Barrett’s esophagus is the only identifiable premalignant condition for esophageal adenocarcinoma. Endoscopic eradication therapy (EET) has revolutionized the management of Barrett’s-related dysplasia and intramucosal cancer. The primary goal of EET is to prevent progression to invasive esophageal adenocarcinoma and ultimately improve survival rates. There are several challenges with EET that can be encountered before, during, or after the procedure that are important to understand to optimize the effectiveness and safety of EET and ultimately improve patient outcomes. This article focuses on the challenges with EET and discusses them under the categories of preprocedural, intraprocedural, and postprocedural challenges.
Key points
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Endoscopic eradication therapy (EET) has revolutionized the management of Barrett’s-related dysplasia and intramucosal cancer, a practice that has essentially replaced esophagectomy as the standard of care for management of this patient population and been endorsed by gastroenterology societal guidelines.
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Candidates for EET are patients with Barrett’s-related high-grade dysplasia, intramucosal cancer, and confirmed low-grade dysplasia.
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Evaluation and management should be considered at expert centers and should involve endoscopic mucosal resection of all visible lesions followed by eradication of the remaining Barrett’s esophagus.
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Techniques most commonly used for EET include endoscopic mucosal resection, radiofrequency ablation, cryotherapy, and a combination of therapies termed multimodality EET.
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Patients should be enrolled in surveillance programs given the risk of recurrent intestinal metaplasia and dysplasia.
Introduction
Barrett’s esophagus (BE) is the only identifiable premalignant condition for esophageal adenocarcinoma (EAC), a cancer that has increased nearly six-fold over the past three decades and is associated with a poor 5-year survival rate of less than 20% (all stages) especially when detected at a symptomatic state. BE is believed to progress to EAC in a probabilistic manner through recognizable histologic stages of intestinal metaplasia, low-grade dysplasia (LGD), high-grade dysplasia (HGD), intramucosal cancer, and finally invasive cancer (submucosal invasion and beyond). Endoscopic eradication therapy (EET) has revolutionized the management of Barrett’s-related dysplasia and intramucosal cancer, a practice that has essentially replaced esophagectomy as the standard of care for management of this patient population and endorsed by gastroenterology societal guidelines. The primary goal of EET is to prevent progression to invasive EAC and ultimately improve survival rates. This is achieved with therapies that focus on removal of neoplastic mucosa by endoscopic mucosal resection (EMR) and ablative techniques (used alone or in combination) followed by acid suppression, which result in re-epithelialization with squamous mucosa.
The basic premise of recommending EET is that patients with cancer limited to the mucosa have a low risk (0%–2%) of lymph node metastasis. A systematic review that included 1350 BE-associated intramucosal cancer cases that underwent esophagectomy and lymph node analysis reported a nodal metastasis rate of 1.9% (95% confidence interval [CI], 1.1–2.6). No lymph node metastasis was found in 524 BE-associated HGD cases that underwent esophagectomy. Patients with submucosal invasion, poorly differentiated cancer, size greater than 2 cm, and lymphovascular infiltration should be referred for surgical resection given the high risk of lymph node metastasis (>20%). The basic principles of EET are as follows: (1) resection of all neoplastic visible lesions (lesions typically with the highest grade of neoplasia), (2) eradication of the remaining BE to reduce the risk of metachronous neoplasia (up to 30%), (3) management of adverse events, and (4) enrollment in surveillance programs and address the issue of recurrence of intestinal metaplasia and neoplasia.
With this background, it should be noted that there are several challenges with EET that can be encountered before, during, or after the procedure that are important to understand to optimize the effectiveness and safety of EET and ultimately improve patient outcomes. This article focuses on the challenges with EET discussed under the categories preprocedural, intraprocedural, and postprocedural challenges.
Introduction
Barrett’s esophagus (BE) is the only identifiable premalignant condition for esophageal adenocarcinoma (EAC), a cancer that has increased nearly six-fold over the past three decades and is associated with a poor 5-year survival rate of less than 20% (all stages) especially when detected at a symptomatic state. BE is believed to progress to EAC in a probabilistic manner through recognizable histologic stages of intestinal metaplasia, low-grade dysplasia (LGD), high-grade dysplasia (HGD), intramucosal cancer, and finally invasive cancer (submucosal invasion and beyond). Endoscopic eradication therapy (EET) has revolutionized the management of Barrett’s-related dysplasia and intramucosal cancer, a practice that has essentially replaced esophagectomy as the standard of care for management of this patient population and endorsed by gastroenterology societal guidelines. The primary goal of EET is to prevent progression to invasive EAC and ultimately improve survival rates. This is achieved with therapies that focus on removal of neoplastic mucosa by endoscopic mucosal resection (EMR) and ablative techniques (used alone or in combination) followed by acid suppression, which result in re-epithelialization with squamous mucosa.
