Endoscopic eradication of Barrett s esophagus

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1 TECHNICAL REVIEW Endoscopic eradication of Barrett s esophagus Sachin Wani, MD, Hari Sayana, MD, Prateek Sharma, MD Kansas City, Missouri, USA Barrett s esophagus (BE) is the premalignant lesion of esophageal adenocarcinoma (EAC), a cancer with a rapidly increasing incidence in the Western world, 1 exceeding that of other cancers such as breast, colon, lung, and prostate cancers. 2 Nevertheless, the overall incidence of EAC in white men is only 5 to 7 per 100,000. Because BE can eventually progress to EAC, patients with BE are followed in surveillance programs to detect dysplasia and/or early EAC. Such progression involves the development of lowgrade dysplasia (LGD) to high-grade dysplasia (HGD) before the eventual development of adenocarcinoma. 3 Although BE patients without dysplasia are treated with medical and/or surgical antireflux therapy to control their reflux symptoms and esophageal acid exposure, such therapies have failed to reverse the premalignant epithelium. 4,5 In BE patients with HGD and/or early EAC (confined to the mucosa), esophagectomy has long been considered the primary treatment option because of the high risk of progression to EAC, the potentially high probability of coexisting (subclinical) invasive EAC, and because the removal of the entire diseased segment would eliminate the risk of future cancer. 6 Although some of the previous surgical series found a high rate of coexisting cancer (as high as 40%), 7 a recent systematic review cited a low (12.7%) prevalence rate of invasive EAC in patients undergoing esophagectomy for HGD. Furthermore, if there were no endoscopically visible macroscopic lesions, this rate dropped to 3%. 8 Interestingly, removal of the diseased esophageal segment may not prevent recurrence of the columnar lined esophagus in a patient who probably is genetically predisposed to BE and neoplasia. This was convincingly demonstrated in a surgical series Abbreviations: ALA, aminolevulinic acid; APC, argon plasma coagulation; BE, Barrett s esophagus; EAC, esophageal adenocarcinoma; EET, endoscopic eradication therapy; HGD, high-grade dysplasia; LGD, low-grade dysplasia; MPEC, multipolar electrocoagulation; NDBE, nondysplastic Barrett s esophagus; NS, not significant; OR, odds ratio; PDT, photodynamic therapy; RFA, radiofrequency ablation; RR, relative risk. DISCLOSURE: The following author disclosed financial relationships relevant to this publication: P. Sharma: grant support from Barrx Medical and Olympus. The other authors disclosed no financial relationships relevant to this publication. Copyright ª 2010 by the American Society for Gastrointestinal Endoscopy /$36.00 doi: /j.gie in which 47% of patients undergoing curative radical subtotal esophagectomy had subsequent evidence of a columnar-lined esophagus during a median follow-up of 3 years. 9 Finally, esophagectomy has been associated with a 1% to 5% mortality rate and 30% to 50% morbidity rate, even in expert centers. 7,10 Given these shortcomings, endoscopic eradication therapy (EET) has been attempted in BE (both dysplastic and nondysplastic) patients with variable results. Although, in principle, EET appears attractive, a number of questions need to be addressed. Who are the ideal candidates? What type of therapy should be used? Is the risk of EAC reduced after EET? Should these patients be continued in surveillance programs post-eet? Is the benefit of BE eradication worth the risk? Does EET truly prevent the development of EAC? This technical review provides an evidence-based approach to these questions. METHODS Search strategy This review is based on a critical review of the available scientific literature on the topic identified in Medline and PubMed (January 1992 to January 2009) with search terms that included Barrett s esophagus, Barrett s oesophagus, esophageal adenocarcinoma, esophageal cancer, ablation, argon plasma coagulation, multipolar electrocoagulation, laser, radiofrequency ablation, cryoablation, endoscopic mucosal resection, esophageal stricture, buried glands, and esophageal perforation. Eligible studies Clinical trials or observational studies that described the efficacy and effectiveness of endoscopic therapies (mucosal ablative therapies and EMR) in the management of BE patients (nondysplastic BE [NDBE], LGD, HGD, and intramucosal EAC) were eligible for inclusion in this review. Only studies that reported a follow-up of at least 6 months and included at least 5 patients treated with EET were included. Outcome measures and data extraction Studies reporting on endoscopic eradication of BE and associated neoplasia had to provide information on the Volume 71, No. 1 : 2010 GASTROINTESTINAL ENDOSCOPY 147

2 Ergonomics and GI endoscopy Wani et al TABLE 1. Strength of recommendation using the GRADE classification and implications for patients, clinicians, and policy makers Strong recommendations For patients: Most individuals in this situation would want the recommended course of action and only a small proportion would not. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences. For clinicians: Most individuals should receive the intervention. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator. For policy makers: The recommendation can be adapted as policy in most situations. Weak recommendations For patients: The majority of individuals in this situation would want the suggested course of action, but many would not. Decision aids may be useful in helping individuals make decisions consistent with their values and preferences. For clinicians: Examine the evidence or a summary of the evidence individually. For policy makers: Policy making will require substantial debates and involvement of many stakeholders. GRADE, Grading of Recommendations Assessment, Development, and Evaluation. following measures: (1) complete eradication of intestinal metaplasia; (2) complete eradication of dysplasia or cancer where applicable; (3) mean/median number of sessions; and (4) complications associated with the procedure including perforation, laceration, bleeding, chest pain, stricture formation, and buried glands. Two authors (S.W., H.S.) independently screened the titles and abstracts of all studies identified by the above search strategy, and full articles for all potentially relevant studies were obtained. Only articles published in the English language were included. The full text of these reports was assessed independently for eligibility. Any disagreement between the 2 assessors was resolved by discussion with the senior author (P.S.). A data collection form was developed to extract relevant information from each included study and maintained in an Excel spreadsheet. Other than the outcome measures stated above, additional information regarding the study design and patient characteristics (mean or median age with standard deviation, histological grade of dysplasia, mean length of BE with range) was also collected. Level of evidence The recommendations in this technical review are intended for use by health care providers and apply to adult patients. These recommendations are not intended to replace clinical judgment but rather to provide general guidelines applicable to the majority of patients. Clinicians need to integrate recommendations with their own clinical judgment and with individual patient circumstances, values, and preferences. They are intended to be flexible, in contrast to standards of care, which are inflexible policies designed to be followed in every case. Specific recommendations are based on relevant published information. The quality of evidence and strength of recommendations have been assessed using the Grading of Recommendations Assessment, Development, and Evaluation system (Tables 1 and 2), a system that has been adopted by multiple national and international societies. This system is based on a sequential assessment of quality of evidence, followed by assessment of the balance between benefits and downsides (harms, burden, and costs) and subsequent judgment of the strength of recommendation. TECHNIQUES FOR ERADICATION OF BE AND ASSOCIATED NEOPLASIA Several techniques have been developed for the eradication of BE and associated neoplasia (Table 3). In the reported studies, all patients undergoing EET received high-dose proton pump inhibitor therapy, whereas in some studies, patients underwent Nissen fundoplication. Technological details of each of these techniques have been described previously In the following sections, a brief technical aspect of each endoscopic eradication technique with a specific focus on BE patients is discussed. Argon plasma coagulation Argon plasma coagulation (APC) is a noncontact thermal technique that uses a high-frequency, monopolar current of ionized argon gas resulting in coagulation of the epithelium with a 1- to 3-mm depth of injury. Argon gas flows through a catheter that is passed through the working channel of the endoscope. The depth of tissue coagulation is dependent on the argon flow rate, the generator power setting, the duration of application, and the distance from the mucosa. 14 Energy settings ranging from 40 to 90 W have been reported for eradication of BE. 17 The equipment required for APC is inexpensive, easy to use, and available in most endoscopy units. 18 APC has been described as the primary endoscopic treatment modality (circumferential, noncircumferential, or BE length limited ablation) and in some cases used as an adjunct 148 GASTROINTESTINAL ENDOSCOPY Volume 71, No. 1 :

