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www.expert-reviews.com ISSN 1473-7140© 2009 Expert Reviews Ltd10.1586/14737140.9.3.303

Natural historyBarrett’s esophagus (BE) is the replacement of the squamous epithelium that normally lines the distal esophagus by columnar-lined epithe-lium. This is thought to occur when chronic gastroesophageal reflux damages the squamous esophageal mucosa leading to a metaplastic process in which columnar cells replace squa-mous mucosa [1]. The development of esopha-geal adenocarcinoma is a multistep process that seems to involve progression through increasing grades of dysplasia (metaplasia to low-grade dys-plasia [LGD] to high-grade dysplasia [HGD]) to invasive carcinoma, thus making surveillance for progression to adenocarcinoma possible [2–6]. However, it has been shown that this does not

always occur in a linear manner; some will not progress through the depicted continuum of dysplasia, some will remain stable and other lesions may even regress [7,8]. Thus, the risk for carcinogenesis should be considered to occur in a probabilistic rather than linear manner [9]. The rate of progression from nondysplastic intesti-nal metaplasia (IM) to dysplastic and then to adenocarcinoma is not well understood. In a cohort of 1376 patients diagnosed with IM for the first time, 91 (6.6%) had adenocarcinoma at the time of their index endoscopy, 42 (3%) had HGD and 101 (7.3%) had LGD. The vast majority, 1142 patients (83.1%), had no dyspla-sia. When patients without dysplasia were fol-lowed for a mean of 4.1 years, 2% subsequently

Jennifer D McAllaster, Daniel Buckles and Mazin Al-Kasspooles†

†Author for correspondenceAssociate Professor of Surgery, Surgical Oncology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Mailstop 2005, Kansas City, Kansas 66160, USA Tel.: +1 913 588 6565 Fax: +1 913 588 7540 mal-kasspooles@kumc.edu

The incidence of esophageal adenocarcinoma is increasing in the USA, now accounting for at least 4% of US cancer-related deaths. Barrett’s esophagus is the main risk factor for the development of esophageal adenocarcinoma. The annual incidence of development of adenocarcinoma in Barrett’s esophagus is approximately 0.5% per year, representing at least a 30–40-fold increase in risk from the general population. High-grade dysplasia is known to be the most important risk factor for progression to adenocarcinoma. Traditionally, esophagectomy has been the standard treatment for Barrett’s esophagus with high-grade dysplasia. This practice is supported by studies revealing unexpected adenocarcinoma in 29–50% of esophageal resection specimens for high-grade dysplasia. In addition, esophagectomy employed prior to tumor invasion of the muscularis mucosa results in 5-year survival rates in excess of 80%. Although esophagectomy can result in improved survival rates for early-stage cancer, it is accompanied by significant morbidity and mortality. Recently, more accurate methods of surveillance and advances in endoscopic therapies have allowed scientists and clinicians to develop treatment strategies with lower morbidity for high-grade dysplasia. Early data suggests that carefully selected patients with high-grade dysplasia can be managed safely with endoscopic therapy, with outcomes comparable to surgery, but with less morbidity. This is an especially attractive approach for patients that either cannot tolerate or decline surgical esophagectomy. For patients that are surgical candidates, high-volume centers have demonstrated improved morbidity and mortality rates for esophagectomy. The addition of laparoscopic esophagectomy adds a less invasive surgical resection to the treatment armanentarium. Esophagectomy will remain the gold-standard treatment of Barrett’s esophagus with high-grade dysplasia until clinical research validates the role of endoscopic therapies. Current treatment strategies for Barrett’s esophagus with high-grade dysplasia will be reviewed.

Keywords: argon plasma coagulation • Barrett’s esophagus • endoscopic mucosal resection • esophagectomy • high-grade dysplasia • minimally invasive esophagectomy • photodynamic therapy • radiofrequency ablation

Treatment of Barrett’s esophagus with high-grade dysplasiaExpert Rev. Anticancer Ther. 9(3), 303–316 (2009)

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developed adenocarcinoma, 3.6% HGD and 16.1% LGD [10]. A Veterans Administration cohort study demonstrated that patients with dysplasia on index biopsy were more likely to have disease progression [11]. The highest risk for the development of esopha-geal adenocarcinoma is HGD and it is estimated that 30–59% of patients with HGD progress to esophageal adenocarcinoma within 5 years [12,13].

In addition to the high rate of esophageal adenocarcinoma development in patients with HGD, unexpected cancer has been found in up to 50% of esophageal resections for HGD [14–16]. Controversy exists as to whether this high number of occult malignancies in esophagectomy specimens results from progres-sion of HGD to adenocarcinoma or from a missed cancer/sam-pling error on surveillance. Proponents of the latter theory have advocated more intensive surveillance biopsy protocols. Random biopsy of BE mucosa results in missed cancer in nearly 50% of cases [17,18]. Intensive surveillance biopsy protocols have resulted in improved identification of adenocarcinomas in BE with HGD [18,19]. However, a recent retrospective review by Williams et al. revealed a 29% occult malignancy rate in patients with HGD, despite an intensive 1-cm interval biopsy protocol [20].