The basic premise of recommending EET is that patients with cancer limited to the mucosa have a low risk (0%–2%) of lymph node metastasis. A systematic review that included 1350 BE-associated intramucosal cancer cases that underwent esophagectomy and lymph node analysis reported a nodal metastasis rate of 1.9% (95% confidence interval [CI], 1.1–2.6). No lymph node metastasis was found in 524 BE-associated HGD cases that underwent esophagectomy. Patients with submucosal invasion, poorly differentiated cancer, size greater than 2 cm, and lymphovascular infiltration should be referred for surgical resection given the high risk of lymph node metastasis (>20%). The basic principles of EET are as follows: (1) resection of all neoplastic visible lesions (lesions typically with the highest grade of neoplasia), (2) eradication of the remaining BE to reduce the risk of metachronous neoplasia (up to 30%), (3) management of adverse events, and (4) enrollment in surveillance programs and address the issue of recurrence of intestinal metaplasia and neoplasia.
With this background, it should be noted that there are several challenges with EET that can be encountered before, during, or after the procedure that are important to understand to optimize the effectiveness and safety of EET and ultimately improve patient outcomes. This article focuses on the challenges with EET discussed under the categories preprocedural, intraprocedural, and postprocedural challenges.
Preprocedural challenges
Candidates for Endoscopic Eradication Therapy
Despite all the advances in biomarkers and challenges associated with the diagnosis of dysplasia, the grade of dysplasia is currently the best biomarker to predict progression in patients with BE and is used frequently to determine if a patient is an ideal candidate for EET.
High-grade dysplasia and intramucosal cancer
The diagnosis of HGD in patients with BE is associated with a high yearly rate of progression to EAC (approximately 6% per year based on a meta-analysis with higher rates reported in other prospective randomized controlled trials). Coupled with evidence demonstrating efficacy and effectiveness of EET, this is an actionable diagnosis. Similarly, several large cohort studies have demonstrated favorable outcomes with EET in patients with BE-related intramucosal cancer. In a series of 1000 consecutive patients who underwent EMR for BE-related intramucosal cancer, complete eradication of neoplasia was achieved in 96.3% of patients at a mean follow-up of nearly 5 years with a long-term remission rate of 93.8%. Thus, patients with BE-related HGD and intramucosal cancer are ideal candidates for EET.
Low-grade dysplasia
There are several issues regarding the natural history of LGD that make the management of this group of patients highly controversial. First and foremost, several studies have demonstrated significant degree of interobserver variability in the diagnosis of LGD, even among expert gastrointestinal pathologists, which has likely contributed to the variable published rates of progression to HGD/EAC. Consistent with previously published studies addressing interobserver variability with diagnosis of LGD, in a multicenter cohort study, we showed that the interobserver agreement among two expert pathologists for the diagnosis of LGD was slight (kappa = 0.14). These data stress the need for revision of criteria used to make the diagnosis of LGD in clinical practice. In this cohort of patients that included 210 patients with BE with LGD, the annual incidence of EAC was 0.44% (95% CI, 0.2–0.98) and 1.83% (95% CI, 1.23–2.74) for a combined end point of HGD/EAC. Similarly, the Danish population-based cohort study reported an annual incidence of 1.27% (95% CI, 0.9–1.79) for HGD/EAC. In a recent retrospective study that included 293 patients with LGD, expert pathology review resulted in down-staging of LGD diagnosis to nondysplastic BE (NDBE) or indefinite for dysplasia in 73% and confirmation of LGD diagnosis in 27% of cases. In patients with confirmed diagnosis of LGD, the risk of progression to HGD/EAC was 9.1% per patient-year compared with 0.6% in patients with NDBE. These data validate the current recommendations that require expert pathologist confirmation of dysplasia in BE especially before making crucial management decisions (EET vs conservative management of surveillance).