3 Wani et al Ergonomics and GI endoscopy TABLE 2. Quality of evidence: definitions and determinants Grade definition High Further research is very unlikely to change our confidence in the estimate of effect. Underlying methodology: Randomized, controlled trials Moderate Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Underlying methodology: Downgraded randomized, controlled trials or upgraded observational studies Low Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Underlying methodology: Well-done observational studies with control groups Very low Any estimate of effect is very uncertain. Underlying methodology: Case reports or case series TABLE 3. Techniques for endoscopic eradication of Barrett s esophagus and associated neoplasia Thermal techniques Argon plasma coagulation Multipolar electrocoagulation Lasers (Nd:YAG, KTP:YAG) Radiofrequency ablation Photochemical techniques Photodynamic therapy Mechanical EMR Others Cryoablation Ultrasonic ablation Nd:YAG, Neodymium-yttrium aluminum garnet; KTP:YAG, potassium titanyl phosphate:yttrium aluminum garnet. to other therapies to touch up areas of residual BE. The vast majority of studies describing the efficacy of APC for BE have included NDBE patients (Table 4) Multipolar electrocoagulation Multipolar electrocoagulation (MPEC) is a thermal contact method that uses electrical energy to increase tissue temperature, resulting in tissue desiccation and destruction. A probe, passed through the working channel of the endoscope, is placed in contact with the BE epithelium, and power is applied until there is evidence of a white coagulum. Several generators are available that provide variable output through both 10F and 7F catheters, with the former providing a slightly larger surface area. 17 The depth of tissue injury is dependent on the power setting, duration of application, and the pressure applied to the tissue. 14,49 Similar to APC, MPEC has been described as a primary endoscopic treatment modality in BE patients (predominantly NDBE) or as an adjunct to touch up residual areas of BE. Table 5 36,39,50-52 summarizes reports of MPEC for ablation of BE. Lasers An intense beam of light is used to produce either contact or noncontact injury of the targeted esophageal epithelium. Of the several types of lasers, neodymium:yttrium aluminum garnet and potassium titanyl phosphate have been used in dysplastic and nondysplastic BE patients. A neodymium:yttrium aluminum garnet laser produces an injury at depths up to 4 to 6 mm, whereas a potassium titanyl phosphate laser produces more superficial injury. These forms of ablative therapy have largely been replaced by other techniques. 14 Studies describing the efficacy of lasers are highlighted in Table Photodynamic therapy Photodynamic therapy (PDT) involves 3 basic steps: administration of a photosensitizer (intravenous sodium porfimer, oral 5-aminolevulinic acid [ALA]), delivery of photoradiation to the photosensitized BE tissue by using small fibers, and finally the formation of oxygen radicals, causingcelldeathandtissueinjury. 16,59 In North America, sodium porfimer is the agent approved by the U.S. Volume 71, No. 1 : 2010 GASTROINTESTINAL ENDOSCOPY 149

4 Ergonomics and GI endoscopy Wani et al TABLE 4. Characteristics of argon plasma coagulation studies in Barrett s esophagus subdivided based on histological grade of dysplasia Author (y) Study design No. patients Follow-up (mo) No. sessions (mean/median) Outcomes Recurrence Progressors NDBE Mork et al Case series CE: 11 (85) 1 (8) 0 (1998) 19 Van Laethem Case series 31 (26 NDBE, 5 et al (1998) 20 LGD) Byrne et al Case series 30 (23 NDBE, 4 (1998) 21 LGD, 3 HGD) CE: 19 (61) 8 (47) CE: 19 (70) NR 0 Grade et al Case series 9 NA 1.7 CE: 7 (78) (1999) 22 Pereira-Lima Case series 33 (18 NDBE, et al (2000) LGD, 1 HGD) CE: 33 (100) 1 0 Schulz et al Case series (2-51) 2 CE: 69 (94) (2000) 24 Morris et al Case series NA (2001) 25 Tigges et al Case series CE: 30 (100) 2 (6) 0 (2001) 26 Kahaleh et al Case series CE: 18 (56) 18 (56) 2 (2 EAC) (2002) 27 Basu et al Case series CE: 30 (60) 23 (68) 0 (2002) 28 Morino et al Case series 23 (2 LGD) CE: 20 (87) 1 (4) 0 (2003) 29 Pagani et al Case series CE: 68 (72) 5 (7) 1 (2003) 30 Familiari et al Case series CE: 13 (100) 3 (23) 0 (2003) 31 Kelty et al RCT (2004) 32 (APC vs PDT) APC: 34 PDT (5-ALA): CE: 33 (97) CE: 17 (50), P!.0001 Hage et al RCT (2004) 33 (APC vs PDT) APC: 14 (3 LGD) PDT (5-ALA): 26 (5 LGD) CE: 5 (36) CE: 5 (19), PZNS NR 0 Ackroyd et al (2004) 34 RCT (APC vs surveillance) APC: 20 Surveillance: CE: 11 (55) CE: 3 (15), P! (5) 0 Pinotti et al Case series CE: 19 (100) 1 (5) 0 (2004) 35 Dulai et al RCT (APC vs MPEC) APC: 26 (2005) 36 MPEC: CE: 15 (58) CE: 17 (65), PZ.57 Pedrazzani Case series CE: 23 (92) 1 (4) 0 et al (2005) 37 (continued on next page) 150 GASTROINTESTINAL ENDOSCOPY Volume 71, No. 1 :

5 Wani et al Ergonomics and GI endoscopy TABLE 4 (continued) Author (y) Study design No. patients Follow-up (mo) No. sessions (mean/median) Outcomes Recurrence Progressors Madisch et al Case series CE: 69 (98) 8 (12) 0 (2005) 38 Sharma et al RCT (APC vs (2006) 39 MPEC) APC: 19 MPEC: CE: 12 (63) CE: 12 (75), PZ.49 NR 0 Manner et al Case series CE: 37 (62) (2006) 40 Bright et al RCT (APC vs (2007) 41 surveillance) APC: 20 (1 LGD) Surveillance: CE: 14 (70) P Z (43) 1 (1 LGD) 2 (2 HGD) Mork et al Case series 25 (2 LGD) 30 4 CE: 21 (84) 14 (66) 0 (2007) 42 Ferraris Case series CE: 94 (98) 17 (18) 0 et al (2007) 43 Formentini Case series CE: 21 (100) 6 (28.5) 0 et al (2007) 44 Bright et al RCT (APC vs (2008) 45 surveillance) APC: 27 (1 LGD) Surveillance: CE: 18 (67) P! (50) 0 2 (2 LGD) LGD Morris et al Case series CE dysplasia: (2001) 25 9 (100) Kahaleh et al Case series CE: 4 (57) IM 5 (71), (2002) 27 LGD 1 (14) 0 Familiari et al Case series CE: 19 (100) NR 0 (2003) 31 Ragunath et al (2005) 46 RCT (APC vs PDT) APC: 13 (12 LGD, 1 HGD) PDT 13: (11 LGD, 2 HGD) 12 5 CE IM: 2 (15), CE dysplasia: 8 (62) CE IM: 2 (15), CE dysplasia: 10 (77), PZNS 1 1 NR 1 (1 EAC) HGD/EAC Van Laethem Case series 10 (7 HGD, 3 et al (2001) 47 EAC) CE HGD: 6 (86), CE EAC: 3 (100) 0 1 (1 EAC) Morris et al Case series CE dysplasia: 9 (100) (2001) 25 Attwood et al Case series 29 (29 HGD) 37 2 CE HGD: 25 (86), CE (2003) 48 IM: 22 (76) 0 4 (4 EAC) NDBE, Nondysplastic Barrett s esophagus; CE, complete eradication; LGD, low-grade dysplasia; HGD, high-grade dysplasia; NS, not significant; NR, not reported; NA, not available; EAC, esophageal adenocarcinoma; RCT, randomized, controlled trial; APC, argon plasma coagulation; PDT, photodynamic therapy; ALA, aminolevulinic acid; MPEC, multipolar electrocoagulation; IM, intestinal metaplasia. Food and Drug Administration (2 mg/kg administered intravenously 48 hours before photoradiation), whereas 5-ALA is used in Europe (60 mg/kg taken orally 4 hours before photoradiation). Light is delivered to the Barrett s tissue with either bare cylindrical diffusing fibers or balloon diffusing fibers. To avoid skin and other mucosal photosensitivity, patients need to avoid light after the procedure. This technique has primarily been used for the management of BE patients with HGD and esophageal adenocarcinoma. Table 7 32,33,46,60-75 summarizes Volume 71, No. 1 : 2010 GASTROINTESTINAL ENDOSCOPY 151