The treatment of BE with HGD is highly dependent on path-ologic evaluation of endoscopic biopsy specimens. However, significant intra- and interobserver variability has been docu-mented [21,22]. A recent study from the Cleveland Clinic (OH, USA) evaluated interobserver variability between HGD and sub-mucosally invasive adenocarcinoma. Using kappa statistics, agree-ment rates between pathologists were as follows: overall agree-ment: fair; agreement for HGD: moderate; agreement for HGD that cannot exclude intramucosal adenocarcinoma: fair; agree-ment for intramucosal adenocarcinoma: fair; and agreement for sub mucosal adenocarcinoma: poor [23]. Discrepancy in pathologic biopsy specimens of BE adds to the controversial decision-making process regarding diagnosis and appropriate treatment, and high-lights the need to consult pathologists with significant expertise in this area before deciding on appropriate management.

EsophagectomyTraditionally, esophagectomy has been the standard treat-ment for BE with HGD. This practice is supported by studies revealing unexpected adenocarcinoma in 30–50% of esophageal resection specimens for HGD [14–16]. Despite improved and more intensive biopsy protocols, the risk of missed malignancy remains [20]. These occult cancers may be invasive and, ulti-mately, lead to death from metastatic disease [11,24,25]. Actuarial survival rates of patients undergoing esophagectomy subsequent to a surveillance endoscopy program are superior to those under-going no surveillance [26], illustrating the benefit of diagnosis and treatment at an early stage. Esophagectomy employed prior to tumor invasion of the muscularis mucosa results in 5-year survival rates in excess of 80% [27–29]. Although esophagectomy can result in improved survival rates for early-stage cancer, it is accompanied by significant mortality, ranging from 3 to 5%, as well as morbidity rates of 18–48% reported in the literature. However, this data is extrapolated from studies evaluating all

cases of esophagectomy, regardless of presence or stage of can-cer [24,30]. Recent studies of esophagectomy in patients with disease limited to early neoplasia (HGD or intramucosal neo-plasia) have demonstrated no mortalities and morbidity rates similar to those previously reported [15,24,25]. Based on these data, it has been advocated that data specifically derived from patients with HGD or intramucosal neoplasia should be used when comparing esophagectomy in this patient population to other treatment modalities, rather than combined mortality and morbidity rates for those with advanced disease [25]. Patient-satisfaction scores have exceeded 95% after esophagectomy [20] and centers with extensive experience (>ten cases per year) have demonstrated reduced mortality rates [31–34]. Esophagectomy is the only treatment modality that clearly prevents progression of HGD to cancer by definitively removing at-risk mucosa and, thus, remains the gold standard.

Although mortality rates from esophagectomy have been reduced at the hands of experienced surgeons at large-volume centers, morbidity rates remain a concern. A less-invasive approach has been sought to counter this problem. Cuschieri first introduced the minimally invasive esophagectomy in the 1990s via a thoracoscopic approach [35]. Since that time, multiple techniques have been described, including various combinations of laparoscopy or laparotomy with thoracoscopy or thoracot-omy, as well as trans-hiatal versus intrathoracic anastomoses. This minimally invasive approach has been found to be safe and associated with excellent perioperative outcomes [36]. Luketich and colleagues reviewed outcomes in 222 patients undergoing minimally invasive esophagectomy for HGD and cancer. A median intensive-care unit (ICU) stay of 1 day and hospital stay of 7 days are promising data points. A mortality rate of 1.4% was reported, comparable to that of open esophagectomy in the current literature. The rate of pneumonia (7.7%) is also favorable compared with that of open resection [37]. Nguyen and associates published outcomes of 104 patients undergoing minimally inva-sive esophagectomy. Median ICU and overall hospital stay were 2 and 8 days, respectively. A mortality rate of 2.9% and major complication rate of 12.5% is comparable to that of Luketich and colleagues [38]. The same group had previously compared outcomes of open esophagectomy versus minimally invasive esophagectomy. Minimally invasive esophagectomy resulted in shorter operative times, less blood loss, fewer transfusions, short-ened ICU days, shortened total hospital days and equal leak rates compared with open esophagectomy [39]. Although these data are promising, randomized trials evaluating the optimal minimally invasive approach and controlled trials of minimally invasive versus open procedures are needed.

Ablation techniquesAblative techniques are based on the theory that elimination of gastric reflux and removal of metaplastic premalignant tissue can prevent the development of Barrett’s-related adenocarcinoma. Ablation techniques can be divided into three separate categories: thermal (laser, argon and radiofrequency), photochemical (photo-dynamic) and mechanical (mucosal resection) [40]. These mucosal

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ablative techniques remove dysplastic lesions and, potentially, the entire metaplastic segment of BE at risk of potential dysplastic or neoplastic events [24].

