Barrett esophagus (BE) is a well-established premalignant condition for esophageal adenocarcinoma (EAC), a lethal cancer with a dismal survival rate. The current guidelines recommend surveillance of patients with BE to detect dysplasia or early cancer before the development of invasive EAC. Recently, endoscopic eradication therapies have been shown to be safe and effective in the treatment of BE-related high-grade dysplasia and early EAC. This article reviews the various treatment options for BE and discusses the current evidence and gaps in knowledge in the understanding of treatment of this condition. In addition, recommendations are provided in context to the recently published guidelines by the American Gastroenterological Association.
Key Points
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Accurate diagnosis and careful detailed inspection of the Barrett segment, using high-definition white light endoscopy, is an essential part of endoscopic evaluation of patients with Barrett esophagus (BE).
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The extent of BE should be defined using standardized reporting criteria, such as the Prague C & M classification, and all visible lesions in the Barrett segment should be described using the Paris classification.
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Endoscopic eradication therapy (EET) have been shown to be safe and effective in the treatment of Barrett-related neoplasia. Efficacy of radiofrequency ablation in the treatment of Barrett-related neoplasia has been demonstrated in a randomized controlled trial.
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The current AGA guidelines recommend against the requirement for use of chromoendoscopy, NBI, or any other advanced imaging for routine surveillance of patients with BE.
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According to the current AGA guidelines:
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EET is only recommended to patients who develop HGD and intramucosal cancer.
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In patients with confirmed LGD, the option to treat should be based on a shared decision between the patient and physician.
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Surveillance is recommended for all patients with BE without dysplasia.
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Introduction
Barrett esophagus (BE) is defined as the presence of metaplastic columnar-lined esophagus of any length on endoscopy and the presence of intestinal metaplasia on biopsy. Approximately, 10% to 15% of patients with gastroesophageal reflux disease develop BE. BE is a well-established premalignant condition for esophageal adenocarcinoma (EAC), a lethal cancer with a dismal survival rate (5-year survival of 15%). The incidence of EAC continues to increase at a greater rate (>500% increase since 1975) than that of common cancers, such as breast, colon, lung, and prostate cancer. Furthermore, in most patients, EAC has an insidious onset becoming clinically apparent only in advanced stages.
Patients with BE are generally thought to progress through stages of dysplasia (low-grade dysplasia [LGD] to high-grade dysplasia [HGD]), with progressive accumulation of abnormal genetic alterations, before finally progressing to EAC. To date, the only reliable predictor for EAC is the development of dysplasia and hence the current societal guidelines recommend surveillance of patients with BE to detect dysplasia or early cancer before the development of invasive EAC.
For decades, patients developing HGD and mucosal cancer were traditionally treated with esophagectomy. Despite being the definitive therapy (by achieving resection of the precursor BE epithelium and the involved lymph nodes) esophagectomy carries a high risk of procedure-related long-term morbidity and mortality. These unacceptably high rates of mortality and morbidity have fueled interest in other forms of less invasive therapy. During the last two decades, innovative endoscopic treatments have been shown to be safe and effective in the treatment of BE and early EAC. This has resulted in an array of endoscopic therapeutic options for patients with BE. This article reviews the various treatment options for BE and discusses the current evidence and gaps in knowledge in the understanding of treatment of this condition. In addition, recommendations are provided in context to the recently published guidelines by the American Gastroenterological Association (AGA).
Introduction
Barrett esophagus (BE) is defined as the presence of metaplastic columnar-lined esophagus of any length on endoscopy and the presence of intestinal metaplasia on biopsy. Approximately, 10% to 15% of patients with gastroesophageal reflux disease develop BE. BE is a well-established premalignant condition for esophageal adenocarcinoma (EAC), a lethal cancer with a dismal survival rate (5-year survival of 15%). The incidence of EAC continues to increase at a greater rate (>500% increase since 1975) than that of common cancers, such as breast, colon, lung, and prostate cancer. Furthermore, in most patients, EAC has an insidious onset becoming clinically apparent only in advanced stages.
Patients with BE are generally thought to progress through stages of dysplasia (low-grade dysplasia [LGD] to high-grade dysplasia [HGD]), with progressive accumulation of abnormal genetic alterations, before finally progressing to EAC. To date, the only reliable predictor for EAC is the development of dysplasia and hence the current societal guidelines recommend surveillance of patients with BE to detect dysplasia or early cancer before the development of invasive EAC.
