Patients with gastroesophageal reflux disease and Barrett’s esophagus can be a management challenge for the treating physician or surgeon. The goals of therapy include relief of reflux symptoms, induction of histologic regression, and prevention of progression of intestinal metaplasia to dysplasia or invasive carcinoma. Antireflux surgery is effective at achieving these end points, although ongoing follow-up and endoscopic surveillance are essential. In cases of dysplasia or early esophageal neoplasia associated with Barrett’s esophagus, endoscopic resection and ablation have supplanted esophagectomy as the standard of care in most cases. Esophageal resection continues to have a role, however, in a minority of appropriately selected candidates.
Key points
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Antireflux surgery is a safe and effective treatment option to control gastroesophageal reflux disease in patients with Barrett’s esophagus.
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Antireflux surgery prevents reflux of acid and nonacid gastric content, and can induce regression in some cases of Barrett’s metaplasia or dysplasia.
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Antireflux has not been proved to be superior to medical therapy in preventing the progression of Barrett’s esophagus to esophageal adenocarcinoma.
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Esophagectomy has been supplanted by endoscopic therapies as the ideal treatment option for most patients with high-grade dysplasia or focal intramucosal adenocarcinoma.
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Esophagectomy may be the preferred treatment option in a minority of select cases with multifocal dysplasia, high-risk tumor characteristics, an esophagus otherwise not worth salvaging, or because of patient preference.
Introduction
Gastroesophageal reflux disease (GERD) is the major risk factor for the development of Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). The treatment of BE is focused primarily on controlling reflux, most commonly with antisecretory medication to abolish gastric acid production. In patients with dysplastic BE or early esophageal neoplasia, endoscopic therapies, including various forms of ablation and resection, have become the primary treatment options to eradicate the pathologic mucosa. Adjunctive medical or surgical antireflux therapies are necessary to control ongoing reflux, in an effort to reduce the recurrence of esophageal metaplasia, dysplasia, or neoplasia.
Although medical therapy is the most commonly used treatment modality for BE, antireflux surgery is a safe and effective alternative and should be considered in all patients to control underlying GERD. In select cases, such as individuals with end-stage esophageal motility disorders, recalcitrant strictures, or long-segment BE (LSBE) with multifocal high-grade dysplasia (HGD) or intra-mucosal adenocarcinoma (IMC), esophagectomy should be considered in the treatment paradigm ( Box 1 ).
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Tumor characteristics with a significant risk of lymph node metastasis
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Poorly differentiated tumors
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Positive deep margin after endoscopic resection
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Lymphovascular invasion
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Invasion beyond the muscularis mucosa
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Dysplastic or neoplastic Barrett’s esophagus, which is difficult to eradicate
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Ultra-long segment Barrett’s esophagus
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Diffusely nodular esophagus with multifocal high-grade dysplasia or intramucosal adenocarcinoma
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Long or large intramucosal adenocarcinomas
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Failed eradication of disease following endoscopic therapy
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Patient unwilling or unable to comply with the required repeat endoscopies and long-term surveillance
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Esophagus not worth salvage
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Recalcitrant stricture
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End-stage motility disorder
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This article reviews the role of antireflux surgery in the management of nondysplastic and dysplastic BE, and highlights the evolution of esophagectomy in the treatment of patients with HGD or early esophageal neoplasia.
Introduction
Gastroesophageal reflux disease (GERD) is the major risk factor for the development of Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). The treatment of BE is focused primarily on controlling reflux, most commonly with antisecretory medication to abolish gastric acid production. In patients with dysplastic BE or early esophageal neoplasia, endoscopic therapies, including various forms of ablation and resection, have become the primary treatment options to eradicate the pathologic mucosa. Adjunctive medical or surgical antireflux therapies are necessary to control ongoing reflux, in an effort to reduce the recurrence of esophageal metaplasia, dysplasia, or neoplasia.
