Outcomes in Patients Who Have Failed Endoscopic Therapy for Dysplastic Barrett s Metaplasia or Early Esophageal Cancer

Outcomes in Patients Who Have Failed Endoscopic Therapy for Dysplastic Barrett s Metaplasia or Early Esophageal Cancer Ben M. Hunt, MD, Brian E. Louie, MD, Drew B. Schembre, MD, Anthony G. Bohorfoush, MD, Alexander S. Farivar, MD, and Ralph W. Aye, MD Division of Thoracic Surgery and Department of Gastroenterology, Swedish Cancer Institute and Medical Center, Seattle; Seattle Gastroenterology Associates, Seattle, Washington Background. Endoscopic therapy (ablation ± mucosal resection) for esophageal high-grade dysplasia (HGD) or intramucosal carcinoma has demonstrated promising results. Little is known about patients who have persistent or progressive disease despite endotherapy. We compared patients who had successful eradication of their disease with those in whom endotherapy failed to try to identify factors predictive of failure and outcomes after salvage therapy. Methods. We performed a single-institution retrospective review of patients treated with endotherapy from 2007 to 2012. Results. Thirty-eight patients underwent endotherapy: 28 had successful eradication of their disease and endotherapy failed in 10 patients. Patients in whom endotherapy failed were more likely to have highgrade dysplasia (HGD) on initial endoscopy, nodules or ulcers, multifocal dysplasia, and persistent nondysplastic Barrett s metaplasia. Patients in whom endotherapy failed also underwent significantly more endotherapy sessions. Seven patients had persistent dysplasia or progression to cancer, and 3 patients had complete eradication of HGD but presented with intramucosal carcinoma an average of 15 months after eradication. The 10 patients in whom endotherapy failed underwent salvage therapy with esophagectomy (7 patients), definitive chemoradiotherapy (1 patient), and endotherapy (2 patients). Patients treated with esophagectomy were disease free at a mean of 25 months postoperatively. Conclusions. HGD on initial endoscopy, multifocal dysplasia, mucosal abnormalities, and failure to eradicate nondysplastic Barrett s metaplasia were associated with failure of endotherapy. Patients with these characteristics should be considered at higher risk for treatment failure, and earlier consideration should be given to esophagectomy if there is persistent, progressive, or recurrent neoplasia. Clinical outcomes are good, even after salvage therapy. Continued endoscopic surveillance is mandatory after successful endotherapy because of the risk of recurrent disease. (Ann Thorac Surg 2013;95:1734 40) Ó 2013 by The Society of Thoracic Surgeons Endoscopic therapy has recently become an accepted first-line treatment for high-grade dysplasia (HGD) and intramucosal cancer (IMC) [1]. Two randomized controlled trials [2, 3] and multiple case series [4 19] have demonstrated low morbidity, low rates of progression to esophageal cancer, and high rates of successful disease eradication with radiofrequency ablation (RFA) or endoscopic mucosal resection (EMR), or both. However, little is known about the outcomes of patients in whom the dysplastic cells persist, those in whom there is recurrence of the dysplasia, or those in whom there is progression from dysplasia to cancer. In patients in whom endotherapy is failing, there is a concern that with Accepted for publication Feb 6, 2013. Presented at the Fifty-eighth Annual Meeting of the Southern Thoracic Surgical Association, San Antonio, TX, Nov 9 12, 2011. Address correspondence to Dr Louie, Swedish Medical Center, 1101 Madison St, Ste 850, Seattle, WA 98104; e-mail: brian.louie@swedish.org. persistent treatment with these modalities, a local curable disease may progress to invasive cancer. In these initial studies, successful treatment with endotherapy has been based on strict entry criteria [3, 7]. However, as more endoscopists perform endotherapy and treat patients who do not meet these strict entry criteria, further research is required to determine which patients may be at higher risk for treatment failure and to review the outcomes of treatment. We identified a group of patients with HGD and IMC in whom endotherapy failed and compared them with patients who had successful endoscopic eradication to try to identify factors that may predict those patients in whom endotherapy will fail and to gather information on the outcomes of salvage treatments after attempted endotherapy. Patients and Methods We performed a retrospective review of patients who underwent RFA or EMR (or both) of HGD or IMC Ó 2013 by The Society of Thoracic Surgeons 0003 4975/$36.00 Published by Elsevier Inc http://dx.doi.org/10.1016/j.athoracsur.2013.02.023