Argon plasma coagulationArgon plasma coagulation (APC) was first introduced as a treat-ment modality for BE in 1997 [41]. APC ablates tissues by deliv-ering a high-frequency current to tissues via the flow of ionized argon gas, resulting in the coagulation of tissue surfaces to a depth of 2–3 mm [42–44]. The depth of tissue necrosis is limited by the decreased conductance of the thermally treated and dried tis-sue, thus limiting the depth of treatment and injury [45]. Current studies are subject to small study size and short-term follow-up. Multiple studies have evaluated APC as a treatment modality for BE with IM alone, but few studies have evaluated the utility of APC as a treatment modality for HGD or early neoplasia. No study evaluating APC in HGD has been subject to randomization. Variable complete remission rates ranging from 38 to 97% have been achieved in patients with Barrett’s IM with recurrence rates of 0–47% [46–53]. Common to many of the endoscopic treatment modalities is the development of subsquamous Barrett’s mucosa after treatment. Areas of Barrett’s metaplasia become ‘buried’ under the healing squamous epithelium and, thus, are obscured from visualization by the endoscopist. This metaplastic mucosa remains at risk for dysplastic events but is hidden from surveillance unless discovered on random biopsies. ‘Buried Barrett’s’ has been documented in APC; it is not a consistently reported outcome in all studies.

Ackroyd and colleagues randomized patients with BE who had previously undergone fundoplication to ablation with APC or surveillance. Complete ablation was achieved in 63% of patients (12 out of 19) in the ablation group versus only 15% (three out of 20) in the surveillance group. Buried glands were observed in 35% at the 1-month follow-up and decreased to 5% at the 1-year follow-up in the APC group [54]. The same group presented 5-year follow-up data of this cohort. Overall, 14 of the 20 patients (70%) treated with APC had more than 95% regression of their previous BE compared with five out of the 20 individuals in the surveillance group. Eight of the 20 treated patients had complete microscopic regression of Barrett’s metaplasia compared with three out of the 20 individuals in the surveillance group. Two patients developed stricture after APC treatment. Both complications were managed endoscopically. Two patients in the surveillance group progressed to HGD; whereas, no patients in the treatment group progressed. This study demonstrated superiority of APC versus surveillance with a minor associated side-effect profile [55]. Ferraris et al. reported on one of the largest study populations (96 patients) with a median follow-up of 36 months (range: 12–98 months). Patients were accrued from a large cohort of BE patients under endoscopic surveillance. The study group had documented acid suppression via either medical therapy or previous fundoplication. Disease in the study population was limited to IM. Complete BE ablation was achieved in 97.9% of patients (94 out of 96). A cumu-lative recurrence of BE occurred in 18% of individuals, which translated into an annual recurrence rate of 6.1%. There was no

evidence of dysplasia or adenocarcinoma on follow-up biopsies and no serious complications occurred [47]. Although this study dem-onstrates that APC can be utilized to ablate metaplastic tissue with a low incidence of complications, it does not address dysplastic tissue. Attwood and colleagues reported on one of the few series of APC as a treatment modality in HGD. In total, 29 patients underwent treatment. Overall, 22 out of 29 patients (75%) had complete regression to neosquamous mucosa. HGD responded in 86% of patients (25 out of 29). Attwood’s results provide one of the longest follow-up periods, with a mean of 37 months (range: 7–78 months) and eight patients followed beyond 5 years. Four patients (14%) progressed to adenocarcinoma after APC treat-ment. Esophageal perforation occurred in one patient and the patient subsequently died after resection. No post-treatment strictures occurred [56].

Available data for APC lack sufficient study size and randomiza-tion. A wide variation in efficacy of APC in the eradication of BE has been reported in the literature [46–52]. Overall, local remis-sion was achieved in 70–100% of patients [42,57–60]. Few studies have been undertaken that include HGD in the treatment arm of APC. Progression to esophageal adenocarcinoma and death due to perforation have occurred in patients undergoing APC [58,60]. Outcome reporting, such as complete local remission, relapse rate and management of relapse of metaplasia or dysplasia, and report-ing of complications must be standardized in order to compare studies. Future studies addressing these issues must be undertaken to further evaluate the role of APC in the treatment of HGD. At this juncture, APC should only be used to treat BE with HGD within the confines of a well-defined trial.

Photodynamic therapyPhotodynamic therapy (PDT) is an ablative treatment for rap-idly proliferating tissues, including dysplastic and malignant lesions [61]. Three elements are essential to PDT: a chemical pho-tosensitizer, light and oxygen. The photosensitizer is taken up by tissues and retained preferentially in neoplastic cells through an unknown mechanism [62]. Endoscopic delivery of light of the proper wavelength to the targeted tissues produces an oxidative photochemical reaction that results in mucosal destruction [63]. Various photosensitizers have been studied, all with different preferential light absorption spectra. Porfimer sodium is the only agent approved for systemic use in the USA. 5-aminolevulinic acid is cleared only for topical use in the USA and, thus, will not be reviewed [64].

