A critical look at endoscopic eradication therapy for Barrett's esophagus: are we putting the cart before the horse?

Abstract

Esophageal adenocarcinoma (EAC) remains one of the few cancers with an increasing incidence in the Western population, and Barrett's esophagus (BE) is the only known premalignant condition for this cancer.1Pohl H. Welch H.G. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence.J Natl Cancer Inst. 2005; 97: 142-146Crossref PubMed Scopus (1078) Google Scholar It seems reasonable that elimination of BE would prevent the development of EAC and would thereby result in decreases in cancer incidence. This sounds like a simple goal. However, despite extensive research over the past 10 to 15 years (including the development of many novel endoscopic treatments for BE), it is currently unclear whether we can truly eliminate BE and whether eradication of BE will decrease the risk of EAC. The article by Allison et al2Allison H. Banchs M.A. Bonis P.A. et al.Long-term remission of nondysplastic Barrett's esophagus after multipolar electrocoagulation ablation: report of 139 patients with 10 years of follow-up.Gastrointest Endosc. 2011; 73: 651-658Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar attempts to address the first question: can we eliminate BE? The authors treated 166 patients with nondysplastic Barrett's esophagus (NDBE) by using multipolar electrocoagulation (MPEC) in an attempt to achieve complete eradication of Barrett's esophagus (CE-BE). Of these 166 patients, 139 patients completed a 10-year follow-up period in which no BE was found at 10 years, efficacy results very similar to contemporary techniques. The investigators are to be commended for being able to evaluate a reasonable number of patients and the duration of follow-up. However, this study also highlights the several challenges associated with evaluating the efficacy of endoscopic eradication therapy (EET) in patients with BE and the many questions that still need to be addressed. Our understanding of the natural history of BE (especially nondysplastic disease) continues to evolve as we are able to study larger cohorts of patients. Although the annual incidence of EAC in patients with NDBE was estimated to be as high as 1.9% in the 1980s and 0.5% to 0.8% in the 1990s and early 2000, more recent estimates from much larger cohorts continue to find lower and lower incidence rates: as low as 0.2% to 0.3% per year.3Sharma P. Falk G.W. Weston A.P. et al.Dysplasia and cancer in a large multicenter cohort of patients with Barrett's esophagus.Clin Gastroenterol Hepatol. 2006; 4: 566-572Abstract Full Text Full Text PDF PubMed Scopus (354) Google Scholar, 4Bani-Hani K. Sue-Ling H. Johnston D. et al.Barrett's oesophagus: results from a 13-year surveillance programme.Eur J Gastroenterol Hepatol. 2000; 12: 649-654Crossref PubMed Scopus (67) Google Scholar, 5Wani S. Falk G. Hall M. et al.Patients with nondysplastic Barrett's esophagus have low risks for developing dysplasia or esophageal adenocarcinoma.Clin Gastroenterol Hepatol. 2010 Nov 27; (Epub)Google Scholar, 6Hameeteman W. Tytgat G.N. Houthoff H.J. et al.Barrett's esophagus: development of dysplasia and adenocarcinoma.Gastroenterology. 1989; 96: 1249-1256Abstract Full Text PDF PubMed Scopus (870) Google Scholar This incidence may be much lower in those with short-segment disease; estimates as low as 0.1% per year. The vast majority of patients (82%) included in the current study by Allison et al2Allison H. Banchs M.A. Bonis P.A. et al.Long-term remission of nondysplastic Barrett's esophagus after multipolar electrocoagulation ablation: report of 139 patients with 10 years of follow-up.Gastrointest Endosc. 2011; 73: 651-658Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar had short lengths of NDBE, and EAC may never have developed in these patients (n = 114), regardless of EET. When the low rate of disease progression is considered, it is uncertain whether the risks of repetitive upper endoscopies and safety of currently available endoscopic therapies is worth the limited benefit from cancer risk reduction. Like many previous studies reporting on the efficacy of EET for BE, this study does not include a control group, making it difficult to generate any conclusions about the efficacy of EET in reducing the risk of EAC development. Is EET for NDBE reducing what is an already low risk for EAC? For those with high-grade dysplasia (HGD) and early EAC, what are the long-term follow-up data regarding reduction in invasive cancer incidence? As more and more patients undergo EET for BE, the issue of subsquamous BE needs to be evaluated and adequately addressed. When it occurs, subsquamous BE resides at the level of the lamina propria and has the potential for malignant transformation.7Biddlestone L.R. Barham C.P. Wilkinson S.P. et al.The histopathology of treated Barrett's esophagus: squamous reepithelialization after acid suppression and laser and photodynamic therapy.Am J Surg Pathol. 