6 Ergonomics and GI endoscopy Wani et al TABLE 5. Characteristics of multipolar electrocoagulation in Barrett s esophagus Author (y) Study design No. patients Follow-up (mo) No. sessions (mean/median) Outcomes Recurrence Progressors NDBE Sharma et al (1999) 50 Case series CE: 11 (100) 3 0 Montes et al (1999) 51 Case series CE: 14 (100) Sampliner et al (2001) 52 Case series CE: 45 (78) NR NR Dulai et al RCT (APC vs (2005) 36 MPEC) APC: 26 MPEC: CE: 15 (58) CE: 17 (65), PZ.57 Sharma et al (2006) 39 RCT (APC vs MPEC) APC: 19 MPEC: CE: 12 (63) CE: 12 (75), PZ.49 NR 0 NDBE, Nondysplastic Barrett s esophagus; CE, complete eradication; NR, not reported; RCT, randomized, controlled trial; APC, argon plasma coagulation; MPEC, multipolar electrocoagulation. TABLE 6. Characteristics of laser therapy studies in Barrett s esophagus Author (y) Study design Laser therapy No. patients Follow-up (mo) No. sessions (mean/median) Outcomes Recurrence Progressors Barham Case series KTP NR 11 (69) 0 et al (1997) 53 Salo et al (1998) 54 Case series Nd:YAG CE IM: 11 (100) Gossner et al Case series KTP 8 (4 LGD, 4 HGD) CE IM, dysplasia: (1999) 55 8 (100) Weston et al Case series Nd:YAG 9 (9 HGD) CE IM: 6 (67), CE (2002) 56 HGD: 7 (78) 2 (25) 0 Fisher et al Case series Nd:YAG 31 (10 NDBE, (2003) LGD, 5 HGD) CE IM: 21 (68) 8 (26) 1 (1 EAC) Bowers et al Case series KTP CE IM: 8 (89) 1 0 (2003) 58 KTP, Potassium titanyl phosphate; NR, not reported; Nd:YAG, neodymium:yttrium-aluminum-garnet; CE, complete eradication; IM, intestinal metaplasia; LGD, low-grade dysplasia; HGD, high-grade dysplasia; NDBE, nondysplastic Barrett s esophagus; EAC, esophageal adenocarcinoma. the studies describing the efficacy of PDT in this patient population. Radiofrequency ablation Ablation with this technique involves a balloon-based catheter (HALO 360 ; Barrx Medical, Sunnyvale, Calif) that delivers high-energy pulse to the esophageal lining resulting in circumferential burn. This system consists of a highpower energy generator, a sizing balloon catheter, and balloon-based ablation catheters with different outer diameters on full inflation. A preset amount of radiofrequency energy is delivered through the electrodes over the balloon resulting in circumferential superficial tissue destruction over a length of 3 cm. An energy density of 10 to 12 J/cm 2 and 2 applications result in an ablative injury that reaches but does not go beyond the muscularis mucosae. 76,77 A focal radiofrequency ablation (RFA) system (HALO 90 ) is also available for ablation of residual BE after circumferential RFA, and other eradication therapies have been used. The studies describing the efficacy of RFA in the treatment of BE patients (NDBE, LGD, and HGD) are highlighted in Table Cryotherapy This is a noncontact method of ablation that results in tissue injury to the esophageal epithelium at a depth of 2mm. 14,17 It uses low-pressure liquid nitrogen spray delivered through a 7F catheter passed through the working channel of a standard upper endoscope (CryoSpray Ablation System; CSA Medical, Inc, Baltimore, Md). The other 152 GASTROINTESTINAL ENDOSCOPY Volume 71, No. 1 :

7 Wani et al Ergonomics and GI endoscopy TABLE 7. Characteristics of photodynamic therapy studies in Barrett s esophagus subdivided based on histological grade of dysplasia Author (y) Study design Method No. patients Follow-up (mo) No. sessions (mean/median) Outcomes Recurrence Progressors NDBE Kelty et al (2004) 32 RCT (APC vs PDT) 5-ALA APC: 34 PDT (5-ALA): CE: 33 (97) CE: 17 (50), P!.0001 Hage et al RCT (APC (2004) 33 vs PDT) 5-ALA APC: 14 (3 LGD) PDT (5-ALA): 26 (5 LGD) CE: 5 (36) CE: 5 (19), PZNS NR 0 LGD Ortner et al Case series 5-ALA CE dysplasia: 5 (71) 1 0 (2002) 60 Ragunath et al (2005) RCT (APC vs PDT) Porfimer sodium APC: 13 (12 LGD, 1 HGD) PDT 13: (11 LGD, 2 HGD) 12 5 CE IM: 2 (15), CE dysplasia: 8 (62) CE IM: 2 (15), CE dysplasia: 10 (77), PZNS 1 1 NR 1 (1 EAC) Overholt et al Case series Porfimer (1999) 61 sodium CE IM: 7 (50), CE dysplasia: 13 (93) 0 1 (1 HGD) Ackroyd Case series 5-ALA CE IM: 0 (0), CE et al (2003) 62 dysplasia: 40 (100) 1 1 (1 EAC) Overholt et al (2003) 63 Case series Porfimer sodium with supplemental Nd:YAG CE IM: 10 (71), CE dysplasia: 13 (93) NR 0 HGD Gossner Case series 5-ALA CE IM: 0 (0), CE: et al (1998) 64 dysplasia: 10 (100) Overholt Case series Porfimer sodium CE IM: 32 (43), CE et al (1999) 61 HGD: 66 (90) CE dysplasia: 58 (79) Wolfsen et al (2002) 65 Case series Porfimer sodium with supplemental APC CE IM: 19 (56), CE HGD: 34 (100) NR 0 May et al Case series 5-ALA, mthpc CE HGD: 12 (100) NR NR (2002) 66 Javaid et al Case series mthpc CE IM: 1 (17), CE (2002) 67 HGD: 6 (100) CE dysplasia: 4 (67) Overholt et al (2003) 63 Case series Porfimer sodium with supplemental Nd:YAG CE IM: 43 (53), CE HGD: 62 (77) NR 3 Wolfsen et al Case series Porfimer sodium CE IM: 36 (52) NR NR (2004) 68 Etienne et al Case series mthpc CE IM: 6 (100), CE (2004) 69 HGD: 6 (100) CE dysplasia: 6 (100) (continued on next page) Volume 71, No. 1 : 2010 GASTROINTESTINAL ENDOSCOPY 153

8 Ergonomics and GI endoscopy Wani et al TABLE 7 (continued) Author (y) Study design Method No. patients Follow-up (mo) No. sessions (mean/median) Outcomes Recurrence Progressors Lovat et al Case series mthpc CE HGD: 5 (71) 3 NR (2005) 70 Pech et al Case (2005) 71 series 5-ALA CE HGD: 34 (97) 6 2 (2 EAC) Weiss et al Case (2006) 72 series Porfimer sodium with supplemental APC/KTP CE IM: 4 (31), CE HGD: 7 (54), 0 4 (4 EAC) Overholt RCT Porfimer et al (2005) 73,y sodium PDT: 138 omeprazole: CE IM: 72 (52), CE HGD: 106 (77), CE dysplasia: 81 (59) CE IM: 5 (7), CE HGD: 27 (39), CE dysplasia: 10 (14), all P! (18 EAC) 20 (20 EAC) Overholt et al RCT Porfimer (2007) 74,z sodium Keeley et al Case (2007) 75 series Porfimer sodium PDT: 48 omeprazole: CE HGD: 106 (77) CE HGD: 27 (39), P!.0001 NR 21 (21 EAC) 20 (20 EAC) CE HGD: 5 (38) RCT, Randomized, controlled trial; APC, argon plasma coagulation; PDT, photodynamic therapy; 5-ALA, 5-aminolevulinic acid; mthpc, meta-tetrahydroxyphenyl chlorine; KTP, potassium titanyl phosphate; CE, complete eradication; IM, intestinal metaplasia; NS, not significant; NR, not reported; EAC, esophageal adenocarcinoma; LGD, low-grade dysplasia; HGD, high-grade dysplasia. y2-year data. z5-year data. device approved for cryoablation (Polar Wand; GI Supply, Camp Hill, Pa) uses carbon dioxide, which results in freezing of target tissue when it emerges from the end of the catheter. This technique requires a decompression tube to be placed in the gastric lumen to prevent overinflation. Cryotherapy induces biological tissue destruction by rapid freezing, resulting in failure of cellular metabolism and creation of a hyperosmotic extracellular environment drawing fluid from cells, followed by thawing leading to disruption of intracellular structures and ischemic necrosis. Delayed cell death by apoptosis has been shown in cells located at the periphery of the cryogenic lesion. 17 A transparent cap may be used to better target difficult areas and avoid fogging of the endoscopic lens. Of all the endoscopic therapies described, there is the least amount of experience with this technique, although initial results have been promising EMR EMR involves local snare excision of the neoplastic lesion and has been increasingly used because it is safe and allows accurate histopathological grading. Several EMR techniques have been described in the treatment of BE-associated neoplasia, including strip biopsy, 90 inject and cut (lift and snare and simple snare technique), 91,92 cap-assisted EMR, 93,94 and ligate and cut technique (multiband mucosectomy). 95,96 The latter 2 techniques have been compared: both are relatively similar in terms of safety, efficacy, and depth of the resected specimen. 97 The multiband mucosectomy technique is a more efficient way to perform piecemeal resections without having to withdraw the endoscope to place each snare, but the resection specimens are marginally smaller. 96 Conceptually, the role of EMR can be categorized into 2 groups: (1) diagnostic and staging tool and (2) therapeutic and curative treatment option. Studies describing the efficacy of various EMR techniques are highlighted in Table , EFFICACY OF ERADICATION THERAPIES NDBE Although all ablative techniques have been used in the treatment of NDBE, APC, MPEC, and RFA are the most widely studied techniques. Several prospective case series have demonstrated the feasibility and safety of APC in the eradication of NDBE. Unfortunately, considerable variation exists between studies in terms of energy used, endpoints (eg, complete vs partial eradication, percentage of reduction of the BE 154 GASTROINTESTINAL ENDOSCOPY Volume 71, No. 1 :

