Saraswathi Arasu, DO and Michael S. Smith, MD, MBA
Barrett’s esophagus (BE) is the only identifiable premalignant condition for esophageal adenocarcinoma (EAC). It is an aggressive malignancy associated with a dismal 5-year survival rate of less than 15% and increasing annual incidence.1 In fact, EAC is the fastest-growing cause of cancer mortality. It is estimated that patients with BE have at least a 20-fold increase in odds of developing EAC. Among patients with BE containing high-grade dysplasia (HGD), the annual incidence rate of progression into EAC is approximately 6.58 per 100 patient-years. Furthermore, even for patients with low-grade dysplasia (LGD), the cumulative risk of disease progression to HGD or EAC can be as high as 14% among those who do not undergo ablative treatment.2 The metaplasia-dysplasia-neoplasia sequence from BE to invasive EAC provides inherent opportunities to halt the progression and decrease the incidence and prevalence of BE-related EAC, which ultimately can affect morbidity and mortality.
Esophagectomy formerly was the gold standard for the treatment of EAC because of the very low rate of nodal metastasis (0% to 2%). With new and improved endoscopic therapeutic options, the paradigm has shifted to favor endoscopic management. Endoscopic mucosal resection (EMR) has proven to be a safe, effective, and less-invasive alternative to surgery for treating such patients. Given that areas of HGD with visible abnormalities are more likely to harbor EAC within the same tissue region, EMR has the added benefit of being diagnostic as well as therapeutic, by providing a larger tissue specimen for accurate histopathology assessment when compared to a forceps biopsy sample. Similarly, endoscopic submucosal dissection (ESD) may potentially improve diagnostic yield with an even greater extent of resection; albeit current data are lacking.
Technical and Clinical Success
Endoscopic treatment in patients with BE containing HGD or superficial (T1a) EAC can lead to complete eradication of neoplasia in 80% to 100% of cases and complete eradication of all intestinal metaplasia (IM) in more than 75% of cases.3 This is important because risk of progression from HGD to EAC is approximately 10% per year.3
Endoscopic Mucosal Resection
Endoscopic resection is the therapy of choice for dysplastic BE associated with visible lesions and T1a EAC. While submucosal invasion increases the likelihood of metastasis, superficial submucosal involvement (SM1) does not necessarily preclude endoluminal intervention with curative intent. For T1b adenocarcinomas with involvement of the second submucosal layer or beyond (SM2 to SM3), endoscopic therapy should not be considered curative. Available EMR options include band ligation, and cap-assisted and snare techniques, which are described in detail in other chapters in this book. These EMR techniques can be used as monotherapy or in combination with field-ablation techniques such as radiofrequency ablation (RFA), cryoablation, and photodynamic therapy.
Band ligation and cap and snare techniques appear to have similar success rates4 for resection, reaching up to 85% to 98%. Two randomized, controlled trials (RCTs) that compared these techniques did not show significant differences between the approaches, either in terms of the depth of resection or complication rates.5,6 A recent meta-analysis comparing esophagectomy with endotherapy showed no difference in overall remission rate and mortality, with fewer major adverse events in the endotherapy group.7,8
When evaluating EMR monotherapy, complete endoscopic eradication was achieved in 80% in the intention-to-treat analysis and 98.8% in the per-protocol analysis in a study performed by Konda et al.9 Ultimately these patients had a 72% complete remission rate from all IM, and a 100% complete remission from neoplasia. Two similar large, multicenter retrospective studies also reported results for stepwise radical EMR for the treatment of BE-related HGD and intramucosal carcinoma.10,11 These studies included 169 patients who were followed for a median of 32 months, and 90 patients followed for a mean of 65 months. In both studies, high rates of complete eradication of both neoplasia and metaplasia were observed, with success rates ranging from 90% to 97% and 81% to 85%, respectively. These findings are corroborated by the Pech et al12 study, which showed a complete remission rate of 96% achieved in 1000 patients who remained stable over a postresection surveillance period of approximately 5 years.
