Barrett s esophagus (BE) is the precursor lesion to esophageal al adenocarcinoma,

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1 PRINTER-FRIENDLY VERSION AVAILABLE AT GASTROENDONEWS.COM Endoscopic Eradication Therapy for Barrett s Esophagus SHREYAS SALIGRAM, MD, MRCP a,b PRASHANTH VENNALAGANTI, MD a PRATEEK SHARMA, MD a,b a Department of Veterans Affairs Medical Center Kansas City, Kansas b University of Kansas School of Medicine Kansas City, Kansas Dr. Sharma has received grant support from Barrx Medical, CDX Labs, Cook Medical, Ninepoint Medical, and Olympus Inc. Drs. Saligram and Vennalaganti reported no relevant conflicts of interest. Patients with HGD have the highest tendency to progress to esophageal adenocarcinoma. Therefore, endoscopic eradication therapy increasingly is used to treat HGD and early esophageal adenocarcinoma to decrease the progression to invasive disease. Data from the US National Cancer Institute show a 6-fold increase in the incidence of esophageal adenocarcinoma in 2001; the disease now is considered the fastest rising cancer in the United States. 8 Barrett s esophagus (BE) is the precursor lesion to esophageal al adenocarcinoma, which in an invasive stage causes significant morbidity and mortality. Surgery was the mainstay of treatment for patients with high-grade dysplasia (HGD) and adenocarcinoma associated with BE. However, surgery in itself carries substantial morbidity. There has been tremendous progress in the minimally invasive treatment of BE in the past decade. The premise to be aggressive in treating dysplastic BE and early stage of adenocarcinoma is to prevent progression to an advanced stage cancer. Most interventional endoscopists are comfort- able treating dysplasia and intramucosal esophageal cancer, although recently there have been emerging data on the treatment of early submucosal cancer in BE. This article reviews the different modes of and strategies for endoscopic treatment of BE with emphasis on newer techniques. Introduction Barrett s esophagus is defined as displacement of squamocolumnar junction by intestinal metaplasia (IM; goblet cells) proximal to the gastroesophageal junction. The overall population prevalence is estimated at 1.6% 1 with an annual incidence of 62 per 100, In patients with BE, the annual incidence of esophageal adenocarcinoma is reported to be between 0.12% and 0.5%. 3-6 Intestinal metaplasia can have a histologic transformation from no dysplasia to low-grade dysplasia (LGD), HGD, and eventually to esophageal adenocarcinoma. 7 Rationale for Endoscopic Eradication Barrett s esophagus has the potential to transform itself into esophageal adenocarcinoma by genetic alteration of IM, where there is unregulated cell growth due to inactivation of tumor suppressor genes and activation of oncogenes. This genetic activity causes a morphologic change in the lining of the epithelium of the esophagus called dysplasia (cytologic atypia, architectural complexity due to nuclear pleomorphism and hyperchromatism confined to basement membrane). 9,10 The aim of ablation/eradication therapy is to destroy GASTROENTEROLOGY & ENDOSCOPY NEWS JULY

2 this abnormal lining of the esophagus and reinstate the neosquamous epithelium. Natural History of Dysplasia in BE Before embarking on endoscopic therapy for BE, it is important to understand the risks for dysplasia and cancer in these patients. Contemporary literature suggests that the reported rate of progression of cancer or dysplasia from IM, or nondysplastic BE, is low. 6 Nondysplastic BE, which is the early stage of the condition, has the lowest incidence of transforming to dysplasia or esophageal adenocarcinoma. A retrospective study of 1,204 patients diagnosed with nondysplastic BE during index endoscopy and followed for a mean period of 5.52 years found that 98.6% and 97.1% were cancer free after 5 and 10 years, respectively. Per-year incidence of esophageal adenocarcinoma was reported to be 0.27%, 0.48% for HGD, and 3.6% for LGD. 11 A recent meta-analysis, which included 11,434 patients diagnosed with nondysplastic BE and followed for 58,547 patient-years, reported a low annual incidence of cancer, at 0.3%. 