Although medical therapy is the most commonly used treatment modality for BE, antireflux surgery is a safe and effective alternative and should be considered in all patients to control underlying GERD. In select cases, such as individuals with end-stage esophageal motility disorders, recalcitrant strictures, or long-segment BE (LSBE) with multifocal high-grade dysplasia (HGD) or intra-mucosal adenocarcinoma (IMC), esophagectomy should be considered in the treatment paradigm ( Box 1 ).
- •
Tumor characteristics with a significant risk of lymph node metastasis
- ○
Poorly differentiated tumors
- ○
Positive deep margin after endoscopic resection
- ○
Lymphovascular invasion
- ○
Invasion beyond the muscularis mucosa
- ○
- •
Dysplastic or neoplastic Barrett’s esophagus, which is difficult to eradicate
- ○
Ultra-long segment Barrett’s esophagus
- ○
Diffusely nodular esophagus with multifocal high-grade dysplasia or intramucosal adenocarcinoma
- ○
Long or large intramucosal adenocarcinomas
- ○
- •
Failed eradication of disease following endoscopic therapy
- •
Patient unwilling or unable to comply with the required repeat endoscopies and long-term surveillance
- •
Esophagus not worth salvage
- ○
Recalcitrant stricture
- ○
End-stage motility disorder
- ○
This article reviews the role of antireflux surgery in the management of nondysplastic and dysplastic BE, and highlights the evolution of esophagectomy in the treatment of patients with HGD or early esophageal neoplasia.
Goals of therapy for Barrett’s esophagus
Although most patients treated for GERD without BE can be managed successfully with medical therapy alone, those patients identified with BE are at increased risk for the development of EAC and may require a more intense treatment regimen. Such patients should (1) undergo a detailed endoscopic examination, with multiple biopsies per established protocols, to rule out dysplasia or early neoplasia; (2) be treated aggressively for reflux to prevent further mucosal injury; and (3) be enrolled in an ongoing endoscopic surveillance program for early detection of progression of disease. The ideal treatment of BE should control troublesome reflux symptoms, result in healing of mucosal injury, induce regression of Barrett’s epithelium to normal squamous mucosa, and prevent progression of BE to EAC, all with few side effects.
Limitations of medical therapy in patients with Barrett’s esophagus
Long-term, continuous control of reflux is critical in patients with BE to allow healing of the esophageal mucosa and to prevent progression of disease. Patients with GERD and BE compared with those without BE, however, have increased amounts of acid and bile reflux, and a higher prevalence of incompetent lower esophageal sphincters, hiatal hernias, and impaired esophageal motility. Consequently, control of GERD in patients with BE is much more challenging than in patients with GERD without BE.
Although the primary treatment end point in patients with GERD is symptom control, it has been shown in patients with BE that control of reflux symptoms does not equate to control of gastric pH or esophageal acid exposure. Greater than 50% of patients with BE have pathologic levels of esophageal acid exposure despite relief of symptoms. To maintain tight control of acid production, strict adherence to daily, and often twice daily, proton pump inhibitor (PPI) is necessary, making patient compliance a challenge. Additionally, antisecretory medications are directed at abolishment of acid production alone; they are ineffective at controlling the reflux of biliopancreatic substrates and nonacid gastric contents (eg, pepsin) that can contribute to ongoing mucosal injury.
Benefits of antireflux surgery
Antireflux surgery is a safe and effective alternative to medical therapy for patients with BE. Surgery corrects an incompetent lower esophageal sphincter and concomitant hiatal hernia, preventing the reflux of acid, bile, and other nonacid substrates. Complete reflux control can lead to healing and regression of Barrett’s mucosa, and may reduce the risk of progression to cancer. Surgery also eliminates the concern for patient compliance with medical therapy, and may reduce the cost of treatment compared with life-long antisecretory therapy.
