantly longer segments of Barrett’s esophagus, but, even in this group, a greater than 95% area reduction was achieved in all cases, with small columnar islands present in only 3 patients. Overall, the median post-treatment length of Barrett’s esophagus was 0 cm (0-0.1; range 0-0.5), as compared with 4.0 cm (3-8; range 2-13) pretreatment (p < 0.05), and the median reduction GASTROINTESTINAL ENDOSCOPY
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Table 2. Initial endoscopic findings in the two patient groups
Length of circumferential Barrett’s esophagus (cm) Total length of Barrett’s esophagus (cm) Hiatal hernia (Y:N) Initial histology SIM? (LGD?)
Ablation group (n = 20)
Surveillance group (n = 20)
3.5 (2-7) (range: 0-11)
2.0 (2-4.5) (range: 0-16)
NS*
4.0 (3-8) (range: 2-13)
4.0 (2-5) (range: 2-19)
NS*
1:19
1:19
NSy
20 (0)
20 (2)
NSy
p Value
Quantitative data are summarized as median (interquartile range) and the range. SIM, Specialized intestinal metaplasia; LGD, low-grade dysplasia. *Mann-Whitney U test. yFisher exact test.
in area of Barrett’s epithelium was 100% (99%-100%; range 95%-100%). A good correlation (r = 0.80) was seen between the length of Barrett’s esophagus and the number of treatments necessary to achieve complete ablation (Fig. 1). Biopsy specimens taken from the neosquamous epithelium confirmed the presence of normal squamous epithelium in all cases, although in 7 patients (35%), there was evidence of buried columnar glands (with intestinal metaplasia) beneath the squamous epithelium. One patient in the ablation group died at 9 months because of cardiac disease. Follow-up data at 12 months were, therefore, available for 39 patients (19 ablation, 20 surveillance) (Table 3). After 1 year, 11 of 19 (58%) patients in the ablation group had no macroscopic evidence of Barrett’s esophagus. Ten of these were the same patients in whom complete ablation was observed at the 1-month post-final treatment endoscopy. In one of the patients in whom ablation previously had been complete, there was evidence of relapse in the form of columnar islands. This patient had symptoms of recurrent reflux, and endoscopy at 12 months confirmed that the fundoplication had come undone. In another patient, there was further regression of Barrett’s epithelium with the disappearance of the previously noted columnar islands. The median length of Barrett’s epithelium at 1 year in the ablation group was 0 cm (0-0; range 0-3). In 3 patients, residual Barrett’s epithelium took the form of small columnar islands alone. No change was seen at 1 year in the length of columnar epithelium in 4
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Figure 1. Correlation between length of Barrett’s esophagus and number of treatment sessions (r = 0.80; p < 0.0001).
Table 3. Endoscopic findings at 1 year in the two patient groups Ablation group (n = 19)
Surveillance group (n = 20)
Patients with 8:11 macroscopic residual Barrett’s esophagus (Y:N) Length of Barrett’s 0 (0-0) esophagus (cm) (range: 0-3) Histopathology 11 squamous 6 SIM 2 fundic Buried Barrett’s 1:18 glands (Y:N) Dysplasia (Y:N) 0:19
17:3
p Value <0.01*
2 (1-3) <0.001y (range: 0-13) 3 squamous <0.001z 10 SIM 7 fundic 0:20 NS* 0:20
NS*
Quantitative data are summarized as median (interquartile range) and the range. NS, Not significant. *Fisher exact test. yMann-Whitney U test. zChi-square test.