With regards to the decision regarding EET, current American Gastroenterological Association recommendations suggest either surveillance at 6 to 12 months or EET, and the concept of shared decision making between the patient and endoscopist is emphasized. However, a recent randomized controlled trial (discussed later) that compared radiofrequency ablation (RFA) with surveillance showed that ablation was associated with a 25% reduction in risk of progression to HGD/EAC. Thus, RFA should be considered in patients with BE with a confirmed diagnosis of LGD on a case-by-case basis (diagnosis confirmed on more than one endoscopy, by expert gastrointestinal pathologists, possibly multifocal LGD, and in centers reporting a high rate of LGD progression).
Nondysplastic Barrett’s esophagus
Several arguments have been made for ablation of patients with NDBE, the two most common being lack of impact of endoscopic surveillance on mortality from BE-associated EAC and effectiveness and safety of RFA. The paradigm of surveillance in NDBE was challenged in a recent case-control study that compared the frequency of surveillance endoscopy among 38 cases (BE cases who subsequently died as a result of EAC) with a sample of 101 living cases with BE (control subjects) matched for age, sex, and follow-up evaluation. Endoscopic surveillance was not associated with a decreased risk of death from EAC (adjusted odds ratio, 0.99; 95% CI, 0.36–2.75). However, there are several reasons for not ablating all patients with NDBE: (1) low risk of HGD and cancer in NDBE as demonstrated by several contemporary studies, (2) prohibitively higher number of cases required to ablate to prevent one case of EAC in patients with NDBE, (3) risk of recurrence of intestinal metaplasia and lack of data on long-term cancer risk postablation, (4) need for ongoing surveillance even postablation and achieving the end point of complete eradication of intestinal metaplasia, (5) ablation is associated with well-defined risks and adverse events, and (6) decision analysis studies have shown that ablation of NDBE is not cost-effective. The authors do not recommend ablation of patients with NDBE and future studies should focus on risk stratification and identifying patients with NDBE at highest risk of progression who might benefit the most from EET.
Treatment Options: Endoscopic Eradication Therapy Versus Esophagectomy
Before embarking on EET, it is critical to not only discuss the indications with the patient but also to review the available treatment options for Barrett’s-related neoplasia. Given the high tumor-free survival rates, esophagectomy was long considered as the standard of care for patients with BE-related HGD and early EAC, treatment with which all other therapies are compared. However, esophagectomy is associated with an overall operative mortality rate of 2% and a major morbidity rate of 10%; these estimates have been reported from high-volume centers and those with a multidisciplinary care approach. It should be noted that there are no randomized controlled trials comparing esophagectomy with EET and neither is such a trial expected in the foreseeable future. In a recent population-based study using the Surveillance, Epidemiology, and End Results (SEER) database that identified 2016 patients with early EAC, comparable 2- and 5-year EAC-specific survival rates were reported between patients undergoing EET and surgical resection. Similar results were reported when analyses were limited to stage T0 and T1a. Cox proportional hazards regression models showed that the hazard ratio for EAC-free survival in the EET group was not different from that of the esophagectomy group (hazard ratio, 1.42; 95% CI, 0.9–2.03). These results are consistent with previous studies reporting no difference in cumulative mortality and survival in patients with BE-related intramucosal cancer and HGD undergoing EET and esophagectomy. These results provide confidence that EET is a reasonable and acceptable alternative to esophagectomy in the management of patients with Barrett’s-related neoplasia.
Informed Consent and Establishment of Clinical and Procedural Goals
Informed consent
The informed consent process should involve a clear discussion of all treatment options along with the merits and disadvantages of each treatment option. It is recommended that this discussion occur in an office setting and should include discussion of the following points: (1) diagnosis and grade of dysplasia along with natural history estimates regarding progression to HGD/EAC, (2) proposed evaluation plan (endoscopy, endoscopic ultrasound [EUS], and use of advanced imaging techniques), (3) proposed treatment plan and need for multiple sessions every 2 months to achieve the end point of complete remission of dysplasia and intestinal metaplasia (quote personal data if available), (4) discuss the short-term (chest pain, bleeding, perforation, strictures) and long-term (recurrence and progression to cancer) adverse events related to EET, (5) need for ongoing surveillance to address the issue of recurrence and progression to cancer, and (6) need for repeat EET to maintain remission of intestinal metaplasia.