Ann Thorac Surg HUNT ET AL 2013;95:1734 40 FAILED ENDOTHERAPY IN EARLY ESOPHAGEAL CANCER 1735 (or both) at a single referral center from 2007 to 2012. Patients were identified from a prospectively maintained database and included in this study if they had biopsy specimens with HGD or IMC, or both. For inclusion, the patients were required to have undergone initial treatment with EMR with curative intent or RFA with the HALO system (Covidien /BarrX, Sunnyvale, CA), or both. Patients were excluded if they had EMR for staging followed by esophagectomy, if they received photodynamic therapy, or if they did not have HGD/IMC on centralized review of their biopsy results, which was performed by gastrointestinal pathologists experienced with Barrett s metaplasia. Systematic biopsies were performed after HGD or IMC was identified to confirm the diagnosis and to assess for synchronous disease. Endoscopic ultrasonography was used for patients with nodular Barrett s metaplasia or if IMC was identified before any treatment and again before esophagectomy was performed. EMR was undertaken if there was a visible lesion or a small potentially resectable area of dysplastic Barrett s metaplasia, with a goal of removing all visible raised or nodular mucosa. EMR was performed with a cap or with a multiband mucosectomy technique. RFA was performed after washing the mucosa with 60 to 100 ml of dilute N-acetyl cysteine, with either a 360-degree balloon catheter or a 90-degree scope-mounted cap using the standard protocol of 12 J at 40 W per ablation, with each area undergoing 2 ablations followed by removal of coagulum and then another 2 ablations. sessions were performed at 8-week intervals or when mucosal healing was achieved to minimize the risk of stricture. Multiple sessions of endotherapy (EMR or RFA, or both) were permitted. Ablation was continued with a goal of complete eradication of dysplasia, neoplasia, and nondysplastic Barrett s metaplasia, but complete eradication of metaplasia was not required for the treatment to be considered successful for this series. Argon plasma coagulation ablation was permitted only after initial treatment with RFA. The decision to stop endotherapy was made by the treating endoscopists (DBS, BEL, and AGB) after an attempt at repeated EMR failed, there was obvious multifocal cancer progression, or the judgment of the patient and endoscopist was to change treatment. Treatment failure in this study was defined as the pathologic finding of persistent dysplastic/neoplastic disease (ie, failure to eradicate the disease), presumed progression of disease based on biopsy results performed using the Seattle protocol [20], or recurrent disease after a diseasefree surveillance interval of 2 successive endoscopies with biopsies. Successful treatment was defined by eradication of IMC and HGD on a minimum of 2 successive endoscopies with biopsies. All biopsy specimens, including those for patients referred to our center, were reviewed by experienced gastrointestinal pathologists at our center. The tests used for statistical comparisons were the t test for continuous variables, Pearson s c 2 test with Yates continuity correction for discrete variables, and Fisher s exact test for discrete variables with cell frequencies less than 5. All p values were 2-tailed, and no adjustments were made for multiple comparisons. A p value less than 0.05 was considered statistically significant. All statistical analyses were performed using R software (www.rproject.org). The Institutional Review Board of Swedish Medical Center approved this study and waived the requirement for informed consent because of the study s retrospective nature. Results Forty-one patients who had undergone endotherapy were identified. Three were excluded during pathologic review because the presumed HGD was reclassified as lowgrade dysplasia (LGD) by 2 pathologists; therefore, 38 patients were included in this analysis. Twenty-eight patients (74%) had successful eradication of dysplasia and cancer with no recurrence. failed in 10 patients (26%): 1 failure was caused by progression from IMC to multifocal IMC, 6 failures resulted from progression from HGD to IMC, and 3 failures were due to recurrence of IMC. One patient had recurrence at 12 months with IMC at the neosquamocolumnar junction and underwent esophagectomy; IMC developed in 1 patient at 13 months by eruption through the neosquamous lining, and the patient underwent salvage EMR; and IMC developed in 1 patient at 20 months in a section of nondysplastic Barrett s metaplasia shorter than 1 cm, and the patient underwent esophagectomy. Demographics were similar between the 2 groups except that the treatment success group had a higher body mass index (Table 