For decades, patients developing HGD and mucosal cancer were traditionally treated with esophagectomy. Despite being the definitive therapy (by achieving resection of the precursor BE epithelium and the involved lymph nodes) esophagectomy carries a high risk of procedure-related long-term morbidity and mortality. These unacceptably high rates of mortality and morbidity have fueled interest in other forms of less invasive therapy. During the last two decades, innovative endoscopic treatments have been shown to be safe and effective in the treatment of BE and early EAC. This has resulted in an array of endoscopic therapeutic options for patients with BE. This article reviews the various treatment options for BE and discusses the current evidence and gaps in knowledge in the understanding of treatment of this condition. In addition, recommendations are provided in context to the recently published guidelines by the American Gastroenterological Association (AGA).
Histopathology and rationale for endoscopic eradication therapy
There are worsening grades of cytologic and architectural changes on the continuum from LGD to invasive esophageal cancer. These are generally described as cytologic (stratified, hyperchromatic nuclei with nuclear enlargement, increased nuclear-to-cytoplasmic ratio, prominent nucleoli, increased mitotic figures, and loss of nuclear polarity) or architectural (crypt budding, branching, marked crowding, cribriform formation, and variation of crypt size and shape). The current diagnoses of LGD, HGD, and EAC are based on the recommendations of the Vienna classification. Intramucosal cancer is defined by the invasion of neoplasia into the surrounding lamina propria or muscularis mucosae but not into the submucosa. Presence of unequivocal stromal desmoplasia is consistent with submucosal EAC.
Previously, patients with HGD and intramucosal cancer were routinely treated with esophagectomy. Esophagectomy is considered to be a definitive therapy for BE because it resects the premalignant tissue along with the dysplastic lesion and the surrounding lymph nodes, and hence is considered to have very low risk of recurrence of cancer. In a retrospective study, cancer-free survival in 46 patients undergoing esophagectomy for T1a EAC in a tertiary care center was reported to be 95% at 5 years. However, esophagectomy has been associated with a defined morbidity and mortality risk. This perception has led to the rapid development of endoscopic therapeutic options. Observational data suggest that endoscopic eradication therapy (EET) is highly effective and that the long-term survival in patients with HGD and early EAC is similar to those undergoing esophagectomy. Moreover, a cost-effectiveness model of endoscopic ablation of HGD in patients with BE concluded that endoscopic ablation was more effective than surveillance or esophagectomy. Previous surgical series have shown that in patients with HGD or intramucosal cancer, the risk of lymph node metastases is 0% to 3%. A recent systematic review that included 1874 patients with HGD and mucosal EAC undergoing esophagectomy showed overall risk of lymph node metastasis of 1.39% (95% confidence interval [CI], 0.86–1.92). Specifically, in the group of patients with mucosal EAC the risk of lymph node metastases was 1.93% (95% CI, 1.19–2.66). This compares favorably with the perioperative mortality rate associated with esophagectomy. In contrast, in patients with submucosal EAC, lymph node metastasis is reported in excess of 20% of cases. Therefore, EET is recommended in patients with HGD or intramucosal cancer but not in patients with EAC involving the submucosa.
Accurate diagnosis and staging
Role of Advanced Imaging and Endoscopic Ultrasound
Careful and detailed examination with high-definition white light endoscopy of the Barrett segment is an essential part of the management of patients with BE. A recent study showed that inspecting the mucosa for more than 1 minute per cm length of Barrett segment was more likely to detect HGD/EAC, underscoring the importance of detailed inspection of the Barrett mucosa. The extent of BE should be defined using standardized reporting criteria, such as the Prague C & M classification. The morphology of visible lesions can have a bearing on the T-staging because nonprotruding, superficial lesions are likely to be associated with submucosal invasion. Therefore, all visible lesions in the Barrett segment should be described using the Paris classification ( Fig. 1 ).
Significant strides have been made in advanced imaging techniques to identify early neoplasia in patients with BE. Advanced imaging technologies, such as narrow band imaging (NBI), autofluorescence imaging, confocal laser endomicroscopy (CLE), and optical coherence tomography, have a role in characterization of visible lesions and detection of flat dysplasia. High-definition endoscopy has been shown to have a higher sensitivity in the detection of Barrett-related neoplasia when compared with standard endoscopy and should be the present standard of care. NBI offers the benefits of chromoendoscopy while making it easy and simple by providing an on-demand, push-button technique to better characterize the mucosal and vascular patterns in detecting dysplasia. These patterns have a high sensitivity and specificity in the detection of dysplasia within the Barrett segment. In a multicenter, randomized, crossover trial of 123 patients, there was no significant difference in detection of dysplasia between routine four-quadrant white light endoscopy biopsies and NBI-directed biopsies; however, NBI required fewer biopsies (3.6 vs 7.6 biopsies per procedure; P = .001). NBI and autofluorescence imaging are considered to be red flag or broad-field technologies that are used to identify dysplastic lesions. A relatively newer technology, CLE, enables real-time, in vivo evaluation of histology. A multicenter randomized controlled trial showed a significant improvement in detection of HGD/EAC with a probe-based CLE. Recently, probe-based CLE criteria for the diagnosis of dysplasia were scientifically created, tested, and validated in BE. These criteria were found to have a high degree of overall accuracy and interobserver variability. Although not ready for prime-time, these are exciting times for advanced imaging techniques and future studies should define its role in the management of patients with BE. The current AGA guidelines recommend against the use of chromoendoscopy, NBI, or any other advanced imaging for routine surveillance of patients with BE.