patients who had incomplete ablation at 1 month. Histopathologic evaluation of biopsy specimens from the neosquamous epithelium again confirmed the presence of normal squamous mucosa in all cases, but buried columnar glands now were seen in only one patient (5%). Biopsy specimens from the residual columnar epithelium contained specialized intestinal metaplasia (SIM) in all but two patients, in whom the biopsy specimens revealed fundic-type epithelium. At no stage was dysplasia or malignancy identified in any patient in the APC group. VOLUME 59, NO. 1, 2004
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Barrett’s esophagus was present in 17 of 20 patients in the surveillance group at 1 year. Partial regression was observed in 11 patients. Complete regression was noted in 3 patients with a diagnosis of short-segment Barrett’s esophagus at randomization. However, in two patients, there was an increase in length of the columnar epithelium. Overall, the median length of Barrett’s epithelium in this group was 2 cm (1-3; range 0-13). Biopsy specimens from the neosquamous epithelium in the 3 patients with complete regression revealed normal squamous epithelium. In patients with residual columnar epithelium, biopsy specimens contained SIM in all but 7 in whom there was fundic-type epithelium. In the two patients with LGD in initial biopsy specimens, biopsy specimens at 1 year confirmed the presence of SIM, but there was no evidence of dysplasia or malignancy. Overall, at 1 year, complete ablation of Barrett’s epithelium was achieved in 11 of 19 patients (58%) in the ablation group, compared with 3 of 20 (15%) in the surveillance group (p < 0.01). In the ablation group, some patients experienced minor side effects, but there was no serious complication. Several patients reported mild retrosternal discomfort and odynophagia immediately after treatment, but this was shortlived (up to 3 days) and responded to treatment with orally administered analgesics. One patient stayed in the hospital for 1 day after the first treatment, but none were re-admitted. There was no post-treatment hemorrhage, stricture, or perforation. DISCUSSION Data to show that either pharmacologic or surgical therapy lead to significant regression of Barrett’s esophagus are sparse, hence, there is considerable interest in ablation therapy. However, there are few rigorous evaluations of ablation therapies, and few of these include patients with previous fundoplication.19,27,34,35 In a non-randomized trial, Salo et al.19 compared patients treated by endoscopic Nd-YAG laser photoablation combined with fundoplication to control patients who declined therapy. Grade et al.36 studied APC ablation in 9 patients with Barrett’s esophagus in whom half of the esophageal circumference was ablated, with the nonablated mucosa serving as the control. The results of one randomized controlled study of PDT ablation of Barrett’s esophagus have been published,26 but there is no similar study of APC ablation therapy. In the present trial, up to 6 APC treatments were performed. Complete ablation was achieved in 12 of 20 patients (60%), and greater than 95% ablation was achieved in all patients. There was a relationship between the length of Barrett’s esophagus and the VOLUME 59, NO. 1, 2004
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ability to achieve complete ablation, a finding consistent with those of other studies.29,35 Similar results have been achieved by using other ablation therapies in patients with Barrett’s esophagus without fundoplication. In a study of 16 patients with Barrett’s esophagus treated with potassiumtitanyl-phosphate laser photoablation and acid suppression, squamous re-epithelialization was achieved in all cases.18 In a study of aminolevulinic acidinduced PDT, ablation of Barrett’s epithelium was noted in 33 of 40 patients,37 with a median area reduction of 30% (range 0%-90%). All patients initially had LGD, and, after treatment, dysplasia was noted in only one patient. Argon plasma coagulation may have advantages over other ablative modalities. The equipment is inexpensive, easy to use, and does not require a laser. In contrast to PDT, there is no need to administer a photosensitizing drug, and systemic photosensitization is avoided. However, adverse effects have been reported with APC, including hemorrhage, stricture,29,34 and perforation,27,35 which can be fatal.27 Argon plasma coagulation produces a shallow depth of damage compared with other treatment modalities, and complications usually are associated with high power settings. The APC power setting used in this study was adequate to achieve the desired effect but not so high as to increase the risk of complications. A drawback of all forms of ablative therapy is the persistence of columnar glands beneath the neosquamous epithelium, which occurs in 6% to 69% of cases.17,18,29,38 In the present study, buried glands were seen in 35% of patients at 1 month and 5% at 1 year. The reason for these apparently better results is unknown. It may be related to the anacid esophageal environment after fundoplication, or it may simply be because of sampling error in this relatively small group of patients. The clinical relevance of buried glands is unknown. Although there are reports of adenocarcinoma developing in patients with buried glands,39,40 the risk is difficult to quantify.41 Studies have demonstrated the ability to ablate Barrett’s epithelium and induce squamous reepithelialization, but the durability of the new epithelium is unknown. In the current study, all but one of the patients in whom complete ablation was observed 1 month after treatment remained free of Barrett’s epithelium at 1 year. In the patient in whom Barrett’s epithelium recurred, the fundoplication had come undone, and the patient had a relapse of reflux-related symptoms. In the present study, some patients with incomplete ablation had further regression of the Barrett’s epithelium over time. The reason is unclear, GASTROINTESTINAL ENDOSCOPY