1). In the treatment failure group, there were significantly more patients with nodular or ulcerated Barrett s metaplasia, multifocal HGD, and HGD on initial endoscopy, but there was no difference in length of Barrett s metaplasia between the two groups (Table 2). Persistent nondysplastic Barrett s metaplasia was significantly more common in the treatment failure arm despite the fact that these patients underwent significantly more endotherapy sessions overall. Similarly, patients in whom endotherapy failed were treated for a longer time, although this did not reach statistical significance. One stricture developed in each group; there was no other morbidity of endotherapy (Table 3). Table 1. Patient Characteristics Characteristic Successful (n 28) Failed (n 10) p Value Body mass index 29 26 0.04 Reflux duration (y) 17 30 0.09 Age (y) 66 72 0.12 Smoking history 46% 80% 0.14 % male 85% 80% 0.64 Hiatal hernia 93% 90% 1 Heartburn primary reflux symptom 43% 50% 0.70

1736 HUNT ET AL Ann Thorac Surg FAILED ENDOTHERAPY IN EARLY ESOPHAGEAL CANCER 2013;95:1734 40 Table 2. Endoscopic Findings Finding Successful (n 28) Failed (n 10) p Value Nodule or ulcer 39% 90% 0.009 Multifocal dysplasia 18% 70% 0.005 HGD present on initial 25% 60% 0.04 endoscopy Length of Barrett s metaplasia (cm) 6 7 0.51 HGD ¼ high-grade dysplasia. The treatment failure group was found to have HGD or IMC on initial endoscopy in 60% of cases. During endotherapy, all disease in the treatment failures had progressed to IMC, which was confirmed on final pathologic examination in all but 1 patient. This particular patient had IMC on biopsy results just before esophagectomy, but only LGD was present in the esophagectomy specimen. In contrast, disease in the treatmentsuccessgroupimprovedfromhgdandimc to neosquamous epithelium and nondysplastic Barrett s metaplasia (Table 4). Seven of the 10 patients in whom endotherapy failed underwent esophagectomy, 1 chose definitive chemoradiotherapy, 1 was medically unfit for surgery and underwent repeated RFA, and 1 had endoscopic resection of the recurrent IMC. Final pathologic examination in the patients who underwent esophagectomy was IMC in 6 patients and LGD in 1 patient; all cases were N0. Patients treated with esophagectomy were disease free a mean of 25 months postoperatively. There was one death (14%) caused by respiratory failure after esophagectomy. Two patients (29%) had morbidity after esophagectomy: 1 had an anastomotic leak and 1 had postoperative respiratory failure. Except for the perioperative death, the remaining 9 patients in whom treatment failed are alive a mean of 41 months after their initial diagnosis with dysplasia. The patients who underwent esophagectomy are all free of Barrett s metaplasia, and there has been no recurrent or metastatic esophageal cancer. Comparatively, 71% of the treatment success group had no evidence of Barrett s esophagus. Ten of these patients have undergone Table 3. Details of Characteristic Successful n 28 Failed n 10 p Value Eradication of nondysplastic 71% 20% 0.008 Barrett s metaplasia Total no. of endotherapy 1.7 (1 3) 2.8 (1 5) 0.006 sessions mean (range) No. of EMR sessions 0.8 (0 2) 1.2 (0 3) 0.17 No. of RFA sessions 1.0 (0 2) 1.6 (0 5) 0.04 Duration of endotherapy (mo) 10 16 0.13 Complications of endotherapy 4% 10% 0.46 EMR ¼ endoscopic mucosal resection; RFA ¼ radiofrequency ablation. laparoscopic antireflux operations, and 3 are currently undergoing preparation for laparoscopic repair. Comment The emergence of EMR and RFA in the treatment of Barrett s metaplasia with HGD or IMC has led to a paradigm shift in the management of early esophageal neoplasia. However, despite the reported success of these therapies, endotherapy will fail in a small percentage of patients because of persistence, progression from dysplasia to invasive cancer, or recurrence of dysplasia or cancer during follow-up. We identified several factors associated with failure of endotherapy: HGD on initial biopsy result, multifocal HGD, nodular or ulcerated Barrett s metaplasia, and failure to completely eradicate nondysplastic Barrett s metaplasia. The presence of multifocal HGD was also identified as a risk factor for recurrence of dysplasia in a previous study of recurrent HGD or IMC after endotherapy. Unlike our study, in which long segments of Barrett s metaplasia were seen in both groups, they had a significant proportion of shorter segments of Barrett s metaplasia in the group in which disease did not recur. RFA was not used in this study, and this may be why piecemeal resection and failure to eradicate nondysplastic Barrett s epithelium were also found to be independent risk factors associated with recurrence [9]. In a different