12 Similar findings were reported from a large population-based study from Denmark, which found that the risk for cancer in patients with nondysplastic BE was less than 0.2% per year. Low-grade dysplasia has a lower degree of dysplastic cells and is the initial stage of dysplasia. Several studies have shown varying results for LGD developing into HGD or cancer. A multicenter study including 210 patients with LGD followed for an average of 6.2 years reported a low incidence of esophageal adenocarcinoma (0.44% per year) and HGD (1.6% per year). Combined esophageal adenocarcinoma and HGD was 1.83% per year with a mean time of progression to esophageal adenocarcinoma of 4.41 years. Based on survival analysis, 97.4% of patients were cancer free after 5 years of follow-up. 13 Based on this study, only 2.6% of patients developed cancer at the end of 5 years; overall, patients with LGD had a low risk for developing malignancies. However, other studies found a higher incidence (up to 13.6% per year) of combined HGD and esophageal adenocarcinoma developing from LGD This inconsistent incidence in the rate of LGD that becomes HGD and cancer was long suspected to reflect a sampling error and significant interobserver variability among pathologists. 13,17 The natural course of LGD thus appears to be highly variable. A recent multicenter randomized controlled trial from Europe suggested higher rates of progression of LGD to cancer. The study included 136 patients with LGD, with 68 randomized to undergo radiofrequency ablation (RFA) and 68 monitored by surveillance endoscopy every 6 to 12 months. After 3 years of follow-up, 1.4% of patients undergoing RFA and 8.8% being followed without RFA developed esophageal adenocarcinoma. 18 By comparison, a recent meta-analysis of cancer risk in patients with LGD (24 studies; 2,694 patients) showed a 0.5% risk for cancer. 19 Clearly, LGD remains a difficult disease to diagnose. High-grade dysplasia has a greater prevalence of dysplastic cells and is the advanced stage of dysplasia. Timely treatment at this stage can prevent dysplasia from progressing to cancer. A 2008 meta-analysis found a high incidence of esophageal adenocarcinoma (6% per year) in patients with HGD who had not undergone ablation or surgery. Of the 236 patients who met the inclusion criteria for the study, 69 developed esophageal adenocarcinoma within 1.5 to 7 years of followup. 20 A multicenter sham control trial in 2009 assigned 63 patients with HGD randomly to receive either RFA or sham procedure and followed them for 12 months. Although 19% of the patients in the control group experienced spontaneous regression of dysplasia, a significant proportion progressed to esophageal adenocarcinoma. 21 These data and the meta-analysis show beyond doubt that untreated HGD has a significant risk for developing into cancer. Endoscopic Eradication Esophagectomy is effective in treating early-stage esophageal adenocarcinoma but is a radical therapy and carries a significant morbidity (30%-40%) and mortality (1%-4%) Therefore, it is used for patients at a high risk for or with the presence of lymph node metastasis. A systematic review of 1,350 patients who underwent esophagectomy for intramucosal (T1a) esophageal adenocarcinoma showed that only 26 (1.39%) had lymph node metastasis in the final pathology. 28 A retrospective review of 70 patients with T1a esophageal adenocarcinoma and 56 patients with submucosal (T1b) esophageal adenocarcinoma revealed lymph node metastasis in 1.3% and 22%, respectively. Lymphovascular invasion, tumor size of at least 2 cm in diameter, and poor differentiation were associated with an increased risk for lymph node metastasis. 29 All T1b lesions, regardless of the depth of T1b (SM1 indicates invasion into the superficial third of the submucosa, SM2 invasion into the middle third, and SM3 invasion into the deepest third of the submucosa), were associated with significant lymph node metastasis (12.9%-20.4%). 30 The risk for lymph node metastasis in early esophageal adenocarcinoma therefore is low and endoscopic eradication therapy can be attempted in the vast majority of patients with T1a lesions. However, endoscopic eradication therapy typically is precluded in patients with T1b esophageal adenocarcinoma because of the higher risk for metastasis to the lymph node. To obtain accurate tumor staging of visible lesions and patients with esophageal cancer, endoscopic mucosal resection (EMR) is performed to assess depth of the lesion. In patients with known cancer on biopsies, the accuracy of TNM staging is enhanced when endoscopic ultrasound is combined with EMR. 31 After accurate staging and resection of early esophageal adenocarcinoma, it is important to ensure that the rest of the BE is eradicated completely to prevent recurrence of cancer. A retrospective study of 349 patients treated with ablation therapy for BE found occurrence of metachronous 2 INDEPENDENTLY DEVELOPED BY MCMAHON PUBLISHING