Approach to Antireflux Surgery for Barrett’s Esophagus
Beginning with Rudolph Nissen’s transabdominal open “gastroplication,” first described in 1956 and modified for laparoscopy by Dallemagne in 1991, modern antireflux surgery has undergone a tremendous evolution over the past half century. Surgery can be accomplished via open transabdominal or transthoracic approaches, but laparoscopic fundoplication has become the gold standard for surgical management of GERD because of decreased morbidity, quicker recovery, improved cosmesis, and superior patient satisfaction over open surgery. Most patients with GERD are candidates for laparoscopic antireflux surgery, although in a select group open surgery may be required because of extensive abdominal adhesions from previous surgery or other patient factors.
The technique of constructing the fundoplication has also evolved over time. The original fundic wrap described by Nissen was approximately 6 cm long and was associated with significant postoperative dysphagia. The modern Nissen technique consists of a short (1.5–2 cm) floppy wrap over a large (56–60F catheter) bougie, affording excellent reflux control but with a lower risk of postoperative dysphagia. If esophageal motility is significantly impaired, a partial fundoplication may be better suited than a 360-degree Nissen wrap to prevent dysphagia. The efficacy of a partial fundoplication in patients with BE is questionable, however, with some studies suggesting decreased long-term control of reflux compared with a complete Nissen fundoplication. Other less used surgical techniques have been described as well, including near-total or subtotal gastrectomy with Roux-en-y reconstruction, or duodenal switch with biliopancreatic diversion. Perioperative risks and long-term gastrointestinal side effects may be increased with these more complex operations, and the data are less robust to support such interventions. As a result, this discussion focuses on the results of fundoplication.
Outcomes of Antireflux Surgery in Patients with Barrett’s Esophagus
Success following antireflux surgery can be assessed in several different domains. Primary end points include symptom relief, normalization of esophageal acid exposure, prevention of dysplasia or neoplasia, and regression of metaplasia or dysplasia. Most data are derived from cohort analyses from high-volume esophageal surgery centers, although there are limited publications comparing medical and surgical therapies.
Safety of antireflux surgery for Barrett’s esophagus
Laparoscopic antireflux surgery is safe with low morbidity and mortality. A recent review of the American College of Surgeons National Surgical Quality Improvement Program database, examining more than 7500 laparoscopic antireflux surgeries performed across the United States, revealed the 30-day operative mortality to be only 0.3%, and morbidity 3.8%. As expected, mortality increased with age, but was only 0.8% for patients older than 70 years.
Control of gastroesophageal reflux disease symptoms
The primary focus of the treatment of GERD is the control of troublesome symptoms, most commonly “typical” heartburn and regurgitation. Studies assessing short-term outcomes of laparoscopic Nissen fundoplication (LNF) have revealed excellent control of such typical GERD symptoms. In one study looking at 100 consecutive patients treated with LNF, including 37 patients with BE, 87% of patients considered themselves “cured” and another 11% had significantly improved symptoms at a median follow-up of 2 years.
When focusing on patients with BE treated with antireflux surgery, similar results for the control of symptoms have been seen. In a cohort of 85 patients followed for a median of 5 years, 77% of patients considered themselves “cured,” and an additional 22% had significant improvement of symptoms, following antireflux surgery. Similarly, a series of 59 patients followed for a median of 59 months revealed that 90% of patients undergoing antireflux surgery had no or only minor postoperative symptoms. “Minor” symptoms were defined as not interfering with quality of life or requiring medication. A third study of 215 patients followed for a median of 8 years after antireflux surgery demonstrated that 86% of patients had control of heartburn and regurgitation. As these studies demonstrate, laparoscopic antireflux surgery results in excellent control of GERD symptoms in most patients with BE.