study, long-segment Barrett s metaplasia and failure to eradicate nondysplastic Barrett s metaplasia were again identified as risk factors for recurrence of HGD/IMC after ablative therapy EMR [11]. This study also identified older age and smoking as risk factors for failure. We also associated these risk factors with failure, but they were not statistically significant in our study (Table 1). Both of these studies used photodynamic therapy as the ablative modality rather than RFA, so their recurrence rate may be higher because of using an ablation technique with a lower rate of complete response [21]. The presence of a nodule and multifocal HGD have both been shown to be associated with an increased rate of occult adenocarcinoma [22]. The preponderance of HGD on initial biopsy results, nodular or ulcerated Barrett s metaplasia, and multifocal HGD in the treatment failure group likely reflects patients with more advanced or aggressive disease. In contrast, in the treatment success group more patients presented with nondysplastic Barrett s metaplasia, then developed HGD while they were undergoing surveillance endoscopies. Failure to eradicate nondysplastic Barrett s metaplasia is a risk factor for endotherapy failure, which may be because the residual Barrett s metaplasia remains as a potential site for development of dysplasia, because there is epithelial damage from ongoing reflux, or because of another underlying problem that prevents these patients from forming neosquamous epithelium. Pursuing endotherapy despite the presence of nodular Barrett s metaplasia and multifocal HGD is an extension of the original treatment criteria for endotherapy. In the early landmark trials, the entry criteria were fairly strict.

Ann Thorac Surg HUNT ET AL 2013;95:1734 40 FAILED ENDOTHERAPY IN EARLY ESOPHAGEAL CANCER 1737 Table 4. Pathologic Condition at Different Stages of Barrett s Metaplasia Treatment Stage Neosquamous Nondysplastic LGD HGD IMC Initial endoscopy Successes (n 28) 0 71% (20) 7% (2) 18% (5) 4% (1) Failures (n 10) 0 40% (4) 0 50% (5) 10% (1) Worst pathology (during surveillance, during endotherapy, or at esophagectomy) Successes (n 28) 0 0 0 71% (20) 29% (8) Failures (n 10) 0 0 0 0 100% Final pathology Successes (n 28) 71% (20) 29% (8) 0 0 0 Failures (n 10) 0 0 10% (1) 0 90% (9) HGD ¼ high-grade dysplasia; IMC ¼ intramucosal cancer; LGD ¼ low-grade dysplasia. Ell and associates [7] screened 667 cases before undertaking 100 endoscopic resections to achieve a 5-year survival of 98%. Similarly, the AIM II [3] trial comparing RFA to sham control included only patients with nonnodular Barrett s metaplasia, dysplasia (low or high grade), and Barrett s metaplasia segments less than 8 cm long. Even though 90% of the treatment failures in the current series would have been excluded from the AIM II trial, 68% of the patients in our treatment success group would have also been excluded from AIM II but had successful eradication of HGD/IMC and preservation of their functioning esophagus. For this reason, we offer patients at high risk for endotherapy failure an attempt at endotherapy. We counsel the patient and set expectations about the success of endotherapy, because embarking on endotherapy often results in multiple endoscopies. Because there are no accepted guidelines on when to abort endotherapy, we usually recommend esophagectomy if there is persistent disease or biopsy results suggest progression after 3 endotherapy sessions or 12 months of treatment, based on the findings in Table 3. We achieved a similar rate of eradication of HGD and IMC (74%) in this series when compared with 81% in the AIM II trial for HGD alone. For patients who are treatment successes, we encourage them to consider laparoscopic antireflux surgery after a 12-month disease-free interval to better control their reflux. We also recommend ongoing endoscopic surveillance at set intervals similar to the recommendations of Titi and colleagues [23]. Our data and those of others [2, 23, 24] support ongoing surveillance, because we identified 3 patients who had biopsy-proven eradication of metaplasia (with disease-free intervals as short as 12 months and as long as 20 months) that was followed by recurrence of dysplasia or cancer. These recurrences were identified at the neosquamocolumnar junction and subsquamous level with eruption through the neosquamous lining. Several other cases of subsquamous HGD/IMC have been reported [2, 23, 24], and the presence of buried dysplastic cells after ablation is concerning. There are a variety of treatment options for patients with persistent, progressive, or recurrent disease, including esophagectomy, repeated endotherapy, and definitive chemoradiotherapy. In this study, the