3 Table. Endoscopic Eradication Therapy for Barrett s Esophagus Thermal ablation therapy Nonthermal ablation therapy Endoscopic resection Argon plasma coagulation Laser therapy Multipolar electrocoagulation Cryotherapy Photodynamic therapy Radiofrequency ablation Endoscopic mucosal resection Endoscopic submucosal dissection lesions in 21.5% of patients at a median of 15 months. The metachronous lesions were not found in the group that had undergone complete eradication of IM (CE-IM). 32 The current practice for endoscopic eradication therapy of BE is resection of any visible lesions by EMR, ablation of residual BE to prevent metachronous lesions or recurrent neoplasm, and follow-up surveillance. Multimodal endoscopic eradication therapy with EMR and RFA commonly is used. Visible or flat lesions are described by Paris classification 33 and endoscopic inspection for visible or flat lesions is performed under white light endoscopy. Advanced imaging techniques including chromoendoscopy and virtual chromoendoscopy; optical frequency domain imaging; or confocal laser endomicroscopy are available but underused. A recent meta-analysis showed that detection of HGD or cancer increased by 34% when clinicians used advanced imaging techniques. 34 Based on the available evidence, the American Gastroenterology Association issued guidelines for endoscopic surveillance and eradication therapy of BE. Endoscopic surveillance should be performed every 3 to 5 years for nondysplastic BE, every 6 to 12 months for LGD, and every 3 months for HGD if endoscopic eradication therapy is not performed. All patients with dysplasia should have the diagnosis confirmed by at least 2 experienced gastrointestinal pathologists. The treatment of early-stage dysplastic lesions is controversial given the variability in the diagnosis and natural history. In a recently concluded multicenter study, which classified LGD as inflammatory and dysplastic, interobserver agreement among expert pathologists was poor, with kappa values for inflammatory and dysplastic lesions of 0.03 and 0.04, respectively. The overall kappa value for LGD was The aim of endoscopic eradication therapy should be to eradicate BE completely once dysplasia has been eradicated to prevent the progression of residual IM to recurrent or metachronous neoplasia. 36 MODALITIES OF ENDOSCOPIC ERADICATION The different modalities of endoscopic eradication therapy are listed in Table. The advent of RFA as primary therapy has displaced some of the older therapies like thermal (multipolar electrocoagulation, argon plasma coagulation, Yag laser) and nonthermal (photodynamic therapy) methods. 37 Argon plasma coagulation for eradication of residual BE tissue after use of EMR and/or RFA is still used for the treatment of focal areas. Endoscopic resection consists of 2 approaches, EMR and endoscopic submucosal dissection (ESD), depending on the depth of the tissue removed. ENDOSCOPIC MUCOSAL RESECTION The 2 types of EMR that can be performed are focal and radical, or wide area. 38 Focal EMR is a technique used to excise visible polypoid, flat, or nodular lesions of esophageal mucosa suspected to be harboring cancer. It serves both as a diagnostic tool for tumor staging and also as a therapeutic tool for excising the neoplastic lesion. Two commonly used techniques are the multiband ligator and the cap-assisted device. 39 The multiband ligator 40 uses suction to draw lesions into a cap and a rubber band is applied to create a pseudopolypoid lesion, which is then snared using electrocoagulation and the specimen is subsequently retrieved. The cap-assisted technique 41 uses saline or diluted epinephrine (1:100,000) to lift the suspected lesion. A prelooping of the snare to the rim of the transparent cap attached to the endoscope tip is performed after raising the suspected lesion. The raised lesion is then sucked into a cap, creating a pseudopolyp, which is then snared by electrocoagulation before the specimen is retrieved (Figure 1). Radical EMR is used to remove larger areas of BE. Side-by-side resections can achieve complete eradication of the neoplastic and metaplastic tissue, and the