9 Wani et al Ergonomics and GI endoscopy TABLE 8. Characteristics of radiofrequency ablation studies in Barrett s esophagus subdivided based on histological grade of dysplasia Author (y) Study design No. patients Follow-up (mo) No. sessions (mean/median) Outcomes Progressors NDBE Sharma Case series CE: 48 (69) et al (2007) 78 PE: 17 (24) NR: 5 (7) 0/70 LGD Roorda et al (2007) 83 Case series CE: 6 (46) NR Fleischer et al (2008) 79 Case series CE: 60 (97) 0/62 Sharma et al (2008) 85 Case series (circumferential) CE dysplasia: 1.9 (focal) 10 (100) CE IM: 9(90) 0/10 Shaheen et al (2009) 84 Sham-controlled RCT RFA 42 Sham CE dysplasia: RFA: 38 (90.5) vs 5 (22.7), LGD/HGD 2/42 P!.001, NNT 1.5; CE IM: 34 (81) vs 1 (4.5), P!.001, NNT 1.3 LGD/Ca 0/42 Sham: LGD/HGD 3/22 LGD/Ca 0/22 HGD Ganz et al (2008) 80 Case series 92 previous EMR CE HGD: 90.2% CE dysplasia: 80.4% CE IM: 54.3% 0/92 Shaheen et al (2009) 84 Sham-controlled RCT RFA: 42 Sham: 21 Studies with NDBE, LGD, and HGD CE dysplasia: 34 (81) vs 4 (19) P!.001, NNT 1.6 CE IM: 31 (73.8) vs 0(0), P!.001, NNT 1.4 RFA: HGD/Ca 1/42 Sham: HGD/Ca 4/21 Roorda et al (2007) 83 Case series 7 (LGD 4, HGD 3) CE dysplasia: 5 (71) NR Pouw et al (2008) 82 Case series 44 (HGD 32, LGD 10, NDBE 2 31/44 EMR) 21 1 (circumferential) 2 (focal) CE dysplasia and IM: 1/44 (2) 43 (98) Hernandez et al (2008) 81 Case series 13 (HGD 1, LGD 2 NDBE 7) CE dysplasia: 100% CE IM: 70% 0/13 NDBE, Nondysplastic Barrett s esophagus; CE, complete eradication; PE, partial eradication; NR, nonresponder; LGD, low-grade dysplasia; IM, intestinal metaplasia; RFA, radiofrequency ablation; NNT, number needed to treat; HGD, high-grade dysplasia; RCT, randomized, controlled trial; Ca, cancer. segment), duration of follow-up, and surveillance protocols. Complete eradication rates have ranged from 36% to 100%, with recurrence rates ranging from 0 to 68% (Table 4). Madisch et al 38 reported a complete eradication rate of 98% in a cohort of 70 patients treated with APC, with a recurrence rate of 12% at a median follow-up of 51 months. In contrast, Mork et al 42 reported a complete eradication rate of 84% in 25 patients treated with APC, with a recurrence rate of 66% during a median follow-up of 30 months. Another case series that included 94 patients treated with APC reported a complete eradication rate of 72% at a mean follow-up of 12.5 months. 30 The number of randomized, controlled trials comparing APC with other ablative modalities is limited. In a randomized, controlled trial, Sharma et al 39 compared APC and MPEC in the long-term efficacy of achieving complete BE eradication. After 2 years, there was no difference in the complete eradication rates between the 2 treatment modalities (APC 63% vs MPEC 75%, PZ.49). There was no difference in the mean number of sessions between Volume 71, No. 1 : 2010 GASTROINTESTINAL ENDOSCOPY 155

10 Ergonomics and GI endoscopy Wani et al TABLE 9. Characteristics of EMR studies in Barrett s esophagus patients with high-grade dysplasia and early esophageal adenocarcinoma Author (y) Study design No. patients Follow-up (mo) No. sessions (mean/ median) Outcomes Recurrence Progressors Seewald et al Case series 12 (3 HGD, 9 EAC) CE IM, dysplasia, EAC: 12 (2003) 92 (100) Giovannini et al Case series 21 (12 HGD, 9 EAC) 18 2 CE IM: 15 (75) (2004) 91 CE HGD/EAC: 17 (86) 2 (2 HGD) 0 Conio et al (2005) 94 Case series 39 (35 HGD, 4 EAC) CE HGD/EAC: 34 (87) 1 (1 HGD) 0 Peters et al (2006) 93 Case series 39 (25 HGD, 14 EAC) 11 3 CE IM: 33 (89) CE HGD/EAC: 37 (95) Larghi et al (2007) 99 Case series 24 (19 HGD, 5 EAC) CE IM: 21 (87) CE HGD/EAC: 24 (100) 1 (1 EAC) 0 Lopes et al (2007) 100 Case series 41 (18 HGD, 23 EAC) CE IM: 31 (76) CE HGD/EAC: 37 (90) 15 (5 EAC, 10 BE) 0 Pech et al (2008) 101 Case series 279 (48 HGD, 231 EAC) CE EAC: 225 (95.7) CE HGD: NA 49 (49 EAC) 0 HGD, High-grade dysplasia; EAC, esophageal adenocarcinoma; CE, complete eradication; IM, intestinal metaplasia; BE, Barrett s esophagus; NA, not available. the 2 groups (APC 3 vs MPEC 4, PZnot significant [NS]). No significant predictors associated with complete remission of BE were identified. Similar results were also obtained by another randomized, controlled trial comparing these 2 modalities. 36 A randomized, controlled trial comparing APC with PDT using 5-ALA in 68 NDBE demonstrated higher complete eradication rates in patients treated with APC (97% vs 50%, P!.0001) at a median follow-up of 12 months. 32 In another article reporting the long-term results (median follow-up 68 months) of a randomized, controlled trial comparing APC with endoscopic surveillance after antireflux surgery, complete eradication was achieved in 8 of 20 (40%) in the APC group compared with 4 of 20 (20%) in the surveillance group. 45 Progression to HGD was noted in 2 patients in the surveillance group, whereas 1 patient in the APC group progressed to LGD. Similar to APC, complete eradication rates for MPEC have ranged from 65% to 100% (Table 5). Montes et al 51 reported a complete eradication rate of 100% in 14 patients treated with MPEC during a mean follow-up of 21.6 months. Conversely, Sampliner et al, 52 in a larger series of patients with NDBE (58 patients, mean follow-up 6 months) reported a complete eradication rate of only 78%. The initial circumferential balloon-based RFA ablation was conducted in 2 serial phases: dosimetry and effectiveness phase. In the effectiveness phase, complete eradication of intestinal metaplasia was achieved in 48 of 70 (69%) patients at 12-month follow-up. 78 In a follow-up study of the same cohort of patients that incorporated the focal ablative device to treat residual BE postcircumferential RFA, complete eradication of BE was achieved in 97% of patients at 30-month follow-up (mean number of sessions 1.9). 79 Limited data exist on the efficacy of cryoablation in this patient population. In a pilot study of 11 BE patients (5 NDBE, 5 LGD, 1 HGD) who underwent a mean of 4.2 sessions, 9 patients (78%) had complete eradication of intestinal metaplasia with complete eradication of dysplasia achieved in all patients at 6-month follow-up. 86 LGD Studies focusing on various endoscopic therapies in this patient population are limited. Trials have frequently included some patients with LGD in the NDBE group, making it difficult to estimate the impact of endoscopic treatment in LGD patients. Furthermore, randomized, controlled trials and studies comparing various endoscopic therapies are rare. In a case series of 19 LGD patients treated with APC, complete eradication of dysplasia was achieved in all patients at a median follow-up of 12 months. 31 In a randomized, controlled trial, Ragunath et al 46 compared the efficacy of APC and PDT (porfimer sodium) in the ablation of patients with dysplastic BE. Both techniques were equally efficacious in achieving complete eradication of intestinal metaplasia (APC 15% vs PDT 15%, PZNS) and dysplasia (62% vs 77%, PZNS). Most studies of the efficacy of PDT in the treatment of this patient population have been case series, and they achieved rates of complete eradication of dysplasia of 71% to 100%. Ackroyd et al 62 reported a complete eradication of dysplasia rate of 100% in 40 LGD patients treated with oral 5-ALA that was maintained at a follow-up of 53 months. Similarly, Overholt et al GASTROINTESTINAL ENDOSCOPY Volume 71, No. 1 :

