Progress in outlining the frequency and risk of recurrent neoplasia after ablation of Barrett's esophagus
Article Outline
Abbreviations: HGD, high-grade dysplasia, LGD, low-grade dysplasial, PDT, photodynamic therapy, RFA, radiofrequency ablation
The introduction of endoscopic techniques that can treat early esophageal neoplasia has been one of the most significant advances in the past decade. EMR, initially developed in Japan by Inoue et al,1 coupled with more widespread mucosal ablation techniques, including photodynamic therapy (PDT) and radiofrequency ablation (RFA) has clearly provided an alternate treatment option to surgical resection. Data to date support endoscopic resection as the treatment of choice for focal mucosal esophageal adenocarcinoma and as an important adjunct to RFA in dysplastic Barrett's epithelium.2, 3 Early esophageal neoplasia is now a common clinical problem; low-grade dysplasia (LGD) will develop in 4% to 5% of patients with Barrett's esophagus, high-grade dysplasia (HGD) will develop in 1%, and adenocarcinoma will develop in 0.5% each year. T1 lesions, once rare, now account for as many as 20% of esophageal adenocarcinoma cases in the United States.
Endoscopic treatment is not without its downside, however. Two major factors play a key role in its application: first a significant prevalence of recurrent neoplasia, estimated to be 20% to 25% at 5 years, and, second, the intensity of diagnostic investigation currently used to detect these recurrences at an early stage. Both are relevant limitations and will have varying importance depending on the age, clinical characteristics, and comorbidities of each individual patient. In a prelude to the current article, the Mayo group retrospectively compared outcomes in 178 patients with mucosal esophageal adenocarcinoma seen between 1998 and 2007.4 One hundred thirty-two of these patients were treated with endoscopic ablation and 46 with surgical resection. At an average follow-up of 3.5 years, recurrent adenocarcinoma developed in 12% of the patients in the endoscopic treatment group (16/132 patients), nearly 10 times the prevalence after surgical resection (1 patient). Although all recurrences were intramucosal cancers and all but one was managed endoscopically, this emphasizes the need to define risk factors for recurrences, bringing us to the current study.
The current study by Badreddine et al5 retrospectively assessed the prevalence of recurrent dysplasia or cancer in 261 patients with early neoplasia and Barrett's esophagus treated with PDT and EMR. The patients were treated over 13 years (1992-2005). The study group was taken from a cohort of 363 patients, with nearly one fourth of them either lost to follow-up (44/363, 12%) or with residual dysplasia despite endoscopic therapy (46/363, 13%). Importantly, the authors chose to include LGD (53/261, 20%), arguing correctly that LGD is a major risk factor for the development of HGD and intramucosal adenocarcinoma and as such should be included in the definition of early neoplasia. Given the pathologic uncertainties surrounding the identification of LGD, their choice of inclusion can and will be criticized, and the prevalence of recurrence increases significantly if these patients are excluded. The vast majority had HGD (152/261, 58%) and the minority intramucosal adenocarcinoma (56, 21%). Recurrent neoplasia occurred in 45 patients (12%) at a median of 17 months after treatment. All patients were maintained on twice-daily proton pump inhibitors and underwent upper endoscopy with 4-quadrant biopsies every 1 cm every 3 months for the first year and every 6 (LGD) or 12 (no dysplasia) months thereafter depending on biopsy findings. Definitions are important. Here, recurrence was defined by the presence of any grade of dysplasia or cancer after 2 consecutive biopsies without dysplasia. The importance of 14 variables was tested by regression analysis for their impact on the risk of recurrence. Again, definitions are important, and the findings might be different given alternate definitions. Hiatal hernia was defined as less than or greater than 2 cm, and body mass index greater than 25 was used to detect the impact of obesity and importantly multifocal dysplasia was not included as a study variable. Increased age, the presence of residual Barrett's esophagus, and smoking were found to be associated with recurrence.
A perusal of the study population is relevant. The vast majority were male (84%), 75% had a body mass index greater than 25, 82% had a hiatal hernia greater than 2 cm, and a surprisingly high 73% had a history of smoking. Also important, only 18% had long-segment (>3 cm) Barrett's esophagus. Two of the 3 factors identified, namely, older age and a history of smoking, are interesting and not immediately intuitive. How to use the findings clinically remains unclear; most of us would not exclude such patients from an attempt at endoscopic treatment, nor would we necessarily increase the intensity of follow-up surveillance.
Several factors likely predisposing to recurrence were not found. This is because they were not tested, as with multifocal dysplasia, or possibly because of a population bias, as with long-segment Barrett's esophagus. Further, no study to date has assessed the importance of persistent reflux. Whether genetic markers will prove more useful than, or add to, the clinical ones is an area of current study. As a testament to the pace of change, this study is already behind the times. The current ablation technology of choice is balloon catheter RFA; PDT has largely disappeared. Similar studies using RFA are now needed.
We have clearly entered a new treatment paradigm for patients with early esophageal neoplasia. The applicability of endoscopic treatment for the overall population of patients referred with esophageal neoplasia remains to be defined, as does the issue of whether similar results can be obtained in the general community by nonspecialty physicians and centers. The presence of occult malignancies, particularly those involving the submucosa with possible nodal metastases, must be considered. Further, the biology that led to the development of dysplasia and cancer remains, making it increasingly clear that eradication of all metaplastic epithelium is the ultimate goal and that the importance of close follow-up cannot be overemphasized. Although the advantages of a less-invasive approach to treatment of HGD/intramucosal carcinoma are intuitive, less obvious is the anxiety that comes with the slow and/or incomplete eradication of neoplasia and the need for serial endoscopic interventions and surveillance over a prolonged time period. Surgical resection remains a viable option, particularly for those with refractory neoplasia, and the young in which the possibility of new tumors arising after 5 years must be considered and, as this excellent article begins to define, perhaps those with a high risk of recurrence. As one of the uncommon few who performs both endoscopic and surgical treatment of esophageal neoplasia, I have little doubt that endoscopic treatment is here to stay and benefits our patients.
Disclosure
The author disclosed the following financial relationships relevant to this publication: Research grant from Takeda Pharmaceutical, research grant from Torax Medical, research grant from Medigus Ltd.
References
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- 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;57:1200–1206
- Eradication of Barrett esophagus with early neoplasia by radiofrequency ablation, with or without endoscopic resection. J Gastrointest Surg. 2008;12:1627–1637
- Endoscopic and surgical treatment of mucosal (T1a) esophageal adenocarcinoma in Barrett's esophagus. Gastroenterology. 2009;137:815–823
- Prevalence and predictors of recurrent neoplasia after ablation of Barrett's esophagus. Gastrointest Endosc. 2010;71:697–703
PII: S0016-5107(09)02893-4
doi:10.1016/j.gie.2009.12.027
© 2010 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.
