Opinion
Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.
EDITORIAL
Radiofrequency Ablation for Barrett Esophagus With Confirmed Low-Grade Dysplasia Klaus Mönkemüller, MD, PhD
The incidence of Barrett adenocarcinoma is increasing substantially and was estimated at 2.8 cases per 100 000 people in the United States in 2010.1 Given the premalignant potential of Barrett intestinal metaplasia, it would be logical to Related article page 1209 simply eliminate preneoplastic tissue. Indeed, if Barrett esophagus was a focally localized, raised, and easily recognizable lesion (ie, polyp), endoscopic removal would be a relatively easy task, and there would be no discussion about how to prevent neoplastic progression in these patients. However, various characteristics of Barrett esophagus prevent such a straightforward proactive approach. First, Barrett esophagus is generally a circumferential lesion of the distal esophagus. This lesion may contain foci of dysplasia, which can be either localized or dispersed, significantly complicating targeted endoscopic interventions. Second, the majority of patients with Barrett esophagus never progress to dysplasia or cancer; it is estimated that only 1% of those with Barrett esophagus will develop esophageal adenocarcinoma.2 Third, a majority of patients with Barrett esophagus and low-grade dysplasia have regression of their lesions over time, which is why endoscopic surveillance, rather than ablation, has been favored.3,4 Fourth, the diagnosis of dysplasia is difficult to establish, and low to moderate interobserver variability in pathological diagnosis has been reported among pathologists from different countries, centers, and even the same group.5,6 Nonetheless, convincing data have demonstrated that expert pathologist–confirmed low-grade dysplasia behaves more aggressively and progresses to high-grade dysplasia and cancer.7,8 In these studies, patients with a previous diagnosis of dysplasia were reclassified as normal by expert pathologists and only those patients with confirmed lowgrade dysplasia have been shown to be at high risk of progressing to high-grade dysplasia and cancer.7,8 This finding has spurred the development of proactive management of Barrett esophagus. Therefore, patients with confirmed lowgrade dysplasia could be an ideal target for endoscopic resection and ablative therapies, such as radiofrequency ablation. Radiofrequency ablation involves the direct application of radiofrequency energy to the esophageal mucosa using special balloons or catheters.9,10 Although several studies have documented the efficacy of radiofrequency ablation for the treatment of high-grade dysplasia and early cancer,9-11 it is still unclear whether ablating Barrett esophagus with lowgrade dysplasia is justified.
In this issue of JAMA, the report by Phoa and colleagues12 provides a strong argument to shift the current approach for earlier intervention in patients with Barrett esophagus and low-grade dysplasia. In this multicenter trial, 136 patients with confirmed low-grade dysplasia were randomly assigned in a 1:1 ratio to undergo either radiofrequency ablation or surveillance (control group). Ablation reduced the risk of progression to high-grade dysplasia or adenocarcinoma from 26.5% to 1.5%, an absolute risk reduction of 25.0%, corresponding to a number needed to treat of 4.0. Furthermore, ablation reduced the risk of progression to adenocarcinoma, from 8.8% to 1.5%, an absolute risk reduction of 7.4%. For patients in the ablation group, 92.6% of dysplasia and 88.2% of intestinal metaplasia was completely eradicated compared with 27.9% of dysplasia and 0% of intestinal metaplasia among patients in the control group. Treatment-related adverse events occurred in 19.1% of patients in the ablation group; however, these were mild. The most common adverse event was esophageal stricture (11.8%), which resolved with a median of 1 endoscopic dilation. Because of the superiority of ablation compared with surveillance, the data and safety monitoring board recommended early termination of the trial. The rigorous conduct of the trial, the centralized expert pathology review, the low rate of loss to follow-up, the high-caliber quality control, the expert center participation, the hands-on training of investigators, and the inclusion of more than the minimum planned enrollment (136 instead of 126 patients) make this an important study in the field. This study by Phoa et al has important implications for the treatment of low-grade dysplasia in patients with Barrett esophagus, supporting a proactive rather than watchful waiting approach. Several important points should be emphasized before proceeding with ablation procedures for all patients with Barrett esophagus and low-grade dysplasia. First, only patients with expert pathologist–confirmed low-grade dysplasia were enrolled in this trial. Of patients initially diagnosed with low-grade dysplasia, only 15% will have the diagnosis confirmed by an expert center7,8; thus 85% of patients diagnosed with low-grade dysplasia would not be eligible for this procedure. However, among wellselected patients in whom the diagnosis of low-grade dysplasia is confirmed by expert pathologist review, the high risk of progression to either high-grade dysplasia or cancer would make ablation therapy worthwhile. In addition, despite expert confirmation of low-grade dysplasia, a large percentage of patients (28%) in the study by Phoa et al had