Control of esophageal acid exposure: postoperative pH monitoring
Antireflux surgery has been shown to control the reflux of gastric acid into the esophagus, and to normalize esophageal acid exposure, in most patients treated for GERD. Because patients with BE represent a challenging patient population with severe reflux disease, control of esophageal acid exposure may not be as effective as in patients with GERD without BE. In a study of 53 patients with BE examined with preoperative and postoperative esophageal pH monitoring (at a median follow-up of 40 months after surgery), a significant reduction in distal esophageal acid exposure as measured by percent time pH less than 4 was seen (27.9% vs 4.0%; P <.001). However, abnormal distal esophageal acid exposure postoperatively was found in 14 of 53 (26%) patients. Similarly, an analysis by Hofstetter and colleagues of 21 patients studied with esophageal pH monitoring before and after antireflux surgery revealed that 4 of 21 (19%) patients had abnormal postoperative distal esophageal acid exposure. All four patients with a positive postoperative pH test had recurrent clinical symptoms of GERD. Although most patients undergoing antireflux surgery for BE can expect excellent reflux control, the lack of universal control of pathologic esophageal acid exposure reinforces the need for ongoing monitoring of patients with BE after antireflux surgery.
Control of histologic mucosal changes
The fate of the metaplastic or dysplastic Barrett’s epithelium may be the most important end point in assessing the results of antireflux surgery in patients with BE. Because esophageal pH monitoring has shown that approximately 20% to 25% of patients may suffer from recurrent reflux, the potential for progression of metaplasia exists. In a study of 77 consecutive patients with BE treated with antireflux surgery (61 undergoing Nissen fundoplication), histologic regression occurred in 28 (36%) patients and 8 (10%) had progression at a median follow-up of 50 months. The cohort included 17 of 25 patients with low-grade dysplasia (LGD) who regressed to BE without dysplasia, and 11 patients with nondysplastic BE who had no further intestinal metaplasia on follow-up. Of the eight patients who progressed, three went from nondysplastic BE to LGD and five from LGD to HGD. No esophageal cancers developed. The authors noted that patients with short-segment BE (SSBE) were more likely than those with LSBE to undergo histologic regression (58% vs 28%; P <.0016), with a median time to regression of 18.5 months. Progression occurred only in patients with LSBE.
Similarly, a study of 58 consecutive patients treated with antireflux surgery and followed for a median of 59 months showed complete regression of BE in eight (14%), regression of LGD to BE without dysplasia in six of eight (75%), and only four (7%) with progression of disease (two from BE without dysplasia to LGD, and two to EAC discovered at 4 and 7 years after surgery). All four patients with progression had abnormal postoperative esophageal pH monitoring.
Another study assessed 109 consecutive patients treated with antireflux surgery for BE, 90 of whom returned for continued endoscopic surveillance. At a median follow-up of 30 months, 30 (33%) patients had complete regression of BE, and only three (3.3%) had progression. Regression occurred only in patients with SSBE (30 of 54; 55%) and in no patients with LSBE. Progression included one patient with preoperative indefinite dysplasia who developed LGD, and two patients with BE with LGD who developed HGD (at 4 years) and EAC (at 10 months).
Antireflux surgery versus medical therapy
To determine whether antireflux surgery is superior to medical therapy in the management of BE, several comparative studies, including small, randomized controlled trials and meta-analyses, have been undertaken.
In a cohort study by Oberg and colleagues, 140 patients with BE without dysplasia were followed for a median of 5.8 years (945 patient-years) with surveillance endoscopies every 1 to 2 years. Only those patients whose two initial surveillance endoscopies were without dysplasia were included to assess for progression of disease. Forty-six patients were treated with antireflux surgery (43 Nissen fundoplications), eight with H 2 blockers (early patients in the cohort), and 85 with PPIs (60% single-daily dose, 40% twice-daily dose). The treatment strategy was at the discretion of the physician. Progression developed in 46 patients (33%) during the course of follow-up, including 39 patients to LGD, four to HGD, and three to EAC. No patients in the surgical arm developed HGD or EAC, and patients treated with antireflux surgery were 2.3 times less likely to develop LGD compared with the patients treated with medical therapy.