majority of patients underwent esophagectomy after staging with endoscopic ultrasonography and positron emission tomography/computed tomography. In patients with negative restaging and IMC at EMR, we offered transhiatal vagal-sparing esophagectomy to take advantage of the superior gastric pull-up function [25]. When there was concern for more advanced cancer, an en bloc esophagectomy was performed. We could be criticized for using a more functional esophagectomy over one with more oncologic principles; however, we felt that with careful restaging and cancer limited to the mucosa seen on endoscopic biopsy results, there was a low likelihood of nodal spread. We do not have enough data to comment on patients in whom endotherapy failed and who were treated with repeated endoscopic therapy or with definitive chemoradiotherapy. Unfortunately, almost no clinical follow-up data have been reported about patients undergoing esophagectomy after endotherapy. Of 44 patients who we identified in the literature, there was follow-up information on only 2: 1 died of metastatic esophageal cancer [5] and 1 was disease free at 19 months [12]. Our series demonstrates good clinical and pathologic outcomes from esophagectomy after failed endotherapy. However, the mortality and morbidity in this very small subset of patients undergoing esophagectomy from our center is higher than previously reported for primary resection of HGD and IMC without endotherapy [10, 15, 17, 19, 25 29]. This may result from patient selection for endotherapy: We pursued endotherapy more aggressively to avoid esophagectomy in patients with high-risk medical comorbidities. Alternatively, endotherapy may have altered the outcomes of esophagectomy; we did encounter more mediastinal fibrosis and obliterated planes in patients with longer segments of Barrett s metaplasia who underwent serial ablation, both for patients who underwent esophagectomy after failed endotherapy and in patients who underwent laparoscopic antireflux surgery after successful endotherapy. There are several limitations to this series. First, this is a retrospective study and the associations we identify

1738 HUNT ET AL Ann Thorac Surg FAILED ENDOTHERAPY IN EARLY ESOPHAGEAL CANCER 2013;95:1734 40 cannot be viewed as causative factors for treatment failure. Second, our failure rate (24%) is higher than that of other reported series of endotherapy. This may be because we do not have an accurate denominator because we are a tertiary referral center and did not capture all patients who underwent endotherapy in our referral population, or because our endoscopists have extended endotherapy to patients who would not have been eligible for inclusion in initial studies. Third, what we call progression of disease during endotherapy may be caused by sampling error because esophageal cancer can be found on final pathologic examination in 11% to 65% of esophagectomies performed for HGD [26 30]. In conclusion, even though endotherapy achieves excellent rates of eradication of HGD and IMC, a small number of patients will have persistent, progressive, or recurrent dysplasia or neoplasia. HGD on initial endoscopy, multifocal dysplasia, mucosal abnormalities (ulcers or nodules), and failure to eradicate nondysplastic Barrett s metaplasia were associated with failure of endotherapy in this series. If endotherapy is attempted in patients with these characteristics, they should be counseled in a multidisciplinary fashion about the potential for failure. Consideration should be given to esophagectomy if there is persistent, progressive, or recurrent neoplasia after more than 1 year of treatment or more than 3 sessions. Continued endoscopic surveillance is mandatory after successful endotherapy because of the risk of recurrent disease. The authors would like to acknowledge the support of the Ryan Hill Foundation and the Foundation for Surgical Fellowships. References 1. 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;143:336 46. 2. 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;62:488 98. 3. Shaheen NJ, Sharma P, Overholt BF, et al. Radiofrequency ablation in Barrett s esophagus with dysplasia. N Engl J Med 2009;360:2277 88. 4. Ell C, May A, Gossner L, et al. Endoscopic mucosal resection of early cancer and high grade dysplasia in Barrett s esophagus. Gastroenterology 2000;118:670 7. 5. Wolfsen HC, Hemminger LL, Wallace MB, Devault KR. Clinical experience of patients undergoing photodynamic therapy for Barrett s dysplasia or cancer. Aliment Pharmacol Ther 2004;20:1125 31. 6. Peters FP, Kara MA, Rosmolen WD, et al. Endoscopic treat ment of high grade dysplasia and early stage cancer in Barrett s esophagus. Gastrointest Endosc 2005;61:506 14. 