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Opinion Editorial
regression of their lesion over time. In this trial, histological confirmation of a 1-time low-grade dysplasia by an expert pathologist was the most important selection criteria. Thus, it is possible that selecting only patients with low-grade dysplasia on multiple endoscopies may further refine the process of selecting patients at risk of progression. Second, better ways to stratify risk among patients with Barrett esophagus are needed to ensure that ablative therapies are offered to those likely to have disease progression. In the multivariable analysis reported in the article by Phoa et al, circumferential Barrett esophagus, time since diagnosis of Barrett esophagus, and time since diagnosis of dysplasia were predictors of progression. However, finding biological, molecular, and histological markers to identify candidates for ablation and resection remains an important clinical and research priority.13-15 Third, radiofrequency ablation did not fully eliminate risk of disease persistence or progression, with one-fourth of patients in the study by Phoa et al requiring additional endoscopic interventions to complete the tissue elimination. This additional “finish-up” approach during surveillance does not decrease the value of radiofrequency ablation, but rather reflects the unique and complex anatomical and biological behavior of Barrett esophagus. Both patients and endoscopists must have full engagement when embarking on a proactive approach to managing low-grade dysplasia. Endoscopists must ARTICLE INFORMATION Author Affiliation: Basil I. Hirschowitz Endoscopic Center of Excellence, Division of Gastroenterology and Hepatology, University of Alabama at Birmingham. Corresponding Author: Klaus Mönkemüller, MD, PhD, Basil I. Hirschowitz Endoscopic Center of Excellence, Division of Gastroenterology, BDB 396, Boshell Diabetes Bldg, University of Alabama, Birmingham, AL 35294 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Mönkemüller reports receiving grant funding from Covidien (formerly BÂRRX Medical), an educational grant to his institution to conduct a 1-day course dedicated to teach endoscopic resection and ablation techniques for Barrett esophagus. REFERENCES 1. Hur C, Miller M, Kong CY, et al. Trends in esophageal adenocarcinoma incidence and mortality. Cancer. 2013;119(6):1149-1158. 2. Bhat S, Coleman HG, Yousef F, et al. Risk of malignant progression in Barrett’s esophagus patients: results from a large population-based study. J Natl Cancer Inst. 2011;103(13):1049-1057. 3. Sharma P, Falk GW, Weston AP, Reker D, Johnston M, Sampliner RE. Dysplasia and cancer in
1206
be well trained and committed to applying advanced endoscopic imaging and therapeutic methods to remove or ablate any suspicious focus of neoplasia. Increased interventions may lead to a decreased quality of life due to adverse events of ablation and resection; however, there are intrinsic psychological implications for patients who are living with a disease process known to have a high rate of progression. Fourth, the trial by Phoa et al was not powered for the important clinical outcome of advanced cancer or cancerrelated death, but evaluating this end point would be ethically questionable. Indeed, esophageal adenocarcinoma is an aggressive cancer and is associated with esophageal obstruction, early metastasis, and an overall 5-year survival rate of only 20%.1 Fifth, exclusive participation of expert centers in this trial may render the results less reproducible in general practice; however, settings that have well-trained staff and equipment may also perform these endoscopic resection and ablation techniques. The clinical trial by Phoa et al provides important evidence to support the use of radiofrequency ablation not only for patients with high-grade dysplasia and early cancer, but also for carefully selected patients with Barrett esophagus and confirmed low-grade dysplasia. A proactive endoscopic approach to eliminate dysplasia may result in reduced morbidity and mortality related to the progression of this disease.