Although the role of endoscopic ultrasound has been established in the accurate T and N staging of invasive EAC, recent studies have shown only a modest accuracy in delineating T-staging in patients with HGD and intramucosal EAC. Recently, results from a US multicenter cohort of patients with BE (N = 105) assessing the diagnostic accuracy of endoscopic ultrasound in establishing T-stage (depth of invasion) using endoscopic mucosal resection (EMR) as the gold standard showed that the overall accuracy of endoscopic ultrasound was 72% (95% CI, 63–81). Presence or absence of visible lesions did not make a differences in the accuracy rates (69% vs 84%; P = .26). Young and colleagues reported a T-stage concordance rate of 65% in a systematic review, using EMR/surgical pathology as the gold standard. Based on these data, endoscopic ultrasound has a limited role in the evaluation of patients with early neoplasia.
Diagnostic Endoscopic Mucosal Resection
This technique involves the use of a diathermic snare or an endoscopic needle for resection of a neoplastic lesion or intestinal metaplasia to the level of submucosa. Accurate T-staging is critical in making therapeutic decisions in patients with dysplastic BE. EMR has evolved into an important diagnostic and therapeutic tool in the evaluation and management of BE-related neoplasia ( Fig. 2 ). In a study comparing preoperative EMR with histologic examination on esophagectomy specimens, there was perfect agreement between the two. Studies comparing routine biopsies of visible lesions with EMR report a 30% to 48% rate in change in diagnosis after obtaining an EMR. Moreover, in a study comparing 251 EMR specimens with biopsy, EMR improved interobserver agreement among expert gastrointestinal pathologists when compared with biopsy specimens (κ = 0.43 vs 0.35 for HGD; P = .018). This improvement in interobserver variability has been attributed to a larger tissue sample with limited architectural distortion. Although EMR is routinely recommended for visible lesions, the data are limited on its role in flat dysplasia.
Endoscopic eradication therapies and supporting evidence
The primary goal of endoscopic therapy is to prevent the development of invasive EAC by treating the dysplastic lesion, thereby improving patient survival. However, patients who develop dysplasia are at higher risk of recurrence of neoplasia and metachronous lesions from the remaining segment of BE, which occurs in up to 30% of patients undergoing EET. Therefore, complete ablation of the entire Barrett segment should be the goal in all patients undergoing EET.
Radiofrequency Ablation
Radiofrequency ablation (RFA) uses a catheter with an inflatable balloon at its tip that is connected to an energy generator. This catheter is passed through the working channel of an endoscope. The balloon at the tip of the catheter has bipolar heating elements that can cause superficial tissue injury. When the balloon is inflated and radiofrequency energy is applied over a circumferential Barrett segment, it causes ablation of the mucosa that is in contact with the balloon and can treat 3 cm of circumferential BE with each application ( Fig. 3 ). To treat smaller areas, such as islands, noncircumferential BE, and residual BE after treatment, a focal ablation device that works on the same principles of RFA is available. There is level 1 evidence demonstrating high rates of complete eradication of dysplasia and intestinal metaplasia in patients with BE with HGD and LGD. In a randomized sham-controlled trial of 127 patients in an intention-to-treat analysis, complete eradication was achieved in 81% of patients with HGD who underwent RFA compared with 19% of control subjects ( P <.001). In a follow-up cross-over of this study describing durability of RFA, after 3 years dysplasia remained eradicated in more than 85%, whereas intestinal metaplasia remained eradicated in more than 75% of patients without maintenance RFA. Among 64 patients with LGD (42 RFA, 22 sham) included in this study, at 1-year follow-up complete eradication rates of LGD (90% vs 23%; P <.001) and intestinal metaplasia (81% vs 4%; P <.001) were significantly higher in patients undergoing RFA when compared with control subjects. There is no randomized controlled trial demonstrating efficacy of RFA in patients with nondysplastic BE. In a multicenter study, patients with nondysplastic BE who had complete response to RFA 2.5 years after ablation were enrolled in a 5-year outcomes study. Using per protocol analysis, they report a complete response to metaplasia in 92%. Based on Kaplan-Meier analysis, it is estimated that 91% of patients would have complete response and that the mean duration of complete response would be 4.2 years. The main strengths of this technique include a precise and controlled delivery of a predetermined standardized radiofrequency energy, simplicity and ease of procedure, and its association with low stricture rate.