Overholt and colleagues first described the results of PDT in combination with acid suppression in 1993 [65]. The same group later reported on one of the largest study populations to date, with 100 patients followed for 4–48 months (mean: 19 months) after PDT. Laser therapy was used in combination with PDT to treat small islands of Barrett’s mucosa. Complete elimination of Barrett’s mucosa was seen in 43%. Dysplasia was eliminated in 78%. Ten out of 13 malignancies were ablated. In total, 13 patients with BE and intramucosal adeno carcinoma were included in the study. Of these 13, three were found to have per-sistent malignancy. One subsequently died of noncancer-related

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causes. The remaining two were found to have lymph node involvement at surgical resection. Two patients with HGD devel-oped cancer after PDT. Only HGD was found at subsequent surgical resection. The most common complication was stricture (34%); however, all responded to endoscopic management [66]. Panjehpour et al. reported elimination of HGD in 95% of cases and 100% elimination of intramucosal cancer with PDT. Laser ablation was required in 19 out of 60 patients for insufficient response or skipped areas after initial PDT. Stricture was found to be the most common complication. The study evaluated the effect of oral prednisone on stricture formation with no differ-ence between the PDT-only versus the PDT plus prednisone group, with rates of 16 and 29%, respectively. Patients receiving subsequent courses of PDT for residual disease were at higher risk of stricture formation when there was overlap of the treat-ment fields [67]. Wolfsen et al. studied 102 patients with HGD or intramucosal carcinoma. Patients were given one PDT treatment and subsequently thermoablated with an argon beam coagula-tor for any persistent or recurrent disease. Complete ablation of glandular epithelium was achieved in 56% of individuals (76% of intramucosal carcinoma and 52% of HGD). Similar to the aforementioned studies, stricture formation accounted for the majority of complications (20%). An overall complication rate of 41% was reported, with complications ranging from stricture, photocutaneous toxicity, atrial fibrillation, congestive heart fail-ure and esophageal perforation [68]. A multicenter, randomized controlled study evaluated PDT plus omeprazole versus ome-prazole alone in 200 patients with HGD. The 5-year follow-up results represent the longest series to date. The PDT arm received a maximum of three PDT courses over 5 years. Courses of PDT were separated by at least 3 months. At 1-year follow-up, PDT treatment resulted in complete elimination of Barrett’s mucosa in 41% and elimination of HGD in 72%. Development of adenocarcinoma was significantly less in the PDT treatment group than with omeprazole alone (15 vs 29%) [69]. Ragunath et al. randomized 13 patients to each study arm comparing PDT versus APC in the management of HGD. These two modali-ties were found to be equally effective in eradicating Barrett’s mucosa, but PDT was more effective in eradicating dysplasia, with 77% eradication of HGD at 1 and 12 months versus 62 and 67%, respectively, for APC. PDT was also associated with a lower incidence of buried glands (one out of 13 versus two out of 13 individuals); however, a larger study is needed to lend any relevance to this finding [70,71].

Photodynamic therapy is a promising technique, with com-plete resolution of HGD in 52–95% of cases [65–68]. Drawbacks include a significant rate of esophageal stricture, residual dys-plasia, IM and residual subsquamous Barrett’s mucosa (bur-ied Barrett’s; Table 1) [65–71]. Adenocarcinoma with lymph node involvement has progressed from dysplasia in patients under-going PDT [66]. Buried Barrett’s, incomplete dysplasia abla-tion and subsequent carcinoma development require careful endoscopic surveillance after porfimer sodium PDT [62]. These short comings have led to the continued pursuit of a more ideal endoscopic resection technique.

Radiofrequency ablationIn recent years, catheters have been developed that are designed to deliver thermal energy to the esophageal mucosa with radi-ofrequency. This device is now commercially available under the trade name HALO and is manufactured by Barrx Medical. This modality has been utilized to ablate BE with and with-out dysplasia. Energy delivery is automated and rapid at a pre-defined depth, using balloon-based (HALO360) and plate-based (HALO90) devices [40,72–75]. The balloon is inflated under endo-scopic visualization using balloons with different diameters that allow esophageal mucosal contact to be optimized, while attempting to minimize the risk of esophageal trauma due to over distention [74]. The main advantage of this approach is a uniform and circumferential ablation at a defined depth (limited to the muscularis mucosa) [40,72–75].

Initial work documented the safety parameters of radio frequency ablation (RFA) as well as its effectiveness. Ganz et al. evaluated RFA energies in porcine esophageal epithelium. Treatments at 12 J/cm2 resulted in no submucosal injury or stricture [73]. Further dosing regimens in humans prior to undergoing esophagectomy also revealed no submucosal injury at 10–12 J/cm2 [74]. Dunkin et al. reported similar findings, with complete ablation of human esophageal epithelium at 8, 10 and 12 J/cm2 without submu-cosal injury. Complete epithelial ablation occurred in the zones treated with 10 and 12 J/cm2. The maximum depth of injury extended to the muscularis mucosa [75]. The clinical effectiveness of this modality as a tool for the ablation of IM with dyspla-sia has been investigated in the ongoing Ablation of Intestinal Metaplasia (AIM) trials. These trials were conducted in two serial phases: the first a dosimetry phase and the second an effective-ness phase. The initial phase evaluated the dose response and safety of delivering RFA of 6–12 J/cm2 to the mucosa of patients with BE without dysplasia. Patients were enrolled to dosing regi-mens of 6-, 8-, 10- and 12-J/cm2 treatment groups. All patients underwent esophagogastroduodenoscopy and biopsy at 1 and 3 months to monitor for acute adverse events and to halt dose escalation to the next sequential dose if serious adverse events occurred. The first enrolled patient exhibited no effect at a dose of 6 J/cm2 and, thus, the enrollment of subjects at this setting was terminated. Treatment effect was seen at 8 J/cm2 and all further doses. Complete histological remission rates at 3 months were 30 and 36% for the 10- and 12-J/cm2 groups, respectively, superior to those of the lower energy groups (0% complete histo-logical remission for both 6- and 8-J/cm2-treatment groups). There were no major adverse events in the higher energy treat-ment groups and symptoms were transient. No buried glandular mucosa was demonstrated. Subsequently, the effectiveness trial was based on dosing at 10 J/cm2. In the effectiveness portion of the study (AIM-II), 70 patients were treated. Patients underwent ablation at baseline, followed by endoscopy and biopsy at 1, 3, 6 and 12 months. A second ablation was performed at 4 months for any patient with residual BE at 1 or 3 months. Residual BE was present in 36 out of 70 patients after one treatment, and these patients subsequently received an additional treatment at the same settings. At 12 months, 70% of patients demonstrated complete