a large multicenter cohort of patients with Barrett’s esophagus. Clin Gastroenterol Hepatol. 2006;4(5):566-572. 4. Spechler SJ, Sharma P, Souza RF, Inadomi JM, Shaheen NJ; American Gastroenterological Association. American Gastroenterological Association technical review on the management of Barrett’s esophagus. Gastroenterology. 2011;140(3):e18-e52. 5. Coco DP, Goldblum JR, Hornick JL, et al. Interobserver variability in the diagnosis of crypt dysplasia in Barrett esophagus. Am J Surg Pathol. 2011;35(1):45-54. 6. Downs-Kelly E, Mendelin JE, Bennett AE, et al. Poor interobserver agreement in the distinction of high-grade dysplasia and adenocarcinoma in pretreatment Barrett’s esophagus biopsies. Am J Gastroenterol. 2008;103(9):2333-2340. 7. Sikkema M, Looman CW, Steyerberg EW, et al. Predictors for neoplastic progression in patients with Barrett’s Esophagus: a prospective cohort study. Am J Gastroenterol. 2011;106(7):1231-1238. 8. Curvers WL, ten Kate FJ, Krishnadath KK, et al. Low-grade dysplasia in Barrett’s esophagus: overdiagnosed and underestimated. Am J Gastroenterol. 2010;105(7):1523-1530. 9. Fleischer DE, Overholt BF, Sharma VK, et al. Endoscopic radiofrequency ablation for Barrett’s esophagus: 5-year outcomes from a prospective multicenter trial. Endoscopy. 2010;42(10):781-789.
10. Shaheen NJ, Sharma P, Overholt BF, et al. Radiofrequency ablation in Barrett’s esophagus with dysplasia. N Engl J Med. 2009;360(22):22772288. 11. Phoa KN, Pouw RE, van Vilsteren FG, et al. Remission of Barrett’s esophagus with early neoplasia 5 years after radiofrequency ablation with endoscopic resection: a Netherlands cohort study. Gastroenterology. 2013;145(1):96-104. 12. Phoa KN, van Vilsteren FGI, Weusten BLAM, et al. Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized trial. JAMA. doi:10.1001/jama.2014.2511. 13. Mokrowiecka A, Wierzchniewska-Lawska A, Smolarz B, et al. Amplification of Her-2/neu oncogene in GERD—Barrett’s metaplasia— dysplasia—adenocarcinoma sequence. Hepatogastroenterology. 2013;60(125):1063-1066. 14. Bird-Lieberman EL, Dunn JM, Coleman HG, et al. Population-based study reveals new risk-stratification biomarker panel for Barrett’s esophagus. Gastroenterology. 2012;143(4):927-935, e3. 15. Prasad GA, Wang KK, Halling KC, et al. Utility of biomarkers in prediction of response to ablative therapy in Barrett’s esophagus. Gastroenterology. 2008;135(2):370-379.
JAMA March 26, 2014 Volume 311, Number 12
Copyright 2014 American Medical Association. All rights reserved.
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Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.
EDITORIAL
Radiofrequency Ablation for Barrett Esophagus With Confirmed Low-Grade Dysplasia Klaus Mönkemüller, MD, PhD
The incidence of Barrett adenocarcinoma is increasing substantially and was estimated at 2.8 cases per 100 000 people in the United States in 2010.1 Given the premalignant potential of Barrett intestinal metaplasia, it would be logical to Related article page 1209 simply eliminate preneoplastic tissue. Indeed, if Barrett esophagus was a focally localized, raised, and easily recognizable lesion (ie, polyp), endoscopic removal would be a relatively easy task, and there would be no discussion about how to prevent neoplastic progression in these patients. However, various characteristics of Barrett esophagus prevent such a straightforward proactive approach. First, Barrett esophagus is generally a circumferential lesion of the distal esophagus. This lesion may contain foci of dysplasia, which can be either localized or dispersed, significantly complicating targeted endoscopic interventions. Second, the majority of patients with Barrett esophagus never progress to dysplasia or cancer; it is estimated that only 1% of those with Barrett esophagus will develop esophageal adenocarcinoma.2 Third, a majority of patients with Barrett esophagus and low-grade dysplasia have regression of their lesions over time, which is why endoscopic surveillance, rather than ablation, has been favored.3,4 Fourth, the diagnosis of dysplasia is difficult to establish, and low to moderate interobserver variability in pathological diagnosis has been reported among pathologists from different countries, centers, and even the same group.5,6 Nonetheless, convincing data have demonstrated that expert pathologist–confirmed low-grade dysplasia behaves more aggressively and progresses to high-grade dysplasia and cancer.7,8 In these studies, patients with a previous diagnosis of dysplasia were reclassified as normal by expert pathologists and only those patients with confirmed lowgrade dysplasia have been shown to be at high risk of progressing to high-grade dysplasia and cancer.7,8 This finding has spurred the development of proactive management of Barrett esophagus. Therefore, patients with confirmed lowgrade dysplasia could be an ideal target for endoscopic resection and ablative therapies, such as radiofrequency ablation. Radiofrequency ablation involves the direct application of radiofrequency energy to the esophageal mucosa using special balloons or catheters.9,10 Although several studies have documented the efficacy of radiofrequency ablation for the treatment of high-grade dysplasia and early cancer,9-11 it is still unclear whether ablating Barrett esophagus with lowgrade dysplasia is justified.