procedure is repeated every 2 to 3 months until all visible BE has been removed. This technique frequently is used in patients with noncircumferential BE, and those with maximal extents of lesions up to 4 to 5 cm in diameter. SHORT-TERM RESULTS Few studies have used EMR as the sole treatment for eradication of all BE tissue. The majority of studies have used a multimodal approach, such as initial focal EMR followed by ablation to evaluate the efficacy of EMR in treating HGD and early esophageal adenocarcinoma. A retrospective study of 49 patients (67% HGD and 33% T1a adenocarcinoma) who underwent radical EMR with a mean follow-up of 22.9 months reported CE-IM in 97% of cases. No recurrence of dysplasia or cancer was observed in the 32 patients who completed the eradication protocol. However, nearly one-third of patients developed symptomatic stenosis that was successfully dilated. 42 A multicenter randomized clinical trial enrolled 25 patients in a radical EMR group and 22 patients in combined modality group (focal EMR with ablation GASTROENTEROLOGY & ENDOSCOPY NEWS JULY

4 Figure 1. Barrett s esophagus with visible lesion pre and post endoscopic mucosal resection. therapy). During a mean follow-up of 24 months, 92% of patients in the radical EMR group achieved CE-IM compared with 96% in the combined modality group; similar high rates of CE-dysplasia or cancer were observed (100% in the radical EMR group vs 96% in the group receiving combined modality). 43 Based on these studies and several others, radical EMR appears to have good short-term efficacy in treating HGD and early esophageal adenocarcinoma. 44,45 LONG-TERM RESULTS Robust data now exist for long-term efficacy of EMR in patients with HGD and early esophageal adenocarcinoma. A prospective study of 100 T1a patients who underwent EMR with a mean follow-up of 36.7 months revealed CE-dysplasia or cancer in 99% with metachronous lesions noted in 11% that was successfully retreated with EMR. 46 A retrospective study of 132 T1a patients with a mean follow up of 43 months found that of the 75 patients who underwent EMR alone, 96% achieved CE-dysplasia or cancer, with 11% recurrences. All were successfully treated with a repeat EMR. 47 Another recent retrospective study of 76 patients with HGD or T1a cancer who underwent radical EMR and were followed for a mean of 40.6 months reported a CE-IM rate of 71% and CE-dysplasia or cancer in 100%. 48 COMPLICATIONS Adverse events associated with EMR generally are uncommon. Dysphagia, strictures requiring dilation, 43,49-53 bleeding both immediate and delayed for more than 48 hours after the procedure 42,53-56 chest pain, and perforation are among the reported complications. 57 Resection of more than 50% of the esophageal circumference is associated with higher rates of strictures. 50 Radical EMR has been linked to more complications than focal EMR, including a high rate of strictures. 42,43,57-62 ENDOSCOPIC SUBMUCOSAL DISSECTION This technique is used for en bloc resection of larger lesions. Pioneered in Japan mainly for early gastric lesions, the practitioner uses a coagulation tip to mark around the lesion. Diluted epinephrine with 10% glycerol (multiple other agents like hyaluronidate, mannitol, epinephrine, and indigo carmine can be used as well) is injected into submucosa to separate the lesion from the muscle layer. The mucosa initially is resected by needle knife and subsequently submucosal fibers and vessels by hook knife. The resected lesions are obtained for histopathology. The advantage of ESD over EMR is that larger lesions (7 cm) can be resected en bloc and more accurate information about depth of the lesion can be obtained. 63,64 SHORT-TERM RESULTS A single published study evaluated the outcome of ESD. The trial included 29 patients known to have large T1a cancers, with a median diameter of 2 cm, in the setting of BE. The patients underwent ESD. They were followed for a mean period of 17 months. An R0 resection was achieved in only 38.5% of the patients. CE-IM and neoplasia was achieved in 53.6% and 96.4% of patients, respectively. The CE-IM rate increased to 80% when additional treatment with RFA was performed. 65 LONG-TERM RESULTS As ESD is relatively new, few studies have reported the long-term efficacy of the technique. One such study, of 25 patients (both T1a and T1b) who underwent the procedure with a mean follow-up of 30.6 months, showed that en bloc resection was achieved in 100% of 4 INDEPENDENTLY DEVELOPED BY MCMAHON PUBLISHING