Cryotherapy
Cryotherapy is a noncontact technique that involves tissue destruction of metaplastic epithelium by intracellular disruption and ischemia that is produced by “freeze-thaw” cycles using liquid nitrogen or carbon dioxide. This is delivered through a catheter that can be passed through the working channel of any endoscope. The targeted spray is directed toward the BE segment to effectively induce a freeze cycle. An orogastric tube is introduced to help removal of excessive nitrogen or carbon dioxide and hence prevent perforation of viscus. Multiple freeze and thaw cycles are induced in each segment of the Barrett epithelium to produce effective ablation ( Fig. 4 ). The freeze-thaw cycles tend to cause intracellular damage while preserving the extracellular matrix and theoretically are thought to produce minimal fibrosis and effectively fewer strictures. Recent data suggest that cryotherapy is safe and effective in the treatment of HGD. In a multicenter prospective study of 77 patients, complete response to cryotherapy was seen in 94% in patients with HGD (17 patients) and 100% in patients with EAC (7 patients). In a retrospective study of 98 patients, complete eradication of HGD was seen in 97% of patients. There are no randomized controlled trials evaluating the role of cryotherapy in BE-related neoplasia. Anecdotally, the use of cryotherapy is limited to patients who have developed post-EMR stricture and those who have failed to achieve complete remission with RFA.
Endoscopic Resection of All BE
Endoscopic eradication using EMR alone involves focal EMR of visible lesions followed by complete eradication of the remaining Barrett segment with stepwise EMR. Most experts believe that EMR resection of the entire Barrett segment can be performed in patients with Barrett segment length of less than or equal to 5 cm. There are several techniques of EMR, including cap-assisted EMR after saline lift and band ligation with snare resection (multiband mucosectomy). A randomized controlled trial comparing these two techniques demonstrated that there is no difference in the thickness of specimen and resection of submucosa; however, the multiband ligation technique had a shorter procedure time and produced smaller EMR specimens. Based on several case series, the complete eradication of neoplasia and intestinal metaplasia ranges from 85.4% to 100% and 75.6% to 97%, respectively. In a study with 169 patients, after a median follow-up of 32 months, the eradication of neoplasia and intestinal metaplasia was found to be durable (95.3% and 80.5%, respectively). In this technique, despite EMR being the primary tool for treatment of dysplasia and intestinal metaplasia, touch-up treatments with argon plasma coagulation may be required. One of the strengths of stepwise EMR as a modality for complete resection of the Barrett segment includes the availability of tissue for histologic evaluation. However, there are significant risks that have been reported: bleeding in 0% to 46%, perforation in 1% to 5%, and strictures in 2% to 88% of patients undergoing complete EMR of the Barrett segment.
Multimodal EET
Multimodality EET involves the initial performance of EMR of visible lesions or abnormal mucosal patterns on advanced imaging followed by eradication of intestinal metaplasia in the remaining Barrett segment by using mucosal ablative techniques, such as RFA, cryotherapy, or argon plasma coagulation.
A multicenter prospective study of 24 patients found RFA after initial diagnostic EMR of visible lesions to be safe and effective. A retrospective analysis comparing histologic outcomes and complication rates between patients that underwent RFA therapy after an initial diagnostic EMR and those who underwent only RFA therapy showed comparable rates of dysplasia and strictures. In a case series report of 349 patients that received multimodal therapy (EMR, photodynamic therapy, and argon plasma coagulation), complete eradication was achieved in 94.5% and a long-term complete response was seen in 94.4%. Predictors of recurrence of intestinal metaplasia after multimodality therapies were long-segment BE, multifocal neoplasia, piecemeal resection, receiving no ablative therapy after initial complete response, and more than 10 months duration to achieve complete response. A randomized controlled study, only one of its kind, comparing stepwise EMR and initial diagnostic EMR followed by RFA in patients with BE segment length of less than or equal to 5 cm with HGD and early EAC showed no difference between the two groups for complete eradication of dysplasia (100% vs 96%) and intestinal metaplasia (92% vs 96%). However, patients who underwent stepwise EMR were more likely to develop strictures (88% vs 14%; P <.001) and require more therapeutic endoscopies (6 vs 3; P <.001). Based on these data, it is recommended that patients with HGD and early EAC undergo EMR of visible lesion followed by RFA to the remaining Barrett segment for complete eradication of intestinal metaplasia.
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