7. Ell C, May A, Pech O, et al. Curative endoscopic resection of early esophageal adenocarcinomas (Barrett s cancer). Gas trointest Endosc 2007;65:3 10. 8. Ganz RA, Overholt BF, Sharma VK, et al. Circumferential ablation of Barrett s esophagus that contains high grade dysplasia: a U.S. Multicenter Registry. Gastrointest Endosc 2008;68:35 40. 9. 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;57:1200 6. 10. Prasad GA, Wu TT, Wigle DA, et al. Endoscopic and surgical treatment of mucosal (T1a) esophageal adenocar cinoma in Barrett s esophagus. Gastroenterology 2009;137: 815 23. 11. Badreddine RJ, Prasad GA, Wang KK, et al. Prevalence and predictors of recurrent neoplasia after ablation of Barrett s esophagus. Gastrointest Endosc 2010;71:697 703. 12. Lyday WD, Corbett FS, Kuperman DA, et al. Radiofrequency ablation of Barrett s esophagus: outcomes of 429 patients from a multicenter community practice registry. Endoscopy 2010;42:272 8. 13. Pouw RE, Wirths K, Eisendrath P, et al. Efficacy of radio frequency ablation combined with endoscopic resection for Barrett s esophagus with early neoplasia. Clin Gastroenterol Hepatol 2010;8:23 9. 14. Korst RJ, Santana Joseph S, Rutledge JR, et al. Effect of hiatal hernia size and columnar segment length on the success of radiofrequency ablation for Barrett s esophagus: a single center, phase II clinical trial. J Thorac Cardiovasc Surg 2011;142:1168 73. 15. Pech O, Bollschweiler E, Manner H, Leers J, Ell C, H olscher AH. Comparison between endoscopic and surgical resection of mucosal esophageal adenocarcinoma in Barrett s esophagus at two high volume centers. Ann Surg 2011;254: 67 72. 16. Shaheen NJ, Overholt BF, Sampliner RE, et al. Durability of radiofrequency ablation in Barrett s esophagus with dysplasia. Gastroenterology 2011;141:460 8. 17. Zehetner J, DeMeester SR, Hagen JA, et al. Endoscopic resection and ablation versus esophagectomy for high grade dysplasia and intramucosal adenocarcinoma. J Thorac Car diovasc Surg 2011;141:39 47. 18. Caillol F, Bories E, Pesenti C, et al. Radiofrequency ablation associated to mucosal resection in the oesophagus: experi ence in a single centre. Clin Res Hepatol Gastroenterol 2012;36:371 7. 19. Luna RA, Gilbert E, Hunter JG. High grade dysplasia and intramucosal adenocarcinoma in Barrett s esophagus: the role of esophagectomy in the era of endoscopic eradication therapy. Curr Opin Gastroenterol 2012;28:362 9. 20. Reid BJ, Levine DS, Longton G, Blount PL, Rabinovitch PS. Predictors of progression to cancer in Barrett s esophagus: baseline histology and flow cytometry identify low and high risk patient subsets. Am J Gastroenterol 2000;95: 1669 76. 21. Mccann P, Stafinski T, Wong C, Menon D. The safety and effectiveness of endoscopic and non endoscopic approaches to the management of early esophageal cancer: a systematic review. Cancer Treat Rev 2011;37:11 62. 22. Tharavej C, Hagen JA, Peters JH, et al. Predictive factors of coexisting cancer in Barrett s high grade dysplasia. Surg Endosc 2006;20:439 43. 23. Titi M, Overhiser A, Ulusarac O, et al. Development of subsquamous high grade dysplasia and adenocarcinoma after successful radiofrequency ablation of Barrett s esoph agus. Gastroenterology 2012;143:564 566.e1. 24. Hornick JL, Blount PL, Sanchez CA, et al. Biologic properties of columnar epithelium underneath reepithelialized squa mous mucosa in Barrett s esophagus. Am J Surg Pathol 2005;29:372 80. 25. Peyre CG, DeMeester SR, Rizzetto C, et al. Vagal sparing esophagectomy. Ann Surg 2007;246:665 71; discussion 671 4. 26. Zaninotto G, Parenti AR, Ruol A, Costantini M, Merigliano S, Ancona E. Oesophageal resection for high grade dysplasia in Barrett s oesophagus. Br J Surg 2000;87:1102 5. 27. Tseng EE, Wu TT, Yeo CJ, Heitmiller RF. Barrett s esophagus with high grade dysplasia: surgical results and long term

Ann Thorac Surg HUNT ET AL 2013;95:1734 40 FAILED ENDOTHERAPY IN EARLY ESOPHAGEAL CANCER 1739 outcome an update. J Gastrointest Surg 2003;7:164 70. discussion 170 1. 28. Sujendran V, Sica G, Warren B, Maynard N. Oesophagec tomy remains the gold standard for treatment of high grade dysplasia in Barrett s oesophagus. Eur J Cardiothorac Surg 2005;28:763 6. 29. Mirnezami R, Rohatgi A, Sutcliffe RP, Hamouda A, Mason RC. Transhiatal oesophagectomy: treatment of choice for high grade dysplasia. Eur J Cardiothorac Surg 2009;36:364 7. 