1998; 22: 239-245Crossref PubMed Scopus (151) Google Scholar, 8Kelty C.J. Ackroyd R. Brown N.J. et al.Endoscopic ablation of Barrett's oesophagus: a randomized-controlled trial of photodynamic therapy vs. argon plasma coagulation.Aliment Pharmacol Ther. 2004; 20: 1289-1296Crossref PubMed Scopus (108) Google Scholar, 9Chennat J. Konda V.J. Ross A.S. et al.Complete Barrett's eradication endoscopic mucosal resection: an effective treatment modality for high-grade dysplasia and intramucosal carcinoma--an American single-center experience.Am J Gastroenterol. 2009; 104: 2684-2692Crossref PubMed Scopus (211) Google Scholar This can lead to dysplasia and/or EAC in patients who may have appeared to be successfully treated with EET (endoscopically normal esophagus). As a result, patients who have undergone EET, either for NDBE or dysplastic BE, frequently undergo continued endoscopic surveillance with biopsies of the neosquamous epithelium to evaluate for the presence/absence of subsquamous BE. However, the ability to detect subsquamous BE is dependent on the depth of endoscopic biopsies with an adequate biopsy being one that obtains significant lamina propria. Recent studies have questioned whether current biopsy procurement methods can obtain adequate tissue specimens (ie, with full-thickness squamous mucosa and lamina propria) to evaluate for subsquamous BE with published estimates for the proportion of biopsy specimens that are adequate to evaluate for this endpoint (contain lamina propria) varying from 37% to 86%.10Gupta N. Mathur S. Singh V. et al.Adequacy of esophageal squamous mucosa specimens obtained during endoscopy: are standard biopsies sufficient for post-ablation surveillance in Barrett's esophagus (BE)?.Gastroenterology. 2010; 138: S-17Abstract Full Text PDF Google Scholar, 11Pouw R.E. Gondrie J.J. Rygiel A.M. et al.Properties of the neosquamous epithelium after radiofrequency ablation of Barrett's esophagus containing neoplasia.Am J Gastroenterol. 2009; 104: 1366-1373Crossref PubMed Scopus (103) Google Scholar, 12Shaheen N.J. Peery A.F. Overholt B.F. et al.Biopsy depth after radiofrequency ablation of dysplastic Barrett's esophagus.Gastrointest Endosc. 2010; 72 (e1): 490-496Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar, 13Fleischer D.E. Overholt B.F. Sharma V.K. et al.Endoscopic radiofrequency ablation for Barrett's esophagus: 5-year outcomes from a prospective multicenter trial.Endoscopy. 2010; 42: 781-789Crossref PubMed Scopus (189) Google Scholar, 14Overholt B.F. Dean P.J. Galanko J.A. et al.Does ablative therapy for barrett esophagus affect the depth of subsequent esophageal biopsy as compared with controls?.J Clin Gastroenterol. 2010; 44: 676-681Crossref PubMed Scopus (14) Google Scholar If surveillance biopsies are not adequate to ensure the absence of subsquamous BE, how can we be sure that we have truly eliminated the patient's BE? Are our efficacy estimates of CE-BE overestimated because we are not really able to evaluate for subsquamous BE? Assuming that endoscopic therapy can completely eliminate BE, the next question is whether the effect is durable, and if not, how much maintenance therapy is needed? In this article by Allison et al,2Allison H. Banchs M.A. Bonis P.A. et al.Long-term remission of nondysplastic Barrett's esophagus after multipolar electrocoagulation ablation: report of 139 patients with 10 years of follow-up.Gastrointest Endosc. 2011; 73: 651-658Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar 5% of patients who initially achieved CE-BE developed recurrent disease and required repeat endoscopic therapy. However, other cohorts have reported recurrence rates as high as 68%.15Wani S. Gupta N. Domit B. et al.Durability of ablative therapies in Barrett's esophagus (BE): long term results of a randomized controlled trial (RCT) of ablation with argon plasma coagulation (APC) and multipolar electrocoagulation (MPEC).Gastroenterology. 2010; 138: S333-S334Google Scholar Even in patients treated with other modalities such as EMR and radiofrequency ablation, recurrence rates of 8% to 17% have been reported.16Gupta N. Abrams J. Early D. et al.Multi-modality endoscopic therapy for complete eradication of Barrett's esophagus.Gastroenterology. 