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remission of BE. Again, no major complications or buried glan-dular mucosa occurred in the study population [76]. This trial has been extended indefinitely with the addition of a focal ablation device (HALO90). Fleischer et al. reported the 30-month follow-up results of the addition of the focal ablation device. In total, 61 out of the 69 patients with residual IM in the AIM trial under-went subsequent focal ablation. At 30-month follow-up biopsies, complete remission of IM was achieved in 98% of individuals (60 out of 61 patients). No strictures and no buried glandular mucosae were detected at the follow-up biopsy [77]. Roorda et al. evaluated the safety and efficacy of RFA in BE combined with aggressive proton pump inhibitor (PPI) therapy. A total of 13 patients (one with intramucosal cancer [TisNO], two with HGD, four with LGD and six with non dysplastic BE) underwent RFA after exten-sive pretreatment evaluation, including esophageal motility, pH monitoring during PPI therapy, CT scan, endoscopic ultrasound (EUS) and endoscopic mucosal resection (EMR; discussed later) for nodules. Repeat ablation was performed if residual disease was documented at 3-month follow-up endoscopy. A mean of 1.4 ablation sessions was performed. Complete elimination of dysplasia was achieved in 71% of individuals (five out of seven patients). Ablation efficacy was found to be better in those with maximal pH control. No buried glands, stricture or major com-plications occurred [40]. Hernandez et al. reported similar results, with 70% complete eradication and 30% partial eradication of BE in a prospective study of the first ten patients to complete the 1-year follow-up. Patients were maintained on double-dose PPI throughout treatment. Endoscopy was performed at 3 and 12 months post ablation, with repeat ablation for residual BE. No major complications occurred. One case of buried Barrett’s metaplasia was detected, the first reported in a RFA series [72]. The AIM Dysplasia Trial, the first randomized study evaluating RFA, evaluated the technique compared with a sham procedure, with interim results available in abstract form. This multicenter trial evaluated 127 patients with BE and dysplasia, with 58 reaching the end point at the time of abstract publication. Patients were stratified according to degree of dysplasia, as documented by one central pathology institute. Patients were then randomized to RFA or a sham procedure. Stepwise circumferential and focal ablation was carried out in the treatment arm, with a maximum of four treatment sessions. One stricture occurred in the treatment arm that resolved with dilation. There were no major complica-tions in the treatment arm. The study showed clear superiority of RFA compared with a sham procedure. In the HGD subgroup, complete clearance was obtained in 67% of individuals (ten out of 15 patients) with RFA and 0% of individuals (none out of seven patients) in the control group. In the LGD subgroup, 96% of individuals (23 out of 24 patients) had complete clearance of dysplasia compared with 33% of individuals (four out of 12 patients) in the control group. IM was completely cleared in 60% of the HGD group and 83% of the LGD group, compared with no clearance of IM in the control groups [78]. Although the final data have not been published, Pouw reported further results of the AIM Dysplasia Trial, citing 85% clearance of dysplasia with RFA (24% in the sham treatment arm) and 77% clearance of

IM (0% in the sham arm). Progression of dysplasia occurred in 4.7% of patients in the treatment arm; LGD to HGD in two out of 39 and HGD to early cancer in one out of 25 patients. Five patients presented with stricture, all of which were managed endoscopically. No perforations or deaths occurred [79]. Ganz and colleagues evaluated one of the largest patient cohorts of BE with HGD. A total of 142 patients with BE and HGD underwent cir-cumferential RFA. EMR was performed prior to RFA if a nodular lesion was present. Complete remission of HGD was achieved in 90% of patients. Complete remission of all dysplasia was docu-mented in 80% of individuals, with 54% complete remission of IM. One asymptomatic stricture occurred that did not require treatment. No buried glands were identified. Esophagectomy was performed in two patients. One patient had persistent HGD at the 3-month follow-up biopsy and elected for esophagectomy, with intra mucosal cancer (IMC) on final pathology. One patient was found to have IMC at the 3-month follow-up endoscopy and, subsequently, underwent esophagectomy; surgical pathology revealed IMC [80].