Confirm the diagnosis of dysplasia
Given the significant interobserver variability even among expert gastrointestinal pathologists, the diagnosis of dysplasia should be confirmed by two expert pathologists. If the diagnosis of dysplasia is made at community centers, slides should be obtained and reviewed at expert centers before embarking on EET.
Setting and training
It is well established that esophagectomy for management of EAC should be performed in expert high-volume centers because patient outcomes have been shown to be superior in these centers (lower in-hospital mortality) with a minimum of 15 to 20 esophagectomies per year. Similarly, management of Barrett’s-related neoplasia should be performed in expert centers with access to endoscopic advanced imaging techniques, multidisciplinary team approach (gastroenterologist, surgeon, expert pathologist, radiologist, oncologist, and nutritionist), and the ability to address adverse events related to EET, including surgery. Although the safety of EMR and ablation has been described from expert centers and endoscopists, the adverse event rates from community practices and low-volume centers are not known. A recent prospective cohort study compared mucosal lesion and EAC detection rates in patients with Barrett’s-related neoplasia between a tertiary care center specializing in BE care and the community. A higher number of patients with visible lesions were noted at the tertiary care center leading to a 56% increased cancer detection rate significantly impacting patient management. In addition, data on learning curves, minimum number of procedures required to attain competence, and minimum number of procedures per year required to maintain competence in EET are scant. A recent study showed that performance of 20 EMRs is not sufficient to reach the peak of the learning curve in EMR. Similarly, results from a retrospective study demonstrated a significant correlation between the endoscopist RFA volume and complete eradication of intestinal metaplasia rates. The British Society of Gastroenterology guidelines recommend a minimum of 30 supervised cases of EMR and 30 cases of endoscopic ablation to attain competence and a minimum of 15 EMRs per year to maintain competence. These estimates need validation in future multicenter studies.
Procedural challenges
Accurate Diagnosis and Staging
Given the expanding indications and endoscopic armamentarium for management of patients with Barrett’s-related neoplasia, accurate staging is critical. An inaccurate diagnosis could have substantial deleterious consequences for the patient. The goal is to avoid a patient with benign disease being subjected to esophagectomy and a patient with invasive cancer (submucosal invasion or beyond) undergoing EET instead of surgery.
Advanced imaging techniques
The use of high-definition white-light endoscopy (HD-WLE) should be considered as the standard of care and the first critical step in the evaluation of patients with BE. HD-WLE has been shown to have a higher sensitivity for detection of Barrett’s-related neoplasia compared with standard endoscopy. The rules of BE inspection in patients being considered for EET include use of HD-WLE, cleaning the mucosa using water and/or mucolytic agent, using a distal attachment cap, and spending adequate time to evaluate the BE segment for visible lesions. Most experts believe that HD-WLE detects all lesions that require endoscopic resection. It has been suggested that inspecting the Barrett’s segment for more than 1 minute per centimeter length of BE was associated with detection of more patients with suspicious lesions with a trend toward a higher detection rate of HGD/EAC. The extent of BE should be defined using standardized reporting criteria, such as the Prague C&M, criteria and all visible suspicious lesions using the Paris classification. Although several advanced imaging techniques, such as dye-based or optical chromoendoscopy, autofluorescence, spectroscopy, confocal laser endomicroscopy, and optical coherence tomography, have been evaluated to improve the yield of current surveillance practices, their role in guiding EET has not been evaluated adequately in clinical trials. Advanced imaging techniques, such as narrow band imaging, seem to have a role during EET and help delineate margins of areas that harbor early neoplasia and in surveillance post-EET. Costs, limited data from clinical trials demonstrating improved outcomes, lack of standardized classification systems, additional time in busy clinical practices, and need for training are all impediments to widespread clinical application of advanced imaging techniques.