11 Wani et al Ergonomics and GI endoscopy reported a complete eradication of dysplasia rate of 93% in 14 patients treated with PDT (sodium porfimer) at a mean follow-up of 50.7 months. More recently, in a multicenter, prospective, shamcontrolled, randomized, trial in which subjects with dysplastic BE were assigned 2:1 to either treatment with RFA or a sham procedure. A total of 127 patients were randomized (84 RFA, 43 sham). This trial included 64 patients with LGD (42 RFA, 22 sham). Complete eradication of LGD was achieved in 90% in the RFA group compared with 23% in the sham group (P!.001), and complete eradication of intestinal metaplasia was achieved in 81% vs 4% (P!.001). However, 2 patients in the RFA group progressed to HGD during the trial period. 84 In a case series of 10 LGD patients treated with RFA (circumferential and focal ablation), complete eradication of dysplasia was achieved in all patients, and complete eradication of metaplasia was achieved in 90% of patients at 2-year follow-up. 85 In a follow-up study, the same authors reported a 2-year followup of 39 LGD patients treated with circumferential and focal RFA. Complete eradication of dysplasia was achieved in 95% of patients, and complete eradication of intestinal metaplasia was achieved in 87% of patients. None of the patients progressed to HGD or cancer. 102 HGD AND EARLY CANCER EMR With the increasing therapeutic armamentarium for endoscopic therapies in BE patients with HGD/early cancer, accurate staging is critical and herein lies the importance of diagnostic EMRs. Although EUS has been used to estimate cancer depth, its accuracy has varied in different studies. Standard EUS at 7.5 or 12 MHz accurately predicts the depth of invasion in only 50% to 60% of cases, and high-frequency catheter probes tend to overstage early lesions, leading to overall disappointing and variable results. 103 In a recent large study that compared highresolution endoscopy with high-frequency US catheter probes in 100 patients with early esophageal cancer, the latter was accurate in diagnosing only 2 of 14 patients with submucosal tumor invasion. Overall, there was no significant difference between the 2 techniques in assessing tumor penetration. 104 When using EMR, the depth of tumor invasion can be established by histological criteria that allow clinicians to treat HGD or early cancers using endoscopic therapies with greater confidence. EMR specimens are significantly larger and allow more precise assessment of depth of tumor invasion into the mucosa and submucosa compared with biopsy specimens. Larghi et al, 105 in a series of 40 patients undergoing EMR (25 HGD, 15 EAC), reported that 6 of 25 (24%) patients diagnosed initially with HGD were upgraded to mucosal EAC and 6 of 15 (40%) patients with mucosal EAC were upgraded to invasive EAC. In a recent systematic review, it was shown that EMR was superior to mucosal biopsy as a diagnostic tool and resulted in a diagnosis change in approximately 25% of the patients with HGD/early cancer (either upstaging or downstaging of the lesions). 106 An inaccurate diagnosis could have substantial deleterious consequences for the patient. A patient with benign disease could be subjected to esophagectomy, or a patient with submucosal invasion could undergo endoscopic therapy instead of surgery. Based on the potential to make an accurate histological diagnosis, EMR should be considered as the first step in the management of BE-associated neoplasia before EET. The quality of evidence for this recommendation is moderate, and the strength of recommendation is strong. Therapeutic EMR Recently, the role of complete removal of BE in patients with HGD/early EAC by using EMR has been explored. This technique involves the endoscopic resection of the entire BE, including the neoplastic lesion. It also allows complete histological correlation and may provide a more sustained treatment response during follow-up. EMR can be considered therapeutic if the lesion is confined to the mucosa and clear margins of resection (lateral and basal) are obtained. No randomized, controlled trials comparing EMR with other endoscopic therapies exist. Review of the published literature suggests that the rates of complete eradication of intestinal metaplasia and dysplasia are 75% to 100% and 86% to 100%, respectively , A recent study by the Wiesbaden group provided long-term results on the efficacy and safety of endoscopic treatment in 349 BE patients with HGD and early EAC (61 HGD, 288 early EAC). 101 The majority of patients (nz279) underwent therapeutic EMR. Overall, complete eradication of HGD/early EAC was achieved in 97%, with a longterm eradication rate of 94.5% (mean follow-up 63.6 months). A recurrence rate of 21.5% was reported during the follow-up; 85% of these patients received further endoscopic eradication treatment and achieved a second complete remission. Risk factors associated with recurrence included piecemeal resection (relative risk [RR] 2.4; 95% CI, ]), long-segment BE (RR 1.9; 95% CI, ), no mucosal ablative therapies of BE after complete remission (RR 2.5; 95% CI, ), time until complete remission achieved of more than 10 months (RR 0.3; 95% CI, ), and multifocal neoplasia (RR 2.1; 95% CI, ). This highlights the importance of complete eradication of intestinal metaplasia and not just areas of HGD/EAC. Analysis of data for patients with early EAC treated only by EMR demonstrated a long-term complete remission rate of 95.7% (221 of 231 patients); the overall 5-year survival rate was 84%. In a recent study, Peters et al 93 evaluated the efficacy of this technique in 39 BE patients with early neoplasia (25 HGD, 14 EAC). Complete eradication of early neoplasia Volume 71, No. 1 : 2010 GASTROINTESTINAL ENDOSCOPY 157