Two small, prospective series by Gondrie et al. using the com-bination of EMR and RFA using the HALO360 and HALO90 have resulted in promising results. The first series reported on 11 patients with BE and dysplasia (two with LGD and nine with HGD). All visible lesions were removed endoscopically prior to ablation. After resection, persistence of dysplasia and absence of invasive cancer was confirmed with biopsy. Complete eradica-tion of Barrett’s mucosa was achieved in 100% of patients with a median of two circumferential ablations. Median follow-up revealed no recurrence. No adverse events, strictures or subsqua-mous Barrett’s mucosa were detected [81]. In a second prospective cohort, Gondrie et al. again achieved 100% eradication of dys-plasia and complete clearance of Barrett’s mucosa in 12 patients. The combination of EMR prior to ablation and endoscopic resec-tion of one persistent HGD after five ablation treatments was performed. One symptomatic stricture did result; however, it was felt to be due to piecemeal resection of a lesion as opposed to RFA. No subsquamous IM was detected [82]. These studies are summarized in Table 2.

Although these results of RFA, as well as from the combination of EMR and RFA, are very promising, they are limited by small sample sizes and limited follow-up periods. Extended follow-up studies and larger patient populations will be needed to further validate RFA as a standard treatment for BE. The present stud-ies reveal RFA to be very safe. Only one case of buried Barrett’s mucosa has been reported [72]. The addition of the focal ablation technique (HALO90) has improved eradication rates of dysplasia and metaplasia. Failures of treatment have occurred with docu-mented progression of disease in the above studies. As with all endoscopic treatment modalities, strict and diligent follow-up is mandatory.

Endoscopic mucosal resectionOne major disadvantage of thermal and photochemical ablative techniques is the lack of complete histopathologic evaluation of the diseased tissue prior to therapy. Thus, an occult malignancy

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2. R

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NA

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can be missed. Certain mucosal lesions of the esophagus can be entirely removed by EMR. This technique involves local snare excision of a mucosal lesion [83]. Usually, prior to resection, the mucosal and muscle layers are separated by injection of fluid (saline) into the submucosal layer, allowing for safer resection of the mucosal lesion by protecting the muscular layer from damage [83,84]. EUS should be performed prior to intervention to determine if the lesion is amenable to EMR by evaluating the size and depth of the lesion, the lack of invasion into the submu-cosal layer and the presence of lymphadeno pathy [83,85–87]. CT scanning is also employed to rule out metastatic disease. Surgical series have reported extremely low rates of lymph node involve-ment in intramucosal adenocarcinomas; thus, these lesions can often be endoscopically resected with curative intent [88,89]. Therefore, a local resection technique may be appropriate in patients with HGD or intramucosal adenocarcinoma.

The first report of EMR by Ell et al. studied 64 patients with BE with circumscribed HGD or intramucosal carcinoma. Patients were differentiated into low- and high-risk categories based on lesion diameter, macroscopic appearance and histologi-cal grades. Localized resection was undertaken with promising results: complete local remission was achieved in 97 and 59% of the low- and high-risk groups, respectively. One major complica-tion of bleeding was reported that was managed endoscopically. At a mean follow-up of 12 months, the incidence of recurrence or metachronous carcinomas was 14% [90]. The same group subsequently published results on a larger cohort with a longer follow-up period. No major complications were reported (per-foration or major bleed). Complete local remission was achieved in 99 out of 100 patients. During a mean follow-up period of 36.7 months, recurrent or metachronous carcinomas were found in 11% of patients. All recurrences were successfully treated with repeat endoscopic resection [91]. The prevalence of recurrence, as well as subsequent amenability to repeat endoscopic treatment, underscores the need for strict surveillance after endoscopic treatment. EMR is a technique that is most applicable to raised mucosal lesions and, as such, usually leaves residual Barrett’s mucosa and the potential for unrecognized synchronous lesions, as well as mucosa with the potential for future dysplastic events (metachronous lesions) [92]. Rates of recurrent or metachronous carcinomas have been reported to occur in 11–45% of patients undergoing localized EMR [93–99]. Attempts at completely eradi-cating all of the endoscopically visible IM have been performed. This can often be accomplished by sequentially resecting all of the IM with multiple sessions of localized EMR. This is most easily accomplished in patients with smaller areas of IM. For patients with areas of circumferential IM, successful resection of all of the underlying Barrett’s mucosa has been shown to be possible [100]. Complete removal of Barrett’s mucosa has been achieved with success rates of 62–100% with circumferential EMR, and recurrence rates of 0–12% [92,93,100,101]. However, serious complications occur frequently and generally limit the applicability of this as a therapeutic modality. Up to 30–40% of patients have been reported to develop esophageal strictures after circumferential EMR [93]. Larghi et al. reported data on patients

undergoing complete Barrett’s eradication by EMR in a patient population with BE and either HGD or intramucosal adeno-carcinoma, with a longer follow-up interval (median follow-up: 28 months). Persistent eradication of BE was demonstrated in 21 out of 24 patients (87.5%). Complications included immediate bleeding in two patients, managed endoscopically, and stricture in three patients that were all amenable to endoscopic dilation. In addition, buried Barrett’s was detected in two out of three cases of recurrence [102]. Table 3 summarizes these findings.