Endoscopic Submucosal Dissection
ESD is a technique initially developed in Japan for the en bloc resection of early gastric cancers. While ESD experience remains limited in Western countries, there are some studies from Europe that show favorable resection rates of esophageal lesions. Data reviewed in the European guidelines,13 a collection of generally retrospective observational studies, demonstrate a high rate of en bloc resection (81% to 100%) and complete resection (R0) rates ranging from 38% to 97%. More recently, Coman and colleagues14 performed a prospective study to evaluate the technical success and adverse events of ESD in patients with BE with HGD or early EAC in a single Western tertiary referral center. This study showed R0 and curative resection rates of 81% and 69%, respectively. The en bloc resection rate was 100%.14 Furthermore, the number of incomplete R1 resections appeared to be a consequence of tumor presence both at deep and lateral margins. Of note, this was the first study to show a significant discrepancy between the histology of initial forceps biopsy and that of the actual ESD specimen in BE patients. More recently, Yang et al15 performed a meta-analysis (11 studies involving 501 patients and 524 lesions) evaluating outcomes of ESD for BE neoplasia. Overall, ESD was associated with a pooled en bloc resection rate of 93% with an incidence of recurrence of only 0.17% following curative resection.
Potential Adverse Events
Commonly reported potential adverse events with endoscopic resection include stricture formation, bleeding, and perforation. The risk of esophageal stricture formation is directly associated with the extent of the resection. Indeed, reports on circumferential EMR demonstrate rates of symptomatic strictures on the order of 37.8% and perforations around 1.9%.7,9 Furthermore, when comparing complete BE eradication via radical EMR vs multimodal therapy (EMR followed by RFA), there is a higher stenosis and complication rate with radical EMR alone. A recent randomized trial comparing the 2 approaches16,17 identified that more strictures developed (88% vs 14%), more endoscopies per patient were required (6 vs 3), and more severe complications occurred (24% vs 0%) in the radical EMR monotherapy group. While multiple studies do demonstrate that these strictures respond effectively with endoscopic dilation,3,11,18,19 based on these potential risks, we advocate that endoscopic resection should be restricted to the visible abnormality and ideally less than two-thirds of the esophageal circumference.
Several studies have also shown that the risk of stricture formation remains high even when radical EMR is performed in a stepwise manner (stepwise radical endoscopic resection [SRER]).1 In a multicenter RCT comparing 2 treatment approaches, a higher stricture rate was reported in patients treated with SRER compared to patients treated with focal EMR followed by RFA (88% vs 14%, P < .001).1,17 Efficacy, as measured by rates of complete eradication of dysplasia and IM, were not statistically different between the 2 groups.
Barret et al20 have evaluated outcomes in patients who undergo both EMR and BE field ablation in a single session. With this approach, RFA performed sequentially was not hindered by the EMR and over a median follow-up period of 19 months, sustained complete remission of IM was documented in 95% of patients and was achieved with a single treatment session in 43% of this cohort. However, this study still showed a relatively high rate of stenosis (33%).
ESD permits the en bloc resection of targeted lesions irrespective of size. When compared to EMR, ESD is technically more challenging and is associated with relatively longer procedural times and the potential for more serious adverse events. In the meta-analysis by Yang et al on ESD for BE-associated neoplasia,15 the pooled rate of stricture formation was near 12%. Similar to patients who develop stricture after EMR, nearly all of the ESD patients responded after undergoing endoscopic dilation. In all, the risk of stricture formation is likely more frequently seen with ESD when compared with EMR because of the extent of the resection rather than the technique.
The most feared complication with endoscopic resection techniques is perforation. In terms of EMR, the risk of perforation appears to be higher with radical EMR when compared with stepwise EMR. In the Konda study,9 there was an approximate 2% rate of perforation among patients who underwent complete EMR. Factors previously shown to be associated with a higher risk of complications include the length of the BE segment, use of EMR in conjunction with RFA, and increased age.7,21 Conversely, in the European Society of Gastrointestinal Endoscopy guidelines for ESD that evaluated safety-related outcomes in 37 studies,13 bleeding was observed in up to 22.8% of procedures and perforation occurred in up to 10.7%. However, no significant differences in procedural complications were observed between EMR and ESD patients except for the significantly higher prevalence of esophageal stenosis in ESD. When only outcomes on ESD for BE neoplasia were evaluated in a meta-analysis, the pooled rate of bleeding and perforation were 1.5% and 1.7%, respectively. However, it is important to highlight that these studies were performed by expert endoscopists in ESD centers of excellence.