In this issue of JAMA, the report by Phoa and colleagues12 provides a strong argument to shift the current approach for earlier intervention in patients with Barrett esophagus and low-grade dysplasia. In this multicenter trial, 136 patients with confirmed low-grade dysplasia were randomly assigned in a 1:1 ratio to undergo either radiofrequency ablation or surveillance (control group). Ablation reduced the risk of progression to high-grade dysplasia or adenocarcinoma from 26.5% to 1.5%, an absolute risk reduction of 25.0%, corresponding to a number needed to treat of 4.0. Furthermore, ablation reduced the risk of progression to adenocarcinoma, from 8.8% to 1.5%, an absolute risk reduction of 7.4%. For patients in the ablation group, 92.6% of dysplasia and 88.2% of intestinal metaplasia was completely eradicated compared with 27.9% of dysplasia and 0% of intestinal metaplasia among patients in the control group. Treatment-related adverse events occurred in 19.1% of patients in the ablation group; however, these were mild. The most common adverse event was esophageal stricture (11.8%), which resolved with a median of 1 endoscopic dilation. Because of the superiority of ablation compared with surveillance, the data and safety monitoring board recommended early termination of the trial. The rigorous conduct of the trial, the centralized expert pathology review, the low rate of loss to follow-up, the high-caliber quality control, the expert center participation, the hands-on training of investigators, and the inclusion of more than the minimum planned enrollment (136 instead of 126 patients) make this an important study in the field. This study by Phoa et al has important implications for the treatment of low-grade dysplasia in patients with Barrett esophagus, supporting a proactive rather than watchful waiting approach. Several important points should be emphasized before proceeding with ablation procedures for all patients with Barrett esophagus and low-grade dysplasia. First, only patients with expert pathologist–confirmed low-grade dysplasia were enrolled in this trial. Of patients initially diagnosed with low-grade dysplasia, only 15% will have the diagnosis confirmed by an expert center7,8; thus 85% of patients diagnosed with low-grade dysplasia would not be eligible for this procedure. However, among wellselected patients in whom the diagnosis of low-grade dysplasia is confirmed by expert pathologist review, the high risk of progression to either high-grade dysplasia or cancer would make ablation therapy worthwhile. In addition, despite expert confirmation of low-grade dysplasia, a large percentage of patients (28%) in the study by Phoa et al had
jama.com
JAMA March 26, 2014 Volume 311, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of St. Andrews Library User on 05/13/2015
1205
Opinion Editorial
regression of their lesion over time. In this trial, histological confirmation of a 1-time low-grade dysplasia by an expert pathologist was the most important selection criteria. Thus, it is possible that selecting only patients with low-grade dysplasia on multiple endoscopies may further refine the process of selecting patients at risk of progression. Second, better ways to stratify risk among patients with Barrett esophagus are needed to ensure that ablative therapies are offered to those likely to have disease progression. In the multivariable analysis reported in the article by Phoa et al, circumferential Barrett esophagus, time since diagnosis of Barrett esophagus, and time since diagnosis of dysplasia were predictors of progression. However, finding biological, molecular, and histological markers to identify candidates for ablation and resection remains an important clinical and research priority.13-15 Third, radiofrequency ablation did not fully eliminate risk of disease persistence or progression, with one-fourth of patients in the study by Phoa et al requiring additional endoscopic interventions to complete the tissue elimination. This additional “finish-up” approach during surveillance does not decrease the value of radiofrequency ablation, but rather reflects the unique and complex anatomical and biological behavior of Barrett esophagus. Both patients and endoscopists must have full engagement when embarking on a proactive approach to managing low-grade dysplasia. Endoscopists must ARTICLE INFORMATION Author Affiliation: Basil I. Hirschowitz Endoscopic Center of Excellence, Division of Gastroenterology and Hepatology, University of Alabama at Birmingham. Corresponding Author: Klaus Mönkemüller, MD, PhD, Basil I. Hirschowitz Endoscopic Center of Excellence, Division of Gastroenterology, BDB 396, Boshell Diabetes Bldg, University of Alabama, Birmingham, AL 35294 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Mönkemüller reports receiving grant funding from Covidien (formerly BÂRRX Medical), an educational grant to his institution to conduct a 1-day course dedicated to teach endoscopic resection and ablation techniques for Barrett esophagus. REFERENCES 1. Hur C, Miller M, Kong CY, et al. Trends in esophageal adenocarcinoma incidence and mortality. Cancer. 