5 Figure 2. Barrett s esophagus pre and post radiofrequency ablation. patients but R0 resection was attained in only 72%. The mean size of resected lesions was 1.6 cm. There were no reports of neoplasia recurrence among patients who achieved R0 resection. 64 COMPLICATIONS Although the data are limited, published reports suggest that complications in expert hands are minimal. Some of the known complications are delayed bleeding, sudden cardiac death, incomplete R0 resection, and strictures. 64,65 RADIOFREQUENCY ABLATION Radiofrequency ablation is the most commonly used and best studied ablative therapy currently available for the treatment of BE (Figure 2). RFA can be performed with either a circumferential or focal device. The circumferential ablation device has a 3-cm cylindrical balloon with circular electrodes delivering the preset energy to ablate in a circumferential fashion. The focal ablation device is placed over the tip of the endoscope to ablate smaller areas with preset energy. SHORT-TERM RESULTS Several published studies have evaluated the shortterm efficacy of RFA, which appears to be excellent. A retrospective registry study from 19 centers in the United Kingdom included 335 patients (HGD, 72%; T1a esophageal adenocarcinoma, 24%; and LGD, 4%) treated with either focal EMR and RFA (49%) or RFA alone (51%). After a mean of 2.5 treatments and 12 months of followup, CE-IM and CE-dysplasia were achieved in 62% and 81% patients, respectively. Invasive cancer developed in 3% of patients and the cumulative risk for cancer progression more than 5 years was 8%. 66 Another retrospective study of an American cohort of 54 patients with T1a cancer who underwent focal EMR combined with ablation therapy (81%) with a mean follow-up of 23 months, reported CE-dysplasia/cancer in 96% and CE-IM in 59%. 53 A recent meta-analysis that included 3,802 patients from 18 studies evaluated the efficacy of RFA in treatment of BE during a 20.5-month follow-up period. The overall rates of CE-IM and CE-dysplasia were 78% and 91%, respectively. 67 A recent Cochrane review of 1,074 patients from 16 studies evaluated the efficacy of RFA in treatment of BE during a 12-month follow-up period. The overall rates of CE-IM and CE-dysplasia were 82% and 94%, respectively. 37 Thus, based on the available evidence, short-term efficacy for RFA for CE-IM has been reported to be 62% to 82%, and CE-dysplasia as 81% to 94%. Cancer recurrence was seen in 3% of patients at the end of 12 months. LONG-TERM RESULTS Several recent studies have focused on the longterm efficacy of RFA therapy after achieving initial successful eradication of BE. A multicenter analysis of 448 patients (HGD, 60%; T1a esophageal adenocarcinoma, 11%; LGD, 15%; and nondysplastic BE, 14%) who underwent EMR (55%) and RFA revealed that CE-IM was achieved in 26%, 56%, and 71% at 1, 2, and 3 years, respectively. Kaplan-Meier analysis showed that the incidence of recurrent IM at 1 and 2 years was 20% and 33%, respectively. Younger patients and those with short-segment BE responded much better to RFA. 68 A single-center long-term retrospective study on BE was conducted of 72 patients (HGD, 49%; T1a esophageal adenocarcinoma, 22%; and LGD, 17%). All patients underwent RFA alone. After a mean of 2.3 treatments and 9.5 months of follow-up, CE-IM and CE-dysplasia were achieved in 79% and 89% of patients, respectively. Superficial adenocarcinoma persisted in 5% of GASTROENTEROLOGY & ENDOSCOPY NEWS JULY

6 Figure 3. Barrett s esophagus pre- and post-cryotherapy. patients requiring esophagectomy. Thirty-four patients who achieved CE-IM were followed for 3 years with no further recurrences noted. The overall rate of CE-IM was 73%. 69 RFA therefore appears to have excellent short-term efficacy in achieving CE-IM (71%-93%) and CE-dysplasia (98%-100%). However, during long-term follow up, 15% to 30% of the patients can experience recurrence of IM within 2 to 3 years of achieving CE-IM, thereby requiring ongoing surveillance. COMPLICATIONS RFA is generally well tolerated. Bleeding, mucosal tears, dysrhythmias, chest pain, buried metaplasia (IM buried under neosquamous epithelium), 70 recurrent esophageal adenocarcinoma, and HGD 66,71-75 are among the reported complications. A systematic review in 2011 showed that of 1,004 patients who underwent RFA, only 0.9% had buried metaplasia. 