30. Cameron AJ, Carpenter HA. Barrett s esophagus, high grade dysplasia, and early adenocarcinoma: a pathological study. Am J Gasteroenterol 1997;92:586 91. DISCUSSION DR DANIEL MILLER (Atlanta, GA): Ben, I enjoyed your presentation. I think the most important issue, and you brought it up toward the end, is a lot of our GI medicine colleagues are taking this to a different level. For patients with long segment Barrett s, usually greater than 6 or 9 cm, multiple nodularity, and complications of their Barrett s should undergo an esoph agectomy. Now that our GI colleagues are pushing the limits in regards to endoscopic treatment, I think it is very important, as you have done at your center, that everybody is on the same page from the beginning. Otherwise you will have to bail them out at the end related to endoscopic complications and worse outcomes for the patient. Also, these patients have to know that they are going to have an incredible number of endoscopies with multiple biopsies, even more than they would have had before with their normal high grade dysplasia. My question to you is, do you have any data on the amount of joules that was used in your patients? In the majority of cases we would go with 12 joules for the high grade and intramucosal carcinomas, while some of the GI colleagues have dropped back to 10 joules to decrease edema. Do you have any data on your patients? DR HUNT: All of our endotherapy sessions were 12 joules/cm 2, followed by removal of the coagulum, then 12 Joules/cm 2 again. DR MILLER: Were all of the margins negative in your EMR patients? DR HUNT: Yes, all of the margins on EMR were negative, including the deep margins. DR MILLER: So none of the patients who underwent an esophagectomy were post EMR positive margin patients? DR HUNT: Not in our series. DR MILLER: These were at a later date? DR HUNT: Yes. DR MILLER: All right. Nice job. DR WAYNE L. HOFSTETTER (Houston, TX): Very nice presentation. I have 3 questions and points. The first is that I consider EMR to be a disruptive technology, one that if we allow the gastroenterologists to take over will result in the loss of these cases from the thoracic surgeons. So I believe that this is an easy enough technology for us to learn, that we should be involved in performing the EMR, because this is going to displace resection for high grade dysplasia in T1as in most cases. Were you doing your own EMRs or were these done by others in your institution? DR HUNT: The EMRs were done by 2 gastroenterologists and 1 thoracic surgeon, so by a combination of specialists in our institution. DR HOFSTETTER: An easily learned technique and something I think is worthwhile for a surgeon to be involved in. DR HUNT: Definitely. DR HOFSTETTER: The second point is that piecemeal resection is a surrogate for length of tumor. So if you could include overall length in your analyses, you might get a better idea of who is going to recur. Rather than just looking at length of Barrett s I would advocate looking at the length of the lesion, including the length of the high grade dysplasia with nodularity where present. Finally, if you have not already done this, it would be helpful to include a total denominator of patients undergoing EMR, rather than just those that made it to surgery after failed EMR. A patient which you think deserves observation may be very different than someone else s recommendation. In other words, many people will undergo a diagnostic rather than a therapeutic EMR, and that cutoff between a diagnostic or therapeutic EMR, just as Dr Miller was suggesting, may be different when comparing different gastroenterologists or different surgeons. So who you decide to wait on and watch versus who you decide to do an esophagectomy is going to be different, and knowing where that cutoff point is up front is important to determining who may go on to fail later on. DR HUNT: I agree, and in terms of the length of the tumor, we do look at multifocal dysplasia, so dysplasia found at different levels, but usually there is some nondysplastic epithelium between the levels. I agree that there is a field effect. DR JOSHUA SONETT (New York, NY): Thank you for the paper. Well presented. Obviously EMR and the follow up that is required for this is important, and this is another paper that shows they can possibly fail. I have used it as a warning for us as a surgical group, we should decide to do it, because we re going to be okay at the Barrett s and we re going to be okay at diag nosing them as well, but the question is, will we as surgeons be able to see these patients every 3 to 6 months and do the Swedish protocol where we are doing it every centimeter and really bio psying them as well as the original trial? I can tell you, the original trial done by the group that looked at Barrett s, those results aren t going to be as good as the GI guys out there in the community. I m a little suspect that as we as a group of surgeons do it, I m not sure we re going to be as good at following up as the GI guys, because that s not our thing. If it becomes our thing, it s worth it, but we have to be set and solid and ready to do the follow up every 3 to 6 months of these multiple biopsies on most of these patients that aren t going to go to the OR and buy them that way if we re going to do the upfront therapy. DR HOFSTETTER: Good point. I definitely advocate that this is a program that should be grown in collaboration with your gastroenterologist. In my situation I contribute the resection and patient follow up in clinic with imaging (usually a CT) while our