The major advantage of EMR in the evaluation of dysplastic Barrett’s lesions of the esophagus is improved histo pathologic staging. The management of patients with these lesions is highly dependent on accurate staging. EMR samples are generally larger and deeper than traditional biopsy samples obtained with for-ceps, allowing for the more precise assessment of the depth of tumor invasion in the submucosa. Nijhawan and Wang evalu-ated 25 patients with endoscopically visible nodular lesions and performed EMR. Final pathology revealed superficial adeno-carcinoma in 52% and HGD in 16% of patients. EMR changed staging when compared with EUS alone in 44% of patients [94]. Obviously, inaccurate staging can have significant implications for the patient, since lesions that invade into the submucosa (that have lymphatic drainage in the esophagus) have a significant risk of lymph node metastases, and these lesions should not be man-aged endoscopically. Therefore, every attempt should be made to combine EUS with EMR during the endoscopic evaluation of BE with HGD and esophageal adenocarcinoma.

The combination of EMR with PDT has been evaluated in patients with HGD and early adenocarcinoma. The first report by Buttar and colleagues evaluated the use of EMR and PDT in patients. EMR improved the staging in eight of these patients (47%). After a median follow-up of 13 months, 94% of patients were in remission and nine out of 17 (53%) had complete eradi-cation of Barrett’s mucosa, without any findings of subsqua-mous Barrett’s glands. Complications occurred in nine out of 17 patients without major complications of perforation or major bleed. Stricture accounted for the main complication, affecting 30% of the study population [95]. Other studies have revealed similar results of combined treatment with EMR and PDT, with complete local remission rates of 83–98%. A rate of 18–30% of recurrent and metachronous lesions, as well as failure of therapy to eradicate HGD or early adenocarcinoma, illustrates the need for diligent follow-up. Subsquamous Barrett’s mucosa has been reported in multiple studies [96–99]. May and colleagues advo-cate the prioritized use of EMR in order to obtain tissue for histological evaluation, with PDT as a useful complement to mucosal resection [97]. Other ablative techniques may also serve as treatment adjuncts for eradication of remaining BE after EMR.

Expert commentary The incidence of esophageal adenocarcinoma continues to increase in the USA and Western world. BE is known to be the most important risk factor for the development of esopha-geal adenocarcinoma and disease typically progresses through a sequence of metaplasia, to dysplasia to adenocarcinoma. This

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nd

osc

op

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uco

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do

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known progression allows for surveillance of at-risk patients and affords the opportunity for treatment of HGD. Esophagectomy has traditionally been the gold-standard treatment for HGD as it removes all dysplastic tissue, as well as all Barrett’s mucosa with dysplastic/neoplastic potential.

Recent studies have reported improved morbidity and mortal-ity rates of open esophagectomy compared with previous stud-ies with high-volume centers demonstrating superior results. The significant rate of unexpected adenocarcinoma found in esophagectomy specimens of HGD patients, including a 29% occult malignancy rate in patients subject to intensive surveil-lance programs, supports complete resection of at-risk mucosa. Given the possibility of disease recurrence, missed disease in subsquamous Barrett’s mucosa and progression to adenocar-cinoma in studies of endoscopic ablative techniques, open esophagectomy remains the gold-standard treatment for HGD. Minimally invasive esophagectomy has gained popularity and has been found to be comparable to open esophagectomy with regards to mortality and morbidity, with shorter ICU duration, hospital stay and improvement in rates of pneumonia. Results from minimally invasive esophagectomy are subject to a short follow-up duration and a lack of randomized trials with direct comparison to open esophagectomy.

Although successful, esophagectomy is not without signifi-cant morbidity and mortality, leading researchers to develop less-invasive techniques to intervene in the progression of dis-ease. These techniques include endoscopic ablation therapies. Reports of the efficacy of APC are widely variable, and the vast majority of studies evaluated patients with disease limited to IM. In studies including HGD, standard end points are lack-ing. Further studies are needed prior to the implementation of APC as an accepted treatment for HGD. PDT, likewise, has demonstrated success with eradication of HGD, intramucosal adenocarcinoma and Barrett’s mucosa. Complete resolution of HGD has been achieved in 52–95% of patients in clinical tri-als. Shortcomings of PDT include residual dysplasia, residual

subsquamous Barrett’s mucosa and the progression of dysplasia to carcinoma during treatment. RFA is the newest technique in the endoscopic thermal ablation armamentarium. Although cur-rent trials are limited by small sample sizes and short durations of follow-up, initial results have been promising, with complete eradication of Barrett’s mucosa and no recurrent disease found on repeat endoscopy.