Evaluating disease recurrence in the posttreatment population is challenging, in large part because of deficiencies in currently utilized surveillance techniques. The use of 4-quadrant biopsies to follow treated BE patients leaves a significant portion of mucosa unsampled, and may not either evaluate or reach for sampling subsurface tissues where recurrent disease may dwell. In addition, there is a lack of standardization in terminology when discussing disease recurrence. While there are only a few studies comparing endoscopic resection to esophagectomy (all of them retrospective), endoscopic resection is related to higher recurrence compared to surgery.13,22–24 In general, the literature supports a rate of recurrence following endoluminal treatment between 5% and 40%, with high variability owing to differing methods for detecting recurrence, inclusion or exclusion of the esophagogastric junction in tissue sampling, and variable duration of posttreatment surveillance.7 Specifically, there are reported recurrence rates of 0% to 15% for dysplasia and 5% to 39.5% for IM.17,21,25–26 For EAC, T1a lesions have been shown to have significantly better 5-year recurrence-free and overall survival rates (100% and 91%, respectively) than those showing involvement of the submucosa (60% and 58%).13,27
Endoscopic treatment for management of HGD has been associated with a higher rate of recurrence compared to surgical modalities.3 The literature suggests that, should there be recurrent disease, it will appear soon after achieving endoscopic eradication of IM.28,29 Recurrence rates are widely variable when assessing durability of endoluminal therapy for BE-associated neoplasia. The EURO-II study (EMR and RFA for HGD and superficial EAC) demonstrated an IM eradication rate of rate of 93%, with recurrence of neoplasia and IM at only 4% and 8%, respectively.30 RFA with or without prior EMR in the Ablation of Intestinal Metaplasia Containing Dysplasia trial demonstrated a 91% durability of eradication at 3 years.31 However, results from the United States RFA registry of 5521 patients demonstrated a 20% recurrence rate with a follow-up of 2.4 years.
Following focal EMR, there are multiple modalities available to complete disease eradication. RFA currently has the best available data supporting its use in this role. For example, Pech and colleagues23 had a low rate of recurrence and metachronous neoplasia (14.9%) with postresection RFA. Alternatives to RFA that have been studied include photodynamic therapy, cryotherapy, and argon plasma coagulation. A systematic review of photodynamic therapy for HGD of BE suggests that this approach reduces the risk of progression to cancer compared to surveillance alone, but complications (ie, photosensitivity, pain) are common and HGD persists in 33% to 50% of patients.3,32,33 Cryotherapy has not been evaluated in RCTs in this setting, and argon plasma coagulation only has been reported in small RCTs, although there are high anecdotal success rates.3,34
If EMR is performed on focal regions within a BE segment and the remaining tissue is left untreated, case series have reported significant recurrence of neoplasia. Rates vary from 11% to 30%, with a mean follow-up of 3 years.3,35,36 Ablation of the remaining BE is associated with a lower recurrence rate. Data are not clear on whether SRER or RFA with or without EMR provide lower rates of recurrent IM and dysplasia. One study by Fujii-Lau et al1 showed that patients in the RFA group had higher overall and IM recurrence rates compared to patients treated with SRER. However, there was no difference between the 2 groups with respect to recurrence of dysplasia. Risk factors that influence the rate of recurrence and metachronous neoplasia include multifocal neoplasia, piecemeal resection, length of the treatment phase, and the method of Barrett’s ablation. More studies are needed to optimize the algorithm for endoscopic BE treatment that minimizes the risk of recurrent disease.
