Endoscopic submucosal dissection for Barrett-associated neoplasia: is it ready for the endoscopist’s toolbox?

 

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Esophageal adenocarcinoma continues to be a vexing problem for the Western world, where its incidence has increased at an alarming rate and is projected to continue to increase in the coming decades as well [1]. Compounding this problem is the fact that most patients who have esophageal adenocarcinoma present with late-stage symptomatic disease and accompanying poor survival; in only a small minority has the precursor lesion of Barrett’s esophagus been diagnosed. That said, the treatment of early neoplasia in Barrett’s esophagus has advanced dramatically in recent years. Whereas surgical esophagectomy, with its well-documented limitations, was once viewed as the treatment of choice, endoscopic therapy consisting of endoscopic mucosal resection (EMR) of visible lesions followed by ablation of the residual Barrett’s segment, typically with radiofrequency ablation, has become the standard of care and is endorsed by both professional society guidelines and an international consensus panel [2] [3].

The Wiesbaden group first demonstrated the remarkable efficacy of EMR for early neoplasia in Barrett’s esophagus in a landmark study published in 2007, with a 5-year survival rate of 98 % but a recurrence rate of 11 % [4]. Importantly, lesions eligible for EMR were characterized by the following criteria: lesion diameter smaller than 20 mm and macroscopically Paris type I, IIa, IIb, or IIc lesions smaller than 10 mm; well-differentiated or moderately differentiated grade of adenocarcinoma; lesion limited to the mucosa; and absence of invasion into lymph vessels or veins. The Wiesbaden group subsequently found that recurrence of neoplasia after endoscopic resection was related to factors such as failure to ablate the residual Barrett’s segment completely, multifocal neoplasia, piecemeal resection, and long-segment Barrett’s esophagus [5]. Finally, the group’s long-term results for EMR in patients who had Barrett’s esophagus with mucosal adenocarcinoma were published in the summer of 2014 [6]. In this remarkable study of 1000 patients, the majority were treated with the multiband ligator device, and 49 % underwent piecemeal resection followed by ablation of the residual, nondysplastic Barrett’s segment; complete remission of all high grade dysplasia and intraepithelial neoplasia was noted in 96.3 % of patients, tumor-related death occurred in 0.2 %, and the rate of disease-free survival was 87.1 % at 5 years. Other studies have confirmed the remarkable long-term efficacy and safety of EMR with or without radiofrequency ablation for early neoplasia in Barrett’s esophagus [7] [8] [9] [10]. Therefore, it would appear that most patients who have early neoplasia in Barrett’s esophagus can be treated effectively and safely with endoscopic eradication therapy, as previously described.

Endoscopic submucosal dissection (ESD) is the “new kid on the block,” so to speak, to enter the fray in the endoscopic treatment of Barrett-associated neoplasia. Pioneered in Japan, where it is widely used for the treatment of superficial gastric cancer, ESD has also been employed in the colon and esophagus, most notably for esophageal squamous cell carcinoma. Proponents of ESD point to the ability of this technique to achieve the en bloc resection of larger lesions; in addition, a more precise histologic assessment of lesion margins is possible than can be achieved in piecemeal EMR specimens [11]. However, these advantages come at a price, including increases in procedure time, technical complexity, and complications (e. g., perforation, stenosis, bleeding) in comparison with standard EMR.

To date, little is known about the role, if any, of ESD in the treatment of Barrett’s-associated neoplasia because only small numbers of patients have been described, primarily in Asia. In the one Western study, of 30 patients with high grade dysplasia or intramucosal adenocarcinoma, Neuhaus et al. achieved complete endoscopic resection of the lesion in 97 % of patients and en bloc resection in 90 %, but R0 resection characterized by clear lateral and deep margins was achieved in only 39 % [12].

In the current issue of Endoscopy, Chevaux et al. describe the experience of three endoscopists in the treatment of 75 patients with Barrett’s esophagus and either high grade dysplasia or superficial adenocarcinoma [13]. Of note, these patients were selected from 300 referred to the Louvain group for endoscopic resection with or without ablation. Patients were eligible for ESD if the following conditions were met: presence of high grade dysplasia or superficial cancer; presence of visible lesions (Paris type 0-I or 0-II) that were multiple, had a diameter greater than 15 mm, were poorly lifting, or were suspicious for submucosal invasion (T1sm1); and no signs of metastatic disease. After the procedure, all patients were hospitalized for a minimum of 24 hours and underwent esophagography to exclude perforation, with routine follow-up endoscopy performed at 2 weeks to assess for esophageal strictures and initiate treatment if needed. The median length of the Barrett’s segments was 6 cm (interquartile range [IQR] 4 – 9], and the median lesion diameter was 20 mm (IQR 10 – 30). The median procedure time was 117 minutes (IQR 100 – 145), and the median duration of hospitalization was 2 days.

What did the authors find? ESD was completed in 73 of the patients (97 %), with en bloc resection of the entire lesion in 90 %. The primary end point of curative resection of all cancer with negative vertical and horizontal margins was accomplished in 85 % of the patients. Curative resection of all neoplasia, including cancer and all grades of dysplasia, was accomplished in 56 %. Interestingly, 25 % of the resected lesions had the poor prognostic finding of grade 3 histology. Complications included delayed bleeding in 2.5 %, perforation managed endoscopically in 4 %, and strictures in 60 %. The strictures were managed with a variety of techniques, including prophylactic systemic corticosteroids, balloon dilation, stent placement, and intralesional steroid injection. Finally, despite ESD, metachronous cancers developed in 7 patients.

Where does this leave us with ESD at this time? First, ESD is clearly feasible in expert hands. Second, ESD may be a useful tool in a subset of patients who would be a challenge for conventional EMR techniques, especially those with larger lesions and those with superficial submucosal disease. However, the issue of endoscopic therapy for submucosal adenocarcinoma remains an area of uncertainty, given the risk for lymph node metastases associated with submucosal disease, especially in patients with deeper levels of invasion. Third, this procedure is time consuming, as we already know from other studies. Finally, the complication rate of this technique is considerable and far in excess of the current complication rates for EMR and radiofrequency ablation. Furthermore, there are significant other costs, related to the need for routine hospitalization and repeated endoscopic interventions for strictures. Endoscopic ablation of residual, at-risk Barrett’s epithelium will still be necessary for optimal results and may also be highly problematic in the setting of complex strictures.

For ESD to move forward into more widespread clinical use, multiple hurdles will need to be overcome, and I am not sure that the high bar already set for the endoscopic eradication therapy of Barrett’s neoplasia can be surpassed by this technique. ESD clearly requires considerable training in components already well outlined: expertise in interventional endoscopy, animal laboratory practice, preceptorship by experts in high volume centers (typically in Asia), and finally adequate patient volume to refine and master the technique [14]. How practical is this? One can envision these criteria being met in Europe and North America only in tertiary referral centers with adequate volumes and, importantly, with comprehensive ESD expertise that is applicable to the colon, stomach, and esophagus. However, for this technique really to take off, there needs to be a dramatic increase in the unmet needs of patients who have early adenocarcinoma that cannot be adequately treated with current techniques. It is unlikely that this volume threshold will be met until screening (not surveillance) programs for Barrett’s esophagus and esophageal adenocarcinoma improve to the point at which more patients with early carcinoma are detected. Given the difficulty in reaching these thresholds, we should continue to refine the technique of ESD and limit its application to selected centers in Europe and North America. Furthermore, with the evolution of endoscopic research to high quality clinical trials, it is hard to see ESD coming into widespread use until comparisons are made with the established techniques already in place. For now, we must avoid the trap of performing a procedure just because we can do it.

• References

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