12 Ergonomics and GI endoscopy Wani et al was achieved in all patients (mean number of 3 sessions) and complete removal of BE in 89% of patients. During a median follow-up of 11 months, none of the patients had a recurrence of intestinal metaplasia or dysplasia. Another case series of 41 BE patients (18 HGD, 23 EAC) describing the efficacy of circumferential BE resection reported complete remission rates for metaplasia and dysplasia/cancer of 76% and 90%, respectively. At a mean follow-up of 31.6 months, BE recurred in 10 (24.4%) and early EAC in 5 (12.2%). 100 PDT Of all the endoscopic techniques, PDT clearly has been used most extensively and reported in a randomized, controlled trial. Overholt et al 73,74 were the first to provide long-term results of a randomized, controlled trial that compared 2 competing treatment alternatives in HGD patients. In this study, 208 patients with HGD were randomized 2:1 to receive either omeprazole alone or omeprazole with sodium porfimer PDT. Patients in the PDT arm received a maximum of 3 courses over 5 years, with each course of PDT separated by at least 3 months. All patients were followed by an intensive endoscopic surveillance biopsy protocol, and pathologists at 1 center blindly assessed biopsy specimens. Patients requiring intervening therapy or those who progressed to cancer were considered treatment failures. At the end of 2 years, the results showed a significant difference in favor of the group that was treated with PDT along with omeprazole compared with omeprazole only for complete eradication of HGD (77% vs 39%, P!.0001) and occurrence of cancer (13% vs 20%, P!.006). 73 All patients who completed the first 2 years of the trial per protocol were eligible for follow-up, and of the 102 patients eligible for long-term follow-up, only 61 patients (PDT 48, omeprazole 13) were enrolled in the long-term followup phase. Intent-to-treat analysis showed that, at 5 years, PDT was significantly more effective than omeprazole alone in eradicating HGD (77% [106/138] vs 39% [27/ 70], P!.0001) with a significant difference between survival curves favoring PDT (PZ.004). Patients in the PDT group were less likely to progress to cancer compared with those in the omeprazole group (15% vs 29%, PZ.027), although the trial was not designed to test this outcome. 74 Similarly, in a single-center study, Overholt et al, 63 in their long-term follow-up report (mean follow-up 58.5 months) on 103 BE patients with early neoplasia, showed that complete eradication of HGD wasachievedin94%ofthepatients. Similar efficacy rates have been reported for 5-ALA in the treatment of BE with HGD, with complete eradication rates ranging from 97% to 100%. In addition, several modeling studies have suggested that PDT is a cost-effective treatment option for BE patients with HGD compared with surveillance and esophagectomy RFA RFA is the only other technique besides PDT that has been evaluated in a multicenter, prospective, sham-controlled, randomized trial in BE patients with dysplasia that included 63 patients with HGD (42 RFA, 21 sham). 84 Complete eradication of dysplasia was achieved in 81% in the RFA arm (mean number of sessions 3.5) compared with 19% in the sham group (P!.001), and complete eradication of intestinal metaplasia was achieved in 74% versus 0% (P!.001) with progression to cancer in 1 patient in the RFA arm. In a multicenter registry, 142 BE patients with HGD underwent RFA (24 underwent previous EMR, 5 of whom demonstrated intramucosal adenocarcinoma). At 1-year follow-up of 92 patients, complete eradication of HGD was achieved in 90% of patients, complete eradication of dysplasia in 80%, and complete eradication of intestinal metaplasia in 54% of patients. 80 In another study that included 24 HGD patients treated with circumferential and focal RFA, complete eradication of dysplasia was achieved in 79% of patients and complete eradication of intestinal metaplasia in 67% of patients. 102 APC Experience with APC in the treatment of BE with HGD has been reported in small observational studies. Attwood et al, 48 in a series of 29 patients with HGD treated with APC, reported complete eradication of dysplasia and intestinal metaplasia in 86% and 76% of patients, respectively. At a mean follow-up of 37 months, 4 patients developed cancer, 3 of whom continued with ablation therapy and 1 of whom died of unrelated causes. In another case series that included 7 patients with HGD, complete eradication of HGD and intestinal metaplasia were achieved in 6 and 4 patients, respectively; however, 1 patient died of EAC. 47 Cryoablation Data on the efficacy of cryoablation in the management of HGD patients are limited and published in abstract form. 89 One article included only 1 patient with HGD. 86 Further long-term efficacy data on this technique are eagerly awaited. Multimodality EET Multimodality EET involves removal of the lesion with the highest histological grade by using EMR followed by eradication of the remaining Barrett s epithelium by using mucosal ablative techniques such as PDT, RFA, cryoablation, and APC. There are limited data on the efficacy of multimodality therapies in the management of this patient population. Ablation therapy with PDT has been used as an adjunct to EMR in eradicating the remaining BE segment and thus potentially reducing the risk of recurrent neoplastic lesions. A prospective study (EMR with PDT) in 33 BE patients reported that endoscopic treatment was successful in 93% of the cases, and although 5 patients 158 GASTROINTESTINAL ENDOSCOPY Volume 71, No. 1 :

13 Wani et al Ergonomics and GI endoscopy had a recurrence of HGD, all were successfully resected with EMR. 110 At a median follow-up of 19 months, 93% of the endoscopically treated patients were in remission. Another retrospective cohort study that included 116 patients with HGD and intramucosal cancer (59 HGD, 57 cancers) treated with PDT (26% underwent previous EMR) found complete remission of HGD and intestinal metaplasia rates of 53% and 41%, respectively, at 12-month follow-up. 111 As an extension of the above-mentioned study, the Wiesbaden group also reported complete eradication rates in 200 (136 APC, 64 PDT) of the 349 BE patients with HGD and early EAC treated with multimodality EET for the eradication of all BE to prevent the development of metachronous neoplasia. 101 The vast majority (86%) achieved complete eradication of BE after a mean of 3.1 sessions (range 1-12), with 14% still under treatment at the time of publication. A significantly lower number of patients in the multimodality group developed metachronous neoplasia compared with patients treated with EMR alone (16.5% vs 29.9%, PZ.0014). Metachronous neoplasia developed only in patients with residual Barrett s mucosa in the multimodality group. In a recent study, the Amsterdam group reported a complete eradication of dysplasia and intestinal metaplasia in 43 of 44 (98%) patients (32 HGD, 10 LGD, 2 NDBE) after treatment with multimodality therapy (EMR plus RFA in 31 patients). 82 EET versus surgery Unfortunately, there are no data currently or expected in the foreseeable future that provide conclusive evidence regarding treatment of BE-related neoplasia with EETcompared with surgical therapy. This important question has been addressed mainly by 2 observational studies. In a recent retrospective study that compared longterm survival in a large cohort of patients with HGD, 129 patients were treated with multimodality therapy (PDT with 80% patients undergoing adjunctive EMR) and 70 treated with esophagectomy. 112 Patients treated with EET had a significantly worse performance status making them less likely to be surgical candidates, were older, and had longer BE lengths. Complete eradication rates of HGD at 1- and 3-year follow-up between the EET and surgical groups were 88% and 86%, respectively, with similar overall mortality rates (9% vs 8.5%, PZ.76) during a median follow-up period of 59 and 61 months, respectively. In the surgical arm, the postoperative morbidity and mortality rates were 38% and 1.4%, respectively. In the EET group, cancer developed in 8 patients (6.2%) and 1 patient had a perforation after dilation of a post- PDT stricture that required partial esophagectomy. Another study analyzed cancer-free survival in patients with early esophageal cancer managed with either endoscopic therapy or surgical resection. 113 Using the Surveillance Epidemiology and End Results database of the National Cancer Institute, the authors identified 742 patients with early esophageal cancer, 13% of whom underwent endoscopic therapy. There was no difference in the esophageal cancer-specific mortality in the endoscopic group compared with the surgical group (relative hazard 0.89; 95% CI, , P Z.68). COMPLICATIONS OF EETs Complications are an important issue, especially if consideration is given to these therapies for the endoscopic eradication of low-risk lesions, ie, patients with NDBE. A variety of complications (including life-threatening) have been reported with EETs. In a systematic review and meta-analysis that assessed the incidence of strictures after ablative therapy, Wei et al 114 reported that the highest risk of esophageal stricture formation after ablative therapy was associated with PDT with porfimer sodium (35%) followed by laser ablation (4.5%), APC (3.2%), and MPEC (0.9%). The rate of stricture formation was 30% in the randomized, controlled trial that compared PDT with surveillance in the management of HGD patients. 74 In a retrospective, single-center study of HGD patients undergoing PDT, a history of esophageal stricture (odds ratio [OR] 2.7; 95% CI, ), performance of EMR before PDT (OR 2.7; 95% CI, ), and more than 1 PDTapplication in 1 treatment session (OR 2.2; 95% CI, ) were identified to be the predictors for stricture formation post-pdt. 115 In another retrospective review of 116 patients who underwent treatment with PDT, an overall incidence of strictures was 23%. The length of BE, multiple PDT courses, and the presence of intramucosal carcinoma on pretreatment pathology were independent predictors of post-pdt stricture, whereas EMR did not appear to influence the likelihood of stricture development after porfimer sodium-based PDT. 116 Strictures post-emr have mainly been described in patients undergoing circumferential EMR. 93,95 Rates of strictures described in patients treated with RFA have ranged from 0% to 6% EMR-related major complications include bleeding (w10%) and perforation (!1%) , Similar rates of bleeding (0%-14%) have been reported for mucosal endoscopic ablative therapies, and cases of perforation have been described with all techniques as well. Minor complications of endoscopic therapies include chest pain (APC: 0%-90%, PDT: 0%-88%, MPEC: 0%-38%, RFA: 0%-13%) and odynophagia (APC: 0%- 100%, PDT: 0%-92%, RFA: 0%-50%) ,60-75,78-85 Use of PDT has also been associated with photosensitivity (0%- 69%) and pleural effusions. 32,33,46,60-75 Subsquamous glands and associated dysplasia is a complication that has been described after EETand implies the presence of squamous mucosa completely covering underlying Barrett s metaplasia or dysplasia. Based on this systematic review, the rates of subsquamous glands range from 0 to 30%. Pathologically, subsquamous glands show Volume 71, No. 1 : 2010 GASTROINTESTINAL ENDOSCOPY 159