While we have some guidelines on pretreatment endoscopic surveillance, there are few data regarding suggested time intervals for posttreatment surveillance after endoscopic eradication therapy and what modality is best suited to perform tissue sampling. This is important because the goal of EMR and ablation is to eliminate the subsequent risk of cancer because BE can recur after ablative and excisional therapies. One factor that makes surveillance difficult is that buried IM following ablation techniques has become recognized as an increasingly common phenomenon that may be underestimated by studies using biopsies for surveillance.7
Patterns and location of recurrence are another important factor surrounding the durability of endoscopic therapies that affects the need for surveillance. For example, the esophagogastric junction is a site known for harboring dysplastic lesions in patients with preexisting BE. Lesion depth also can be an issue, as one study using complete EMR for BE eradication revealed subsquamous lesions with HGD or intramucosal cancer in 21% of specimens prior to any other tissue-altering endotherapy.7,37 At least 8 cases of buried neoplasia have been reported in the literature to date, making the concept of subsquamous progression a legitimate concern and raising the question of which technique optimizes surveillance of these sites.7,16 Control of gastroesophageal reflux disease also may play a role in affecting recurrence rates. The presence of a large hiatal hernia (greater than 4 cm), which facilitates esophageal exposure to refluxate, was found to be a significant predictor of recurrence of BE with HGD or intramucosal carcinoma.25,38 While effective intraesophageal pH control has been associated with improved outcomes of RFA endotherapy,25,39 more data are needed to confirm the suspicion that improved reflux control posteradication will decrease recurrence rates.
Current expert opinion suggests posteradication endoscopic surveillance for patients with a history of BE with HGD or carcinoma of every 3 months for the first year following treatment, every 6 months for the second year, and annually thereafter. Patients treated endoscopically for BE with LGD can receive 2 surveillance procedures at 3- to 6-month intervals, followed by annual inspection. In the coming years, further studies will be essential for refining this algorithm, especially when it is adapted for the variety of endotherapies available. It is likely that post-RFA patients may be followed using a different algorithm than post-ESD patients, and other factors such as the extent of resection may generate a more individualized approach.
1. Fujii-Lau LL, Cinnor B, Shaheen N, et al. Recurrence of intestinal metaplasia and early neoplasia after endoscopic eradication therapy for Barrett’s esophagus: a systematic review and meta-analysis. Endosc Int Open. 2017;5(6):E430-E449. doi:10.1055/s-0043-106578.
2. Qumseya BJ, Wolfsen HC, Wani S, Gendy S. 57 significant reduction in the disease progression in Barrett’s esophagus low-grade dysplasia patients treated with endoscopic eradiation therapy compared with surveillance endoscopy: a systematic review and meta-analysis. Gastrointest Endosc. 2016;83(5 Suppl):AB121. doi:10.1016/j.gie.2016.03.034.
3. Bennett C, Vakil N, Bergman J, et al. Consensus statements for management of Barrett’s dysplasia and early-stage esophageal adenocarcinoma, based on a Delphi process. Gastroenterology. 2012;143(2):336-346. doi:10.1053/j. gastro.2012.04.032.
4. Conio M, Repici A, Cestari R, et al. Endoscopic mucosal resection for high-grade dysplasia and intramucosal carcinoma in Barrett’s esophagus: an Italian experience. World J Gastroenterol. 2005;11(42):6650-6655. doi:10.3748.wjg. v11.i42.6650.
5. Pouw RE, van Vilsteren FG, Peters FP, et al. Randomized trial on endoscopic resection-cap versus multiband mucosectomy for piecemeal endoscopic resection of early Barrett’s neoplasia. Gastrointest Endosc. 2011;74(1):35-43. doi:10.1016/j.gie.2011.03.1243.
6. May A, Gossner L, Behrens A, et al. A prospective randomized trial of two different endoscopic resection techniques for early stage cancer of the esophagus. Gastrointest Endosc. 2003;58(2):167-175. doi:10.1067/mge.2003.339.
7. Stier MW, Konda VJ, Hart J, Waxman I. Post-ablation surveillance in Barrett’s esophagus: a review of the literature. World J Gastroenterol. 2016;22(17):4297-4306. doi:10.3748/wjg.v22.i17.4297.
8. Wu J, Pan YM, Wang, TT, Gao DJ, Hu B. Endotherapy versus surgery for early neoplasia in Barrett’s esophagus: a meta-analysis. Gastrointest Endosc. 2014;79(2):233-241.e2. doi:10.1016/j.gie.2013.08.005.
9. Konda VJ, Gonzalez Haba Ruiz M, Koons A, et al. Complete endoscopic resection mucosal resection is effective and durable treatment for Barrett’s-associated neoplasia. Clin Gastroenterol Hepatol. 2014;12(21):2002-2010.e-2. doi:10.1016/j.cgh.2014.04.010.
10. Pouw RE, Peters FP, Sempoux C, Piessevaux H, Deprez PH. Stepwise radical endoscopic resection for Barrett’s esophagus with early neoplasia: report on a Brussels’ cohort. Endoscopy. 2008;40(11):892-898. doi:10.1055/s-2008-1077675.