A study by Attwood and colleagues included a subgroup analysis of patients enrolled in the LOTUS trial, a European, multicenter, randomized, controlled trial that compared laparoscopic antireflux surgery with dose-escalating esomeprazole therapy. Of the 554 patients enrolled in the main study, 60 had BE without dysplasia, including 32 treated with LNF. All patients underwent pH monitoring at baseline and at 6 months after initiation of therapy. Those patients with BE treated with surgery had a significant reduction in esophageal acid exposure compared with patients treated with medical therapy (median percentage exposure time, 13.2% → 0.4% vs 7.4% → 4.9%; P = .002). Despite the differences in pH testing, symptomatic outcomes assessed at 3 years of follow-up were similar, and treatment failures were uncommon in either treatment arm (three medical, one surgical). Histologic follow-up was not reported.
In a study by Parrilla and colleagues, 101 patients with BE were randomized to open Nissen fundoplication (N = 58) versus twice-daily PPI therapy (N = 43) and followed annually. The mean follow-up was 5 years. The success of each treatment was similar, with 91% of patients in each arm of the study having a “good” or “excellent” symptomatic outcome. Objective physiologic testing, including esophageal pH and bile (Bilitec) monitoring, was performed. Surgical therapy was significantly more effective than medical therapy at controlling esophageal acid and bile exposure. There was no significant difference in the histologic changes seen in patients in each arm. No patients in either arm had resolution of BE. In the medical arm, two patients had regression of LGD to no dysplasia but eight patients (20%) developed dysplasia, including one with HGD and one with EAC. In the surgical arm, five patients had regression of LGD, but three patients (6%) had progression during follow-up, including one to HGD and one to EAC.
Two meta-analyses have assessed the impact of medical and surgical therapy in patients with BE on the development of EAC. Chang and colleagues reviewed 25 articles that had at least 1 year endoscopic follow-up after initiation of therapy. The analysis pooled the results of 996 patients treated with antireflux surgery and 700 patients treated with medical therapy, and followed for 3711 and 2939 patients-years, respectively. The surgical analysis included patients undergoing either partial or complete (Nissen) fundoplication. The incidence of EAC was significantly lower in surgically treated patients (2.8 vs 6.3 cases per 1000 patient years; P = .034). The authors noted, however, that this difference was predominantly driven by uncontrolled case-series, suggesting a publication bias. When only controlled studies were considered, the difference between surgical and medical therapy was no longer significant (4.8 vs 6.5 cases per 1000 patient-years; P = .32). The authors also examined the risk of regression and progression of BE. The probability of regression was significantly higher in surgically treated patients (15.4% vs 1.9%; P = .004). When the analysis was limited to controlled studies, the probability of regression remained significantly higher in surgical patients (6.4% vs 0.5%; P = .024). The probability of progression of disease was similar between both groups (2.9% vs 6.8%; P = .054). The authors concluded that, whereas the data suggest antireflux surgery promotes regression of BE better than medical therapy, antireflux surgery is not better at preventing the development of EAC.
A meta-analysis by Corey and colleagues yielded similar results with respect to EAC risk. The authors analyzed 34 publications with a cumulative 4678 patient-years of follow-up in surgical patients, and 4906 patient-years of follow-up in medically treated patients. The incidence of EAC was similar in both groups (3.8 vs 5.3 cancers per 1000 patient-years; P = .29, respectively). The difference between the two therapies was even smaller (3.8 vs 4.3 cancers per 1000 patient-years; P = .33) when the analysis limited the medically therapy arm to studies published in the preceding 5 years to eliminate patients for whom PPI therapy was not the primary medical treatment. The authors concluded that the incidence of EAC in patients with BE was low, and that antireflux surgery did not prevent cancer development better than medical therapy. Both meta-analyses concluded that antireflux surgery should not be recommended as an “antineoplastic” therapy.
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