2010; 139: e18Abstract Full Text Full Text PDF PubMed Google Scholar, 17Pouw R.E. Wirths K. Eisendrath P. et al.Efficacy of radiofrequency ablation combined with endoscopic resection for Barrett's esophagus with early neoplasia.Clin Gastroenterol Hepatol. 2010; 8: 23-29Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar It is clear that additional studies with longer follow-up are needed to answer this question. Future studies should begin to standardize the reporting of follow-up duration because this depends on what point is considered time zero. Unfortunately, this has varied among studies, with Allison et al2Allison H. Banchs M.A. Bonis P.A. et al.Long-term remission of nondysplastic Barrett's esophagus after multipolar electrocoagulation ablation: report of 139 patients with 10 years of follow-up.Gastrointest Endosc. 2011; 73: 651-658Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar using the point at which CE-BE is first achieved as time zero in all patients, whereas others have used the point at which EET begins as time zero.13Fleischer D.E. Overholt B.F. Sharma V.K. et al.Endoscopic radiofrequency ablation for Barrett's esophagus: 5-year outcomes from a prospective multicenter trial.Endoscopy. 2010; 42: 781-789Crossref PubMed Scopus (189) Google Scholar Although the cost-effectiveness of EET for patients with HGD and early EAC has been consistently shown in the literature, the same is not true of LGD and NDBE.18Boger P.C. Turner D. Roderick P. et al.A UK-based cost-utility analysis of radiofrequency ablation or oesophagectomy for the management of high-grade dysplasia in Barrett's oesophagus.Aliment Pharmacol Ther. 2010; 32: 1332-1342Crossref PubMed Scopus (26) Google Scholar, 19Pohl H. Sonnenberg A. Strobel S. et al.Endoscopic versus surgical therapy for early cancer in Barrett's esophagus: a decision analysis.Gastrointest Endosc. 2009; 70: 623-631Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 20Hur C. Nishioka N.S. Gazelle G.S. Cost-effectiveness of photodynamic therapy for treatment of Barrett's esophagus with high grade dysplasia.Dig Dis Sci. 2003; 48: 1273-1283Crossref PubMed Scopus (70) Google Scholar, 21Shaheen N.J. Inadomi J.M. Overholt B.F. et al.What is the best management strategy for high grade dysplasia in Barrett's oesophagus? A cost effectiveness analysis.Gut. 2004; 53: 1736-1744Crossref PubMed Scopus (74) Google Scholar A recent cost-utility model by Inadomi et al22Inadomi J.M. Somsouk M. Madanick R.D. et al.A cost-utility analysis of ablative therapy for Barrett's esophagus.Gastroenterology. 2009; 136 (e1-6): 2101-2114Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar is often used to justify the cost-effectiveness of EET for BE compared with endoscopic surveillance. However, assumptions made in this model are frequently overlooked when discussing this issue, especially for NDBE and LGD. For EET to be cost-effective for patients with NDBE and LGD, the endoscopic treatment must be successful in more than 40% and 28% of patients, respectively, and endoscopic surveillance must be discontinued after achieving CE-BE. If surveillance is continued even after successful ablation of metaplasia, then EET will never be cost-effective and does not make sense for any health care system unless we can prove that it reduces cancer risk. Given the current challenges of EET for BE including the risk of subsquamous BE, the inadequacy of surveillance biopsies of neosquamous mucosa, the rate of recurrent BE, and the need for maintenance therapy, endoscopists struggle with the idea of discontinuing surveillance in these patients. To move the field of EET for BE forward, future studies need to address several key questions. First, how do we ensure that a patient's BE has been completely eradicated? Randomly obtained esophageal biopsy specimens may not be adequate to exclude the presence of residual BE (especially subsquamous BE). We will need improvements in tissue procurement techniques, the development and application of novel imaging modalities (such as broad-field confocal laser endomicroscopy, and optical coherence tomography), and improved biomarkers that can ensure the absence of residual premalignant tissue. Pending development of new surveillance methods, all studies reporting the efficacy of EET for BE should report on the exact surveillance protocol including the methods for tissue procurement, the proportion of surveillance biopsy specimens that contain lamina propria, and the exact definition for lamina propria used. Second, how durable is the neosquamous mucosa that forms