The combination of EMR for nodular lesions with RFA of remaining IM seems to be emerging as an effective and clinically practical strategy. EMR has the advantage of a more accurate histo pathologic staging if disease can be completely removed. EMR has been shown to be effective in the removal of Barrett’s mucosa and the technique has been improved with the addi-tion of circumferential resection, with rates of complete eradi-cation of Barrett’s mucosa between 62 and 100%. However, a significant number of recurrences have been documented, as well as the development of subsquamous Barrett’s mucosa, underlining the need for diligent surveillance endoscopy after resection. Common to all endoscopic modality studies is a lack of randomized control data.

Although promising, all studies of endoscopic ablation tech-niques evaluate recurrence based on endoscopic surveillance. Given the high rate of occult cancer found in esophagectomy specimens, the accuracy of endoscopy to detect recurrence or residual disease has to be called into question. Ideally, a trial where all patients undergo esophagectomy to definitely ana-lyze the esophagus for the presence of disease after endoscopic mucosal ablative techniques is necessary to completely address this issue. Such a trial is unrealistic due to physician bias and poor patient accrual, since most patients with HGD will probably choose a less-invasive treatment modality.

Five-year viewThe high prevalence of BE virtually assures that the manage-ment of patients with HGD will remain an important clinical problem and focus of investigation in the short term. Adherence

Key issues

• The incidence of esophageal adenocarcinoma is increasing in the USA.

• Barrett’s esophagus results in a 30–40-fold increase in the risk of development of esophageal adenocarcinoma.

• High-grade dysplasia is the most important risk factor for progression to adenocarcinoma.

• Esophagectomy is the traditional treatment of Barrett’s esophagus with high-grade dysplasia, but is associated with significant morbidity and mortality.

• Morbidity and mortality rates of esophagectomy are superior at high-volume centers.

• Minimally invasive esophagectomy may result in a decreased hospital stay and fewer pulmonary complications.

• Endoscopic ablative techniques are an alternative to esophagectomy in high-risk surgical patients.

• Combination of endoscopic mucosal resection and thermal ablation allows for superior histological evaluation of tissue via endoscopic mucosal resection and the potential to further ablate residual Barrett’s mucosa at risk of synchronous or metachronous lesions.

• Esophagectomy remains the gold-standard treatment for Barrett’s esophagus with high-grade dysplasia.

• Endoscopic ablative modalities should be offered to patients:– Medically unfit for surgery

– Refusing surgical intervention

– Participating in clinical trials

– In institutional programs with rigorous and accurate surveillance protocols

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ReferencesPapers of special note have been highlighted as:•• of considerable interest

1 Spechler SJ. Clinical practice. Barrett’s Esophagus. N. Engl. J. Med. 346(11), 836–842 (2002).

2 Hameeteman W, Tytgat GN, Houthoff HF et al. Barrett’s esophagus: development of dysplasia and adenocarcinoma. Gastroenterology 96(5), 1249–1256 (1989).

3 Skinner DB, Walther BC, Riddell RH et al. Barrett’s esophagus. Comparison of benign and malignant cases. Ann. Surg. 198(4), 554–565 (1983).

4 Smith RR, Hamilton SR, Boitnott JK et al. The spectrum of carcinoma arising in Barrett’s esophagus. A clinicopathologic study of 26 patients. Am. J. Surg. Pathol. 8(8), 563–573 (1984).

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to endoscopic surveillance protocols will probably result in the increased recognition of patients with BE and dysplastic mucosa. Improvements in technology and increasing availability of both EUS and enhanced endoscopic-imaging techniques will improve the gastroenterologist’s ability to accurately detect HGD and exclude invasive adenocarcinoma. Clinical research will fur-ther validate the role of endoscopic management of patients with HGD. Endoscopic therapies will be increasingly utilized, including EMR to improve staging and pathologic sampling of dysplastic lesions and ablative techniques to eradicate metaplas-tic mucosa. Improvements in surgical techniques and technology at experienced centers will also enhance outcomes and minimize morbidity and mortality for patients with dysplastic lesions and

invasive adenocarcinoma not amenable to endoscopic therapy. In our opinion, eventually, the majority of patients with IM and HGD will be managed at expert centers by endoscopic ablation and surveillance, and minimally invasive esophagectomy will be reserved for patients with invasive adenocarcinoma.

Financial & competing interests disclosureDaniel Buckles has received grant support from Barrx Medical. The authors have no other relevant affiliations or financial involvement with any organi-zation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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Affiliations• Jennifer D McAllaster, MD

Resident, Department of General Surgery, University of Kansas Medical Center, 3901 Rainbow Boulevard, Mailstop 2005, Kansas City, KS 66160, USA Tel.: +1 913 588 6124 Fax: +1 913 588 7540 jmcallaster@kumc.edu

• Daniel Buckles, MD Assistant Professor of Medicine, Division of Gastroenterology and Hepatology, University of Kansas Medical Center, 4035 Delp, 3910 Rainbow Boulevard, Kansas City, KS 66160, USA Tel.: +1 913 588 6003 Fax: +1 913 588 3975 dbuckles@kumc.edu

• Mazin Al-Kasspooles, MD Associate Professor of Surgery, Surgical Oncology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Mailstop 2005, Kansas City, Kansas 66160, USA Tel.: +1 913 588 6565 Fax: +1 913 588 7540 mal-kasspooles@kumc.edu

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