11. Lopes CV, Hela M, Pesenti C, et al. Circumferential endoscopic resection of Barrett’s esophagus with high-grade dysplasia or early adenocarcinoma. Surg Endosc. 2007;21(5):820-824. doi:10.1007/s00464-006-9187-3.
12. Pech O, May A, Manner H, et al. Long-term efficacy and safety of endoscopic resection for patients with mucosal adenocarcinoma of the esophagus. Gastroenterology. 2014;146(3):652-660.e651. doi:10.1053/j.gastro.2013.11.006.
13. Pimental-Nunes P, Dinis-Ribeiro M, Ponchon T, et al. Endoscopic submucosal dissection: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2015;47(9):829-854. doi:10.1055/s-0034-1392882.
14. Coman RM, Gotoda T, Forsmark CE, Draganov PV. Prospective evaluation of the clinical utility of ESD in patients with BE: a Western center experience. Endosc Int Open. 2016;4(6):E715-E721. doi:10.1055/s-0042-101788.
15. Yang D, Zou F, Xiong S, et al. Endoscopic submucosal dissection for early Barrett’s neoplasia: a meta analysis. Gastrointest Endosc. 2018;87(6):1383-1393.
16. Konda VJ, Gonzalez Haba Ruiz M, Hart J, Waxman I. Development of subsquamous cancer after hybrid endoscopic therapy for intramucosal Barrett’s cancer. Endoscopy. 2012;44(Suppl 2 UCTN): E390-E391. doi:10.1055/s-0032-1310139.
17. van Vilsteren FG, Pouw RE, Seewald S, et al. Stepwise radical endoscopic resection versus radiofrequency ablation for Barrett’s oesophagus with high-grade dysplasia or early cancer: a multicentre randomised trial. Gut. 2011;60(6):765-773. doi:10.1136/gut.2010.229310.
18. Giovannini M, Bories E, Presenti C, et al. Circumferential endoscopic mucosal resection in Barrett’s esophagus with high-grade intraepithelial neoplasia or mucosal cancer. Preliminary results in 21 patients. Endoscopy. 2004;36(9):782-787. doi:10.1055/s-2004-825813.
19. Seewald S, Akaraviputh T, Seitz U, et al. Circumferential EMR and complete removal of Barrett’s epithelium: a new approach to management of Barrett’s esophagus containing high-grade intraepithelial neoplasia and intramucosal carcinoma. Gastrointest Endosc. 2003;57(7):854-859. doi:10.1067/mge.2003.237.
20. Barret M, Belghazi K, Weusten B, Bergman JJ, Pouw RE. Single-session endoscopic resection and focal radiofrequency ablation for short-segment Barrett’s esophagus with early neoplasia. Gastrointest Endosc. 2016;84:29-38. doi:10.1016/j.gie.2015.12.034.
21. Gupta M, Iyer PG, Lutzke L, et al. Recurrence of esophageal intestinal metaplasia after endoscopic mucosal resection and radiofrequency ablation of Barrett’s esophagus: results from a US Multicenter Consortium. Gastroenterology. 2013;145(1):79-86.e1. doi:10.1053/j.gastro.2013.03.008.
22. Prasad GA, Wu TT, Wigle DA, et al. Endoscopic and surgical treatment of mucosal (T1a) esophageal adenocarcinoma in Barrett’s esophagus. Gastroenterology. 2009;137(3):815-823. doi:10.1053/j.gastro.2009.05.059.
23. Pech O, Bollschweiller E, Manner H, Leers J, Ell C, Hölscher AH. Comparison between endoscopic and surgical resection of mucosal esophageal adenocarcinoma in Barrett’s esophagus at two high-volume centers. Ann Surg. 2011;254(1):67-72. doi:10.1097/SLA.0b013e31821d4bf6.
24. Das A, Singh V, Fleischer DE, Sharma VK. A comparison of endoscopic treatment and surgery in early esophageal cancer: an analysis of surveillance epidemiology and end results data. Am J Gastroenterol. 2008;103(6):1340-1345. doi:10.1111/j.1572-0241.2008.01889.x.