70 CRYOTHERAPY Cryotherapy is a relatively new technique to ablate BE, using an extremely low temperature between 76 C and 158 C 76 to target tissue for destruction and ablation (Figure 3). A repetitive cycle of rapid-freezing and slow-thawing results in the formation of extracellular and intracellular ice, which disrupts cell membranes and tissue ischemia through vascular thrombosis due to vascular stasis Two types of cryotherapy devices are available: CSA Medical, Inc., with a modified cryodecompression tube, delivers liquid nitrogen at 196 C, and GI Supply, with a suction catheter attached to the tip of the endoscope, uses high-pressure gas carbon dioxide at 78 C. The depth of the tissue injury depends on the duration of the freeze time. The technical advantage of cryotherapy over other ablative therapies is that it is easy to spray over large areas of mucosa, causing destruction without precise close contact. Hence, it is particularly helpful in tortuous esophageal anatomy and at the area of the gastroesophageal junction. However, both robust short- and long-term results are lacking with this technique. SHORT-TERM RESULTS Two small observational studies reported the shortterm efficacy of cryotherapy. A retrospective study of 60 patients followed for a mean period of 10.5 months found that after a mean of 3.4 treatments of liquid nitrogen cryotherapy, CE-dysplasia was achieved in 87% and CE-IM in 57% of treated patients. 79 In another small study, 30 patients with BE (HGD-25 and T1a-5) underwent liquid nitrogen cryotherapy and were followed up for a mean of 12 months. There was downgrading of pathology in 90% of the patients with a mean of 5 sessions. The reported rates of CE-IM, and CE-dysplasia/cancer were 3.3% and 60%, respectively. 80 Finally, a trial of 23 patients treated with 6 treatments of carbon dioxide cryotherapy and followed for a mean of 11.5 months found CE-IM and CE-dysplasia in 95.6% of patients. Twenty-five of these patients had failed earlier treatment with RFA, photodynamic therapy, and EMR. 81 LONG-TERM RESULTS A single retrospective study including 32 patients with HGD evaluated the long-term efficacy of cyrotherapy. Patients underwent a mean of 4 treatments and were followed for a mean 37 months. In this study, CE-HGD was achieved in 96% and CE-IM in 81% of patients. 82 COMPLICATIONS Adverse effects reported with cryotherapy usually are self-limiting. Chest pain and dysphagia are the predominant complications with minimal stricture and rare perforation. Odynophagia and sore throat are some of the other known complications. 79,80,83 6 INDEPENDENTLY DEVELOPED BY MCMAHON PUBLISHING

7 Summary Current evidence suggests that multimodal endoscopic eradication therapy with focal EMR and RFA is the best therapy for treatment of BE with HGD and T1a esophageal adenocarcinoma and should be the preferred management option over surgery. Defining LGD continues to remain a challenge with poor interobserver agreement and wide variability rates in cancer progression reported in the literature (0.5% in a recent meta-analysis to 8.8% in a randomized controlled trial in Europe). Radical EMR is associated with more complicatio ns than focal EMR. Endoscopic submucosal dissection is technically challenging, with low R0 resection rates, making it less attractive. Therefore, the procedure is still in an incipient stage. Cryotherapy appears promising due to its low cost and the ease of the procedure, but more evidence regarding its longterm efficacy is required. Continued surveillance after achieving CE-IM is recommended due to risk for recurrence of intestinal metaplasia, buried metaplasia, and subsequent development of neoplasia. 73,84 References 1. Wang KK, Sampliner RE, Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines 2008 for the diagnosis, surveillance and therapy of Barrett s esophagus. Am J Gastroenterol. 2008;103(3): Coleman HG, Bhat S, Murray LJ, et al. Increasing incidence of Barrett s oesophagus: a population-based study. Eur J Epidemiol. 2011;26(9): de Jonge PJ, van Blankenstein M, Looman CW, et al. Risk of malignant progression in patients with Barrett s oesophagus: a Dutch nationwide cohort study. Gut. 2010;59(8): Shaheen NJ, Crosby MA, Bozymski EM, et al. Is there publication bias in the reporting of cancer risk in Barrett s esophagus? Gastroenterology. 2000;119(2): Bhat S, Coleman HG, Yousef F, et al. 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