2013;119(6):1149-1158. 2. Bhat S, Coleman HG, Yousef F, et al. Risk of malignant progression in Barrett’s esophagus patients: results from a large population-based study. J Natl Cancer Inst. 2011;103(13):1049-1057. 3. Sharma P, Falk GW, Weston AP, Reker D, Johnston M, Sampliner RE. Dysplasia and cancer in
1206
be well trained and committed to applying advanced endoscopic imaging and therapeutic methods to remove or ablate any suspicious focus of neoplasia. Increased interventions may lead to a decreased quality of life due to adverse events of ablation and resection; however, there are intrinsic psychological implications for patients who are living with a disease process known to have a high rate of progression. Fourth, the trial by Phoa et al was not powered for the important clinical outcome of advanced cancer or cancerrelated death, but evaluating this end point would be ethically questionable. Indeed, esophageal adenocarcinoma is an aggressive cancer and is associated with esophageal obstruction, early metastasis, and an overall 5-year survival rate of only 20%.1 Fifth, exclusive participation of expert centers in this trial may render the results less reproducible in general practice; however, settings that have well-trained staff and equipment may also perform these endoscopic resection and ablation techniques. The clinical trial by Phoa et al provides important evidence to support the use of radiofrequency ablation not only for patients with high-grade dysplasia and early cancer, but also for carefully selected patients with Barrett esophagus and confirmed low-grade dysplasia. A proactive endoscopic approach to eliminate dysplasia may result in reduced morbidity and mortality related to the progression of this disease.
a large multicenter cohort of patients with Barrett’s esophagus. Clin Gastroenterol Hepatol. 2006;4(5):566-572. 4. Spechler SJ, Sharma P, Souza RF, Inadomi JM, Shaheen NJ; American Gastroenterological Association. American Gastroenterological Association technical review on the management of Barrett’s esophagus. Gastroenterology. 2011;140(3):e18-e52. 5. Coco DP, Goldblum JR, Hornick JL, et al. Interobserver variability in the diagnosis of crypt dysplasia in Barrett esophagus. Am J Surg Pathol. 2011;35(1):45-54. 6. Downs-Kelly E, Mendelin JE, Bennett AE, et al. Poor interobserver agreement in the distinction of high-grade dysplasia and adenocarcinoma in pretreatment Barrett’s esophagus biopsies. Am J Gastroenterol. 2008;103(9):2333-2340. 7. Sikkema M, Looman CW, Steyerberg EW, et al. Predictors for neoplastic progression in patients with Barrett’s Esophagus: a prospective cohort study. Am J Gastroenterol. 2011;106(7):1231-1238. 8. Curvers WL, ten Kate FJ, Krishnadath KK, et al. Low-grade dysplasia in Barrett’s esophagus: overdiagnosed and underestimated. Am J Gastroenterol. 2010;105(7):1523-1530. 9. Fleischer DE, Overholt BF, Sharma VK, et al. Endoscopic radiofrequency ablation for Barrett’s esophagus: 5-year outcomes from a prospective multicenter trial. Endoscopy. 2010;42(10):781-789.
10. Shaheen NJ, Sharma P, Overholt BF, et al. Radiofrequency ablation in Barrett’s esophagus with dysplasia. N Engl J Med. 2009;360(22):22772288. 11. Phoa KN, Pouw RE, van Vilsteren FG, et al. Remission of Barrett’s esophagus with early neoplasia 5 years after radiofrequency ablation with endoscopic resection: a Netherlands cohort study. Gastroenterology. 2013;145(1):96-104. 12. Phoa KN, van Vilsteren FGI, Weusten BLAM, et al. Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized trial. JAMA. doi:10.1001/jama.2014.2511. 13. Mokrowiecka A, Wierzchniewska-Lawska A, Smolarz B, et al. Amplification of Her-2/neu oncogene in GERD—Barrett’s metaplasia— dysplasia—adenocarcinoma sequence. Hepatogastroenterology. 2013;60(125):1063-1066. 14. Bird-Lieberman EL, Dunn JM, Coleman HG, et al. Population-based study reveals new risk-stratification biomarker panel for Barrett’s esophagus. Gastroenterology. 2012;143(4):927-935, e3. 15. Prasad GA, Wang KK, Halling KC, et al. Utility of biomarkers in prediction of response to ablative therapy in Barrett’s esophagus. Gastroenterology. 2008;135(2):370-379.
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