25. Wani S, Muthusamy VR, Shaheen NJ, et al. Development of quality indicators for endoscopic eradication therapies in Barrett’s esophagus: the TREAT-BE (Treatment With Resection and Endoscopic Ablation Techniques for Barrett’s Esophagus) Consortium. Am J Gastroenterol. 2017;112(7):1032-1048. doi:10.1038/ajg.2017.166.
26. Pech O, Behrens A, May A, et al. Long-term results and risk factor analysis for recurrence after curative endoscopic therapy in 349 patients with high-grade intraepithelial neoplasia and mucosal adenocarcinoma in Barrett’s oesophagus. Gut. 2008;57(9):1200-1206. doi:10.1136/gut.2007.142539.
27. Liu L, Hofstetter WL, Rashid A, et al. Significance of the depth of tumor invasion and lymph node metastasis in superficially invasive (T1) esophageal adenocarcinoma. Am J Surg Pathol. 2005;29(8):1079-1085.
28. Komanduri S, Kahrilas PJ, Krishnan K, et al. Recurrence of Barrett’s esophagus is rare following endoscopic eradication therapy coupled with effective reflux control. Am J Gastroenterol. 2017;112(4):556-566. doi:10.1038/ajg.2017.13.
29. Haidry RJ, Lipman G, Butt MA, et al. 53 six year disease durability outcomes on patients treated with endoscopic therapy for Barrett’s related neoplasia from the UK registry. Gastroenterology. 2015;148(4 Suppl 1):S16. doi:10.1016/S0016-5085(15)30053-6.
30. Phoa KN, Pouw RE, Bisschops R, et al. Multimodality endoscopic eradication for neoplastic Barrett oesophagus: results of an European multicentre study (EURO-II). Gut. 2015;65(4):555-562. doi:10.1136/gutjnl-2015-309298.
31. Shaheen NJ, Overholt BF, Sampliner RE, et al. Durability of radiofrequency ablation in Barrett’s esophagus with dysplasia. Gastroenterology. 2011;141(2):460-468. doi:10.1053/j.gastro.2011.04.061.
32. Overholt BF, Lightdale CJ, Wang KK, et al. Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Barrett’s esophagus: international, partially blinded, randomized phase III trial. Gastrointest Endosc. 2005;62(4):488-498. doi:10.1016/j.gie.2005.06.047.
33. Overholt BF, Wang KK, Burdick JS, et al. Five-year efficacy and safety of photodynamic therapy with Photofrin in Barrett’s high-grade dysplasia. Gastrointest Endosc. 2007;66(3):460-468. doi:10.1016/j.gie.2006.12.037.
34. Li YM, Li L, Yu CH, Liu YS, Xu CF. A systematic review and meta-analysis of the treatment for Barrett’s esophagus. Digest Dis Sci. 2008;53(11):2837-2846. doi:10.1007/s10620-008-0257-3.
35. Peters FP, Kara MA, Rosmolen WD, et al. Endoscopic treatment of high-grade dysplasia and early stage cancer in Barrett’s esophagus. Gastrointest Endosc. 2005;61(4):506-514.
36. May A, Gossner L, Pech O, et al. Local endoscopic therapy for intraepithelial high-grade neoplasia and early adenocarcinoma in Barrett’s oesophagus: acute-phase and intermediate results of a new treatment approach. Eur J Gastroenterol Hepatol. 2002;14(10):1085-1091.
37. Chennat J, Ross AS, Konda VJ, et al. Advanced pathology under squamous epithelium on initial EMR specimens in patients with Barrett’s esophagus and high-grade dysplasia or intramucosal carcinoma: implications for surveillance and endotherapy management. Gastrointest Endosc. 2009;70(3):417-421. doi:10.1016/j.gie.2009.01.047.
38. Yasuda K, Choi SE, Nishioka NS, et al. Incidence and predictors of adenocarcinoma following endoscopic ablation of Barrett’s esophagus. Dig Dis Sci. 2014;59(7):1560-1566. doi:10.1007/s10620-013-3002-5.
39. Akiyama J, Marcus SN, Triadafilopoulos G. Effective intra-esophageal acid control is associated with improved radiofrequency ablation outcomes in Barrett’s esophagus. Dig Dis Sci. 2012;57(10):2625-2632. doi:10.1007/s10620-012-2313-2.