after EET? Studies reporting the long-term follow-up results of patients who received EET for BE should use a standardized definition for the duration of follow-up. If we compare EET for BE with the treatment of cancer, the follow-up period should begin once a patient has achieved CE-BE because this represents the end of induction therapy. The end of follow-up should be marked as the time of the patient's last endoscopy with surveillance biopsies. This method allows an accurate report on the initial effectiveness of EET (induction therapy) and how much therapy is needed to keep patients in a health state that is free of any BE (maintenance of remission). Third, are the benefits of EET for BE worth the risks and costs? Radiofrequency ablation for HGD has been found to reduce the annual rate of EAC development from 19% to 2%, thus requiring 6 patients with HGD to be treated to prevent 1 cancer.23Shaheen N.J. Sharma P. Overholt B.F. et al.Radiofrequency ablation in Barrett's esophagus with dysplasia.N Engl J Med. 2009; 360: 2277-2288Crossref PubMed Scopus (1092) Google Scholar However, patients with NDBE have a much lower risk of the development of EAC, as low as 0.2% to 0.3% per year.3Sharma P. Falk G.W. Weston A.P. et al.Dysplasia and cancer in a large multicenter cohort of patients with Barrett's esophagus.Clin Gastroenterol Hepatol. 2006; 4: 566-572Abstract Full Text Full Text PDF PubMed Scopus (354) Google Scholar, 5Wani S. Falk G. Hall M. et al.Patients with nondysplastic Barrett's esophagus have low risks for developing dysplasia or esophageal adenocarcinoma.Clin Gastroenterol Hepatol. 2010 Nov 27; (Epub)Google Scholar Even if a relative reduction in EAC risk approaches 90% for these patients, more than 550 patients with NDBE would need to be treated to prevent 1 cancer.24Wani S. Puli S.R. Shaheen N.J. et al.Esophageal adenocarcinoma in Barrett's esophagus after endoscopic ablative therapy: a meta-analysis and systematic review.Am J Gastroenterol. 2009; 104: 502-513Crossref PubMed Scopus (165) Google Scholar Finally, as more endoscopic therapies become available, randomized, controlled trials will need to address which therapy (or combination of therapies) has the best effectiveness and safety profile in patients with HGD and early EAC. Should we resect or burn? Burn or freeze? Or maybe we should do a combination of the 3? In this study, Allison et al2Allison H. Banchs M.A. Bonis P.A. et al.Long-term remission of nondysplastic Barrett's esophagus after multipolar electrocoagulation ablation: report of 139 patients with 10 years of follow-up.Gastrointest Endosc. 2011; 73: 651-658Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar were able to achieve good results with MPEC, an ablative technology that is inexpensive, commonly available, easy to use, and has multiple clinical applications. In addition to effectiveness and safety, an ideal ablative technique should have all these characteristics. This is especially important considering the current economic climate of our health care system, in which equal importance is given to effectiveness and cost. As EET technology expands, new devices should strive to meet the many demands (effective, safe, low cost, multiple clinical applications, easy to use) of patients, physicians, and our financially challenged health care system. Endoscopists and clinical scientists should continue with their efforts to identify the “high-risk” group of BE patients who may benefit from active intervention in this era of cost containment so that the limited resources may be applied to the group that needs it the most. As it stands today, these are exciting times in the era of EET for BE. Although we continue to develop new ways to endoscopically treat BE, there are limited high-quality data to answer the many clinically important questions. We must be able to answer the difficult questions and understand the biology of the disease. Until then, little is lost by waiting. The following authors disclosed financial relationships relevant to this publication: Dr. Sharma: grants from Barrx Medical, Olympus, Cook Medical, and Takeda; Dr. Waxman: consultant for Cook Medical, Mauna Kea, and Olympus. The other author disclosed no financial relationships relevant to this publication. Long-term remission of nondysplastic Barrett's esophagus after multipolar electrocoagulation ablation: report of 139 patients with 10 years of follow-upGastrointestinal EndoscopyVol. 73Issue 4PreviewAblation of Barrett's esophagus (BE) has been advocated as a method to eliminate the risk of malignant transformation of BE. Full-Text PDF