Role of endoscopic ultrasound in accurate staging
EUS is frequently used as a staging modality for patients with Barrett’s-related neoplasia who are being considered for EET with the goal of evaluation for advanced cancer (submucosal invasion or beyond and lymph node metastasis). Although the role of EUS in the accurate T and N staging of invasive EAC is well established, the role of EUS in patients with BE with HGD and intramucosal cancer is unclear. A recent population-based study using the SEER-Medicare linked database showed that performance of EUS was associated with improved survival in patients with esophageal cancer for all stages with the exception of stage 0 (HGD only) disease. Results from a multicenter cohort study of patients with BE undergoing EET showed that the accuracy of EUS for determining the depth of invasion using EMR as the gold standard was only 72% (95% CI, 63%–81%). Similarly, a systematic review reported a T-stage concordance rate of 65% using EMR or surgical pathology as the gold standard. Peritumoral inflammation resulting in wall thickening, heterogeneous tissue architectures, anatomic factors in the gastric cardia and distal esophagus, and doubled muscularis mucosae contribute to the limited accuracy rates of EUS in this patient population. A recent meta-analysis that evaluated the use of EUS in patients with BE with HGD and early EAC (N = 656) showed that the overall proportion of patients with advanced disease (≥T1sm or ≥N1 disease) detected on EUS was 14% (95% CI, 8%–22%) and 4% (95% CI, 2%–6%) in the absence of nodules. EUS should be considered in the evaluation of patients with Barrett’s-related neoplasia, given the potential to alter treatment strategies, albeit in a small proportion of patients.
Endoscopic mucosal resection as a diagnostic and staging modality
EMR has evolved into an important diagnostic/staging and therapeutic tool in the management of patients with Barrett’s-related neoplasia ( Fig. 1 ). The superiority of EMR compared with biopsy specimens is related to a larger and deeper tissue specimen with limited distortion providing the ultimate proof of invasion depth and in identification of patients with poorly differentiated cancers with lymphovascular invasion. In addition, interobserver agreement among expert gastrointestinal pathologists is superior for EMR specimens compared with biopsy specimens. Results from a recent US multicenter cohort of 138 patients with BE undergoing EET showed that EMR resulted in a change in diagnosis in 31% of patients (upgrade 10%, downgrade 21%). Another recent study reported that a different diagnosis was reported in nearly 50% of cases after initial EMR compared with previous endoscopic biopsy specimens. Although variable rates of change in diagnosis with EMR have been reported in the literature, the message is clear that EMR is the most accurate staging modality in Barrett’s-related neoplasia. This should be performed with therapeutic intent and whenever feasible, all visible lesions should be removed in a single endoscopic procedure.
Technique for endoscopic mucosal resection
Although several techniques for EMR have been described, the two primary techniques used frequently in clinical practice are cap-assisted EMR after saline lift and band ligation with snare resection (multiband mucosectomy technique). A randomized controlled trial that compared the two EMR techniques showed a shorter procedure time with multiband mucosectomy compared with cap-assisted EMR (34 vs 50 minutes; P = .02). However, specimens obtained using the multiband mucosectomy technique were smaller but no difference in thickness of specimens, resection of submucosa, and adverse event rates was noted. The technique used is a matter of endoscopist preference and both techniques are considered to be equally effective.
Techniques and Modalities for Endoscopic Eradication Therapy
Contemporary treatment options for EET in Barrett’s-related neoplasia include complete EMR of the entire Barrett’s segment; RFA; cryotherapy; and multimodality therapies, a term used to describe the use of combination of treatment modalities (eg, EMR plus RFA).
Endoscopic mucosal resection of entire Barrett’s esophagus
This therapeutic option involves focal EMR of all visible lesions followed by stepwise EMR of the remaining BE to achieve complete eradication ( Fig. 2 ). Several case series have reported high complete eradication of neoplasia (85%–100%) and intestinal metaplasia (76%–97%) using this treatment approach. Recently, a single-center US study reported complete eradication of intestinal metaplasia in 86 of 107 (80.4%) based on intention-to-treat analysis. At a mean follow-up of 40.6 months, durability data showed that complete eradication of neoplasia and intestinal metaplasia was noted in 100% and 72% of patients, respectively. It is generally believed that 5 cm is the upper limit of effective stepwise complete resection of entire BE and limiting resection to less than 50% of the circumference per treatment session may reduce the risk of strictures. The advantage of this technique is complete histologic correlation along with increased depth of tissue resection, which may decrease the incidence of residual subsquamous intestinal metaplasia (SSIM). However, this technique is associated with high rate of strictures requiring nearly twice the number of endoscopies with its associated adverse events, such as perforation, and long-term results are similar to those reported in patients undergoing multimodality therapies. Whether this treatment option should be reserved in a certain subgroup of patients with BE with neoplasia (multifocal disease, diffuse nodularity, deep Barrett’s glands, and regenerative tissue) needs to be addressed in future studies.