14 Ergonomics and GI endoscopy Wani et al features similar to those of both pretreatment and postablation residual nonsubsquamous BE, and the majority of foci demonstrate intestinal-type epithelium (containing goblet cells). 117,118 Variable results in the frequency of subsquamous glands can be attributed to the lack of standardization in the basic definition of subsquamous glands, variation in sampling protocol, tangential specimens, stripping of biopsy samples, and the lack of detailed histological analysis. A detailed evaluation for subsquamous glands is important given the risk of neoplastic progression (although the magnitude of this risk is not well characterized) and hence continued surveillance endoscopy after EET is required. Development of occult EAC from subsquamous glands has been reported. 119,120 Using biopsy samples from patients enrolled in the HGD ablation trial using PDT plus omeprazole versus omeprazole alone, Bronner et al 121 conducted a detailed histological analysis to assess the extent of subsquamous glands after PDT. Histological assessment of more than 33,000 biopsy samples showed no difference in subsquamous glands between the 2 groups when compared per patient (30% vs 33%, PZNS) or per biopsy (0.5% vs 1.3%, PZNS). Although reassuring, this study did not provide any information on the number of biopsy samples that were truly full thickness in nature (demonstrating basal cell layer), allowing an accurate assessment of the prevalence of subsquamous glands. The presence of any intestinal metaplasia is important, and the focus entirely on subsquamous glands can be misleading. The data on the biological properties of subsquamous glands are sparse. Hornick et al 122 demonstrated that subsquamous glands post-pdtshowed reduced crypt proliferation and absence of DNA content abnormalities compared with pre-pdt biopsy samples. Conversely, Krishnadath et al 123 showed that despite pathological downstaging after PDT in 3 BE patients with HGD, increased proliferation and aneuploidy recurred in all patients. The cancer risk of subsquamous glands needs to be defined in future long-term studies. Finally, and more importantly, progression to cancer despite EET has been reported. In a recent systematic review and meta-analysis, 43 cases of esophageal cancers were encountered in patients who underwent endoscopic ablation with baseline histology: 37 of 611 HGD, 2 of 239 LGD, and 4 of 1457 NDBE. 124 This again underscores the importance of surveillance post-eet. PATIENT SELECTION: WHO ARE CANDIDATES FOR EET? Despite several challenges associated with the reading of dysplasia in BE patients (such as sampling error, interobserver variability, and focal presence), at present, the documentation of dysplasia on endoscopic biopsy samples remains the sole predictor of progression to cancer. 125 In multiple studies, the degree of dysplasia has been shown to correlate with the risk of developing EAC; the presence of HGD is associated with the greatest risk. 126 Overall, complete eradication rates of NDBE for the various endoscopic therapies have been variable, ranging from 35% to 100%, with equally variable recurrence rates. Endoscopists are frequently faced with the conundrum of whether NDBE patients should undergo endoscopic eradication given the increasing incidence of EAC. There are several reasons why endoscopic ablation of NDBE cannot be recommended at present. 1. The risk of cancer in BE is low. 127 In a recent large multicenter cohort of BE patients, Sharma et al 128 showed that the incidence of cancer was 1 in 212 patient-years of follow-up (0.5% per year). 2. EET is attempted with the ultimate goal of decreasing cancer risk. In a recent systematic review and metaanalysis, Wani et al 124 determined the cancer incidence in BE patients after ablative therapy and compared these rates with those of cohort studies of BE patients not undergoing ablation. The natural history pooled data showed a cancer incidence of 5.98 per 1000 patient-years (95% CI, ) in NDBE patients, whereas the weighted incidence rate was 1.63 per 1000 patient-years (95% CI, ) in NDBE patients undergoing EET. When comparing the weighted incidence rate of ablative groups with those of historical surveillance controls, an approximate number needed to treat with EET to prevent 1 case of EAC in a given year for NDBE was estimated at Endoscopic therapies are associated with well-defined risks and complications (esophageal strictures, perforation, bleeding). Further, the cost-effectiveness of ablation of NDBE patients has not been demonstrated. In fact, cost-effectiveness models have demonstrated that even endoscopic surveillance may not meet the current criteria for incorporation into clinical practice Recurrence of intestinal metaplasia post EET and the risk of subsquamous glands (see above) are associated with all ablative therapies requiring routine surveillance of these patients The data on the durability of endoscopic therapies are limited along with sparse data on the impact of EET on biomarkers in the neosquamous epithelium None of the reported studies in this patient population have conclusively demonstrated that EET results in a decreased cancer risk. 7. There is a distinct difference in the efficacy demonstrated in clinical trials and the effectiveness of the EET in clinical practice. There are several challenges that need to be addressed such as training, learning curve, uniform follow-up, and availability of advanced imaging techniques that have become an integral part of endoscopic treatment of BE patients GASTROINTESTINAL ENDOSCOPY Volume 71, No. 1 :

15 Wani et al Ergonomics and GI endoscopy Based on the low incidence of cancer in patients with NDBE, the prohibitively large number of patients required to be treated to prevent 1 case of cancer, the lack of long-term durability of the neosquamous epithelium and effectiveness data, and the need for surveillance, EETof NDBE is not recommended. The quality of evidence for the above recommendation, that is, not to perform EET in patients with NDBE, is low and the strength of recommendation is strong. There are several important issues that need to be borne in mind before endoscopic therapies are routinely recommended in the management of BE patients with LGD. These include the following. 1. The natural history of LGD is highly variable and the incidence of EAC ranges from 0.6% to 1.6% per year. Studies frequently reported a small number of patients with short duration of follow-up. In addition, it is difficult to differentiate between prevalent and incident cancers, and data are fraught with selection and referral bias. 132 Preliminary results of a large, multicenter, cohort study that identified 245 BE patients with LGD who were followed for a mean period of 4.5 years showed an annual incidence of cancer of 0.6% (95% CI, ), a rate similar to the risk of cancer in patients with NDBE Because limited data are available on complete eradication rates for LGD and intestinal metaplasia, post- EET surveillance is required. 3. None of the reported studies in this patient population demonstrated that EETs result in a decreased cancer risk. 4. High interobserver variability exists among pathologists in the diagnosis of LGD. 134 Thus, LGD appears to be a poor marker for progression of BE to EAC and identification of LGD patients at risk of progression to HGD/cancer (using clinical, endoscopic, and biomarker profiles) should be a priority. Based on the variable natural history of LGD in patients with BE (probable rates of progression similar to those of NDBE), high interobserver variability among pathologists, the and lack of quality data with long-term follow-up, EET is not recommended. The quality of evidence for this recommendation, ie, not to perform EET in BE patients with low-grade dysplasia, is low and the strength of recommendation is strong. It seems that there are 2 groups of patients who could benefit most from EET. 1. Those with documented HGD. In the BE group, those with HGD have the highest risk of the development of EAC. In a recent meta-analysis by Rastogi et al, 126 the pooled incidence of EAC in HGD patients was 6.58% per year (95% CI, ), suggesting that cancer could potentially develop in approximately 25% to 30% of patients with BE-associated HGD over the next 5 years. The use of EET in HGD patients is supported by the results of 2 randomized, controlled trials comparing EET with surveillance. 74,84 2. Patients with early EAC. For EET to be successful in cancer patients, only mucosal EAC patients (T1a) should be considered, given the extremely low risk (0%-3%) of lymph node metastasis in this situation. 135 The successful use of EET in patients with mucosal EAC has been documented in several small case series and a large cohort study of more than 200 patients (4.5 years of follow-up; 85% 5-year survival). However, once the cancer invades into the submucosa (T1b), the risk of lymph node metastases increases to 20% to 25%; EET for cure cannot be recommended in this patient group. Recently, the Wiesbaden group did attempt EET in a selected group of patients with low-risk T1b cancers; those with invasion of the upper third of submucosa (sm1), absence of infiltration into lymph vessels/veins, histological grade G1/2, and macroscopic type I/II. 136 Although initially EET was able to achieve complete remission in 18 of 19 (95%) patients during a mean follow-up of 62 months (range months), recurrent or metachronous carcinomas were found in 5 patients (28%), all successfully treated with repeat EET. EET is a viable option in the management of BE with HGD and intramucosal EAC. The quality of evidence for the use of EET in BE patients with HGD is moderate and the strength of recommendation is strong. APPROACH TO A PATIENT BEING CONSIDERED FOR ABLATION The approach to a patient being considered for EET starts with a thorough grading and staging of the BE segment using high-quality endoscopes. The availability of advanced endoscopic imaging techniques (high-resolution/ high-definition endoscopy, narrow band imaging, autofluorescence imaging, and confocal microscopy) has significantly affected the detection and characterization of early and subtle mucosal lesions. The extent of the BE segment should be recorded carefully using the Prague C & M criteria, 137 and all visible lesions should be classified using the Paris criteria. 138,139 Mucosal abnormalities should be identified, undergo target biopsy, and be endoscopically resected. The distinction between mucosal (tumor limited to the lamina propria) and submucosal (invasion into the submucosa or beyond) EAC is crucial given that the likelihood of lymph node and/or hematogenous dissemination in patients with intramucosal cancer is extremely low. BE specimens obtained by EMR are significantly larger, allow a distinction between mucosal and submucosal disease, have significantly improved interobserver reliability on neoplasia recognition, and can lead to a change in the management of patients with BE neoplasia. The biopsy and EMR specimens should be reviewed by at least 2 Volume 71, No. 1 : 2010 GASTROINTESTINAL ENDOSCOPY 161