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although it may be that much of the residual Barrett’s epithelium was in the form of isolated columnar islands, which may be more likely to regress than larger areas. The observation that Barrett’s epithelium regressed in the surveillance group was unexpected. In 3 patients with an initial diagnosis of shortsegment Barrett’s esophagus, no residual epithelium was present at 1 year. These findings are consistent with those of other studies. Brand et al.11 noted complete regression in 4 of 10 patients. Among 14 patients, Low et al.42 observed partial regression in 10 with long-segment Barrett’s esophagus and complete regression in two with short-segment Barrett’s esophagus. However, in a review of 11 series, incorporating 340 surgical patients, only 4% had complete regression, and 12% had partial regression.43 Conversely, in a study of 152 patients undergoing open fundoplication with long-term follow-up, there was no regression of Barrett’s esophagus. Furthermore, LGD developed in 15 and adenocarcinoma in 4.44 The results of the present study differ from those of Basu et al.30 In the latter study, 44% of patients had buried glands and 68% had a recurrence of Barrett’s epithelium at 1 year. However, there are significant methodologic differences between the two studies, which may account for these differences: use of different forceps (‘‘jumbo’’ vs. standard), APC power settings (30 vs. 60 W), and definitions of complete ablation. Although all patients in the present study initially had Barrett’s esophagus with SIM, in some patients, residual columnar epithelium at 1 year no longer included SIM. The reason(s) for this is unclear. It may be because of sampling error, although this is unlikely, because a rigid biopsy protocol was followed. Apparent regression of SIM has been noted in patients with short-segment Barrett’s esophagus after fundoplication.45 In the present series, most patients without SIM at 1 year had short-segment Barrett’s esophagus at the time of inclusion in the study. Equally, two patients in the surveillance group, who had LGD at randomization, had no dysplasia at 1 year. Again, it is impossible to know whether this represents true regression or sampling error. In conclusion, APC ablation after fundoplication is safe and effective in almost 60% of patients with Barrett’s esophagus. Whether this leads to a reduction in cancer risk is unknown. REFERENCES 1. Haggitt RC. Barrett’s esophagus, dysplasia and adenocarcinoma. Hum Pathol 1994;25:982-93. 6
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2. Ackroyd R, Williams JL, Wakefield SE, Stoddard CJ, Reed MWR. Surveillance of Barrett’s esophagus: a need for guidelines? Dis Esophagus 1997;10:185-9. 3. Macdonald CE, Wicks AC, Playford RJ. Final results from 10-year cohort of patients undergoing surveillance for Barrett’s oesophagus: observational study. Br Med J 2000; 321:1252-5. 4. van Sandick JW, van Lanschot JJ, Kuiken BW, Tytgat GN, Offerhaus GJ, Obertop H. Impact of endoscopic biopsy surveillance of Barrett’s oesophagus on pathological stage and clinical outcome of Barrett’s carcinoma. Gut 1998; 43:216-22. 5. Wesdorp ICE, Bartelsman J, Schipper MEI, Tytgat GN. Effect of long-term treatment with cimetidine and antacids in Barrett’s esophagus. Gut 1981;22:724-7. 6. Deviere J, Buset M, Dumonceau JM, Rickaert F, Cremer M. Regression of Barrett’s epithelium with omeprazole. N Engl J Med 1989;320:1497-8. 7. Collen MJ, Strong RM. Comparison of omeprazole and ranitidine in treatment of refractory gastroesophageal reflux disease in patients with gastric acid hypersecretion. Dig Dis Sci 1992;37:897-903. 8. Sampliner RE, Garewal HS, Fennerty MB, Aickin M. Lack of impact of therapy on extent of Barrett’s esophagus in 67 patients. Dig Dis Sci 1990;35:93-6. 9. Igbal TH, Neumann CS, Cooper BT. Omeprazole treatment of patients with Barrett’s oesophagus [abstract]. Gut 1993; 34:S19. 10. Sampliner RE, Mackel C, Jennings D, Greski-Rose P. Effect of 12 months of a proton pump inhibitor (lansoprazole) on Barrett’s esophagus: a randomized trial [abstract]. Gastroenterology 1992;102:A517. 11. Brand DL, Ylvisaker JT, Gelfand M, Pope CE. Regression of columnar esophageal (Barrett’s) epithelium after anti-reflux surgery. N Engl J Med 1980;302:844-8. 12. Skinner DB, Walther BC, Riddell RH, Schmidt H, Iascone C, DeMeester TR. Barrett’s esophagus: comparison of benign and malignant cases. Ann Surg 1983;198:554-66. 13. Endo M, Kobayashi Kozu T. A case of Barrett’s epithelialisation followed up for 5 years. Endoscopy 1974;6:48-51. 14. Dooner J, Cleator IG. Selective management of benign esophageal strictures. Am J Gastroenterol 1982;77:172-7. 15. Gurski RR, Peters JH, Hagen JA, DeMeester SR, Bremner CG, Chandrosoma PT, DeMeester TR. Barrett’s esophagus can and does regress after antireflux surgery: a study of prevalence and predictive features. J Am Coll Surg 2003;196:706-13. 16. Sampliner RE, Fennerty MB, Garewal HS. Reversal of Barrett’s esophagus with acid suppression and multipolar electrocoagulation: preliminary results. Gastrointest Endosc 1996;44:523-5. 17. Berenson MM, Johnson TD, Markowitz NR, Buchi KN, Samowitz WS. Restoration of squamous mucosa after ablation of Barrett’s esophageal epithelium. Gastroenterology 1993;104:1686-91. 18. Barham CP, Jones RL, Biddlestone LR, Hardwick RH, Shepherd NA, Barr H. Photothermal laser ablation of Barretts oesophagus: endoscopic and histological evidence of squamous re-epithelisation. Gut 1997;41:281-4. 19. Salo JA, Salminen JT, Kiviluoto TA, Nemlander AT, Ramo OJ, Farkkila MA, et al. Treatment of Barrett’s esophagus by endoscopic laser ablation and antireflux surgery. Ann Surg 1998;228:621-3. 20. Sampliner RE, Faigel D, Fennerty MB, Lieberman D, Ippoliti A, Lewin K, et al. Effective and safe endoscopic VOLUME 59, NO. 1, 2004
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