1740 HUNT ET AL Ann Thorac Surg FAILED ENDOTHERAPY IN EARLY ESOPHAGEAL CANCER 2013;95:1734 40 gastroenterologist is dedicated to the ablation and endoscopic surveillance. I agree that it may not be time efficient or reasonable to assume responsibility for the whole program as you could quickly be faced with an entirely endoscopic practice. DR SONETT: Exactly. As I say, we have a collaboration with them, our GI guys do a lot of it, and pretty much any of these criteria that are anywhere near higher risk, we see them up front, and we counsel them and we say, you know, it s something that s reasonable to keep trying, but you have got to keep your eye on it, because we think you have a really high rate of failure. You may decide you want an esophagectomy now after the risks and benefits are presented because you re 40 where they may be 70 and don t want it. It s a different plan for each patient, but you have got to work together. I m just not convinced that we as a group can take over the whole shebang. DR HOFSTETTER: I agree. DR HUNT: Follow-up is very important in these patients as well. We saw recurrence at 1 to 2 years after establishment of neosquamous epithelium, so we do require a rigorous biopsy protocol even after treatment success. DR BILL PUTNAM (Nashville, TN): One comment and 1 question. The comment would be in reflecting on Paul Uhlig s discussion yesterday about social collaboration; a number of years ago we set up an esophageal conference at our hospital, led by the thoracic surgeons but inclusive of pathology, radiology, our GI medicine physicians, our general surgery colleagues and speech pathology. Twice a month we have an hour and a half discussion on patients who would undergo these types of procedures, so not only are thoracic surgeons presenting patients that may benefit from these types of therapies, but our GI physicians are presenting to us patients that they would recommend undergo these therapies, and there s typically some vigorous debate, adjudicated by the pathologists, of course. So having deep margins positive or lateral margins positive are significant. I think that these esophageal conferences, much like our multidisciplinary conferences for lung cancer, can provide a significant advantage to patients and their subsequent care, yielding for the individual patient a better outcome. My question is, were these patients discussed in a multidisciplinary conference, and if so, how was that conference set up? DR HUNT: There is not a formal conference for all of these patients. A lot of them are referred from community gastroenterologists to gastroenterologists at our cancer center, and that s why we have such a high-risk pool of patients, so many with long-segment Barrett s, so many treatment failures. However, we are very collaborative with the gastroenterologists; 2 of the gastroenterologists are authors on this paper, and we do have a lot of communication between the team members once the high-risk patients are identified, but the surgeons don t see many of the low-risk patients. DR PUTNAM: Having some setup time a couple of times a month for reflection on these patients might be very effective. DR DANIEL L. MILLER (Atlanta, GA): I agree. We do the same at Emory. My last question is, how many of these patients went on to a laparoscopic Nissen? When we have treated them with RFA, we have gotten them to neosquamous epithelial and then they go on to a laparoscopic Nissen. I do not know if that is going to help with your failed therapy in the future or not, but we started this early on, and the patients have liked the combined therapy. DR HUNT: One third of our successes have gone on to fundoplication and 3 more are in evaluation now for fundoplication. However, 2 of the failures had antireflux surgery prior to getting their recurrence. One patient was completely ablated down to neosquamous epithelium, got a fundoplication, and then a year later presented with cancer growing through the neosquamous epithelium. Another patient had a gastric sleeve and a hiatal hernia repair and then developed dysplastic Barrett s after that and was treated with a colon interposition. This reinforces the point that even after treatment success, these patients need ongoing surveillance.