16 Ergonomics and GI endoscopy Wani et al expert pathologists (given the high interobserver variability in the diagnosis of dysplasia) for the presence of dysplasia (nondysplastic vs LGD vs HGD) or cancer (limited to the mucosa, the upper third of the submucosa or beyond, presence of lymphatic/vascular invasion, and degree of differentiation). Although EUS can be performed mainly to rule out lymph node disease, it does not replace endoscopic resection as a diagnostic tool in these patients. After the diagnosis of HGD/early EAC is confirmed, the patient should be counseled regarding his or her options for management including watchful waiting (for HGD only), esophagectomy, and EET. Patients considering EET need to be counseled about the need for multiple procedures, potential complications, lack of long-term data, risk of recurrent lesions and/or progression to invasive EAC, and plans for continued surveillance (possibly lifelong) after EET. Because BE-associated HGD and early EAC are relatively uncommon, gaining experience in the imaging and EET of these lesions should be confined to high-volume centers, and the majority of the endoscopists will not encounter sufficient numbers of such cases in their clinical practice. Thus, for optimal results, patients should be referred to institutions with expertise in these novel imaging techniques and endoscopic therapies. The goal should be to eliminate the entire mucosa at risk (ie, the entire BE segment) by using EMR either alone (as both a diagnostic and therapeutic tool) and/or in combination with mucosal ablation. FUTURE DIRECTIONS Given the uncertainties in the management of HGD, it is important that randomized, controlled trials are conducted to help guide therapy for patients. Unfortunately, head-to-head comparisons of the various treatment options are limited or burdened by their retrospective design. In addition, most trials were conducted at expert centers with limited long-term follow-up data available. Conclusive evidence of the superiority of EET could only be provided by a randomized, prospective study that compares endoscopic therapy with surgical resection. Although this, in principle, would be ideal, justifying a study like this would be very difficult in view of the promising results of endoscopic therapies, the large number of patients required to show the noninferiority of endoscopic therapy, patients not wishing to be confronted with such widely differing strategies, and the risk of unplanned crossovers that will make interpretation of results very complex. Nevertheless, future prospective, multicenter, observational studies could confirm these results. Biomarkers may help predict the response to EET in the future. A recent proof-of-principle prospective study evaluated various biomarkers by using fluorescence in situ hybridization in 126 patients (71 PDT, 55 controls) to determine predictors of response to PDT defined as the absence of dysplasia at surveillance biopsies 3 months after PDT. 140 Biomarkers assessed included 9p21 (site of the p16 gene) and 17p13.1 (p53 gene) loci; gains of the 8q24 (c-myc), 17q (HER2-neu), 20q13 loci, and cells were assessed for loss or gain of chromosomes (aneusomy and polysomy). Significant predictors of response to PDT included shorter BE segment length (OR 0.71; 95% CI, ), PDT (OR 7.1; 95% CI, ), and p16 allelic loss (OR 0.32; 95% CI, ). 140 Thus, the study of molecular biomarkers of cancer progression could not only allow us to identify the group at high risk of progression of BE to cancer but also potentially predict the response to endoscopic therapies. Future studies should focus on improving current technology that may allow us to achieve eradication of BE and BE-associated dysplasia in an efficient manner with fewer sessions and lower complication rates. The development of improved devices to manage and reduce complications associated with EET is highly desirable. SUMMARY AND CONCLUSIONS Multimodality EET is here to stay as a viable treatment option for BE patients with HGD and early mucosal EAC. Alternative treatment approaches, including esophagectomy, should be discussed with these patients; however, a paradigm shift in which the endoscopist plays a major role in the management of BE-related neoplasia seems inevitable. After careful examination of the BE segment by using advanced imaging techniques, EET starts with a diagnostic EMR in this group of patients because EMR has been shown to alter staging. In patients with positive deep margins and/or extensive submucosal invasion, surgical resection is advised, whereas patients with EAC and HGD confined to the mucosa can be treated endoscopically. Short, noncircumferential extents of BE (Prague grade C0M!3) can be eradicated with continued EMR in an effort to resect the entire BE area, whereas in those with longer, circumferential BE segments, a combination of EMR with mucosal ablation should be applied. The therapeutic objective of EET should be the complete treatment and removal of all neoplastic and metaplastic epithelium. At this time, close surveillance of these patients after EET is recommended to identify recurrent lesions. Local availability of equipment for enhanced imaging and endoscopic therapies, the expertise of the endoscopist, the experience of the pathologist in the histopathological evaluation of the resected specimens, and the expertise of the surgeon are all important variables in determining the optimal management of patients with BE undergoing EET. Conversely, the subgroup of BE patients without dysplasia and/or those with LGD should not undergo EET outside of study protocols until further data are available regarding the risks and benefits. 162 GASTROINTESTINAL ENDOSCOPY Volume 71, No. 1 :

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20 Ergonomics and GI endoscopy Wani et al 124. Wani S, Puli SR, Shaheen NJ, et al. Esophageal adenocarcinoma in Barrett s esophagus after endoscopic ablative therapy: a metaanalysis and systematic review. Am J Gastroenterol 2009;104: Odze RD. Diagnosis and grading of dysplasia in Barrett s oesophagus. J Clin Pathol 2006;59: Rastogi A, Puli S, El-Serag HB, et al. Incidence of esophageal adenocarcinoma in patients with Barrett s esophagus and high-- grade dysplasia: a meta-analysis. Gastrointest Endosc 2008;67: 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: Sharma P, Falk GW, Weston AP, et al. Dysplasia and cancer in a large multicenter cohort of patients with Barrett s esophagus. Clin Gastroenterol Hepatol 2006;4: Inadomi JM, Sampliner R, Lagergren J, et al. Screening and surveillance for Barrett esophagus in high-risk groups: a cost-utility analysis. Ann Intern Med 2003;138: Dvorak K, Ramsey L, Payne CM, et al. Abnormal expression of biomarkers in incompletely ablated Barrett s esophagus. Ann Surg 2006;244: Sharma P, Falk GW, Sampliner RE, et al. Management of non dysplastic Barrett s esophagus: where are we now? Am J Gastroenterol 2009; 104: Wani S, Mathur SM, Sharma P. How to manage a Barrett s esophagus patient with low-grade dysplasia. Clin Gastroenterol Hepatol 2009;7: Wani S, Falk G, Sampliner RE, et al. Low-grade dysplasia (LGD) is a poor marker for cancer progression in patients with Barrett s esophagus (BE): preliminary results from a large, multicenter, cohort study. Gastroenterology 2009;136:A Montgomery E, Bronner MP, Goldblum JR, et al. Reproducibility of the diagnosis of dysplasia in Barrett s esophagus: a reaffirmation. Hum Pathol 2001;32: Stein HJ, Feith M, Mueller J, et al. Limited resection for early adenocarcinoma in Barrett s esophagus. Ann Surg 2000;232: Manner H, May A, Pech O, et al. Early Barrett s carcinoma with low-- risk submucosal invasion: long-term results of endoscopic resection with a curative intent. Am J Gastroenterol 2008;103: Sharma P, Dent J, Armstrong D, et al. The development and validation of an endoscopic grading system for Barrett s esophagus: the Prague C & M criteria. Gastroenterology 2006;131: The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon: November 30 to December 1, Gastrointest Endosc 2003;58:S Endoscopic Classification Review Group. Update on the Paris classification of superficial neoplastic lesions in the digestive tract. Endoscopy 2005;37: 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: Received June 23, Accepted July 18, Supported by the Veterans Affairs Medical Center, Kansas City, Missouri. Current affiliations: Division of Gastroenterology and Hepatology, Veterans Affairs Medical Center and University of Kansas School of Medicine, Kansas City, Missouri, USA. Reprint requests: Prateek Sharma, MD, Gastroenterology (111), Department of Veterans Affairs Medical Center, 4801 E. Linwood Blvd., Kansas City, MO GASTROINTESTINAL ENDOSCOPY Volume 71, No. 1 :