Endoscopic Resection

EMR can be performed through a variety of techniques: free-hand, lift-and-cut, cap-assisted, and band-assisted. Injection of saline with a sclerotherapy needle is performed to create a submucosal fluid cushion, and a snare is used to directly entrap the mucosal tissue in the free-hand method. In the lift-and-cut approach, a dual-channel endoscope is used to simultaneously introduce a grasping forceps and snare for lifting and resection. The cap technique involves attaching a clear distal cylindrical device to the tip of the endoscope; this cap has an inner rim in which a crescent-shaped snare is carefully fitted. The target area is injected for submucosal lift, then suction is applied, and tissue is entrapped in the cap by the snare for subsequent mucosal excision. Modifications of the variceal band ligation device embody the band-assisted techniques that allow for injection and then deployment of bands for mucosal pseudopolyp creation. A snare is then introduced and the mucosa is resected either above or below the band.

Focal EMR can be performed for endoscopically visible lesions that are suspicious for malignancy. However, several previously published studies on focal resection demonstrated a high rate of synchronous and recurrent lesion development, which ranged from 14% to 47% and increased with longer observation times. Because of limited efficacy of focal EMR, complete Barrett’s eradication EMR has been advocated and performed in select centers, with the intention of curatively removing all BE epithelium to potentially reduce the risk of synchronous or metachronous lesion development. Complete responses have ranged from 76% to 100%. The complication profile of EMR includes stricture formation incidence rate that approaches 50%, bleeding, and, rarely, perforation. Of note, most esophageal stenoses and bleeding are amenable to endoscopic treatment.

The effect of EMR on final histopathologic staging has been highlighted in the authors’ center’s long-term results with complete Barrett’s eradication EMR that revealed initial EMR upstaged 7 (14%) of 49 and downstaged 15 (31%) of 49 of patients’ final pathology when compared with pre-EMR biopsy HGD results. Moreover, of the upstaged group, four patients had advanced pathology found after index EMR (either submucosal carcinoma or IMC with lymphatic channel invasion). All four of these patients had visible lesions detected on endoscopy. However, these lesions were not described in the referring physicians’ endoscopy reports, and these patients had been recommended by their referring physicians to undergo ablative therapy for presumed BE with HGD solely detected on their biopsies. This is the critical point that distinguishes EMR from all other non–tissue acquiring modalities that would have inadvertently attempted ablation of advanced pathology in the setting of presumed BE HGD treatment.

Endoscopic submucosal dissection (ESD) allows for the en bloc dissection of neoplastic lesions. This technique has been used for the removal of superficial gastric cancers in Japan. This may be a suitable modality for lesions at the gastroesophageal junction or cardia. However, it should be approached with caution in the distal esophagus given the potential for reflux-induced submucosal fibrosis. Yoshinaga and colleagues performed ESD at the gastroesophageal junction in 24 patients for adenocarcinoma (15 with BE) and had no recurrence in their follow-up period, which was a mean of 30 months.

For lesions with superficial submucosal invasion into the sm1 layer, endoscopic resection has been studied in a limited fashion. The Wiesbaden group in Germany classified “low-risk” submucosal cancer as demonstrating invasion into the upper third of the submucosa (sm1), absence of infiltration into lymph vessels and veins, histologic grades G1 and G2, and macroscopic types I and II. Their outcomes of endoscopic resection of these low-risk lesions were described as favorable, with a 5-year survival rate of all 21 patients reaching 66%.

To further investigate the controversy of outcomes of esophageal adenocarcinoma with submucosal invasion, Badreddine and colleagues evaluated esophagectomy specimens from patients with esophageal adenocarcinoma and submucosal invasion. Superficial (upper one third, sm1) and deep (middle third, sm2; deepest third, sm3) submucosal invasion were associated with substantial rates of metastatic lymphadenopathy (12.9% and 20.4%, respectively). Their resulting recommendation was that endoscopic treatment of superficial submucosal adenocarcinoma is not advised for patients who are candidates for surgery.

At present, accurate predictors of nodal spread independent of tumor depth are lacking. These parameters are necessary before recommending endoscopic resection with or without concomitant ablation as curative treatment for even superficial submucosal neoplasia. Therefore, the role of ESD in the setting of BE neoplasia remains to be defined, and should only be performed in research protocolized fashion in centers with expertise in endoscopic excisional techniques and management of potential complications. Additionally, esophagectomy should be readily available at these centers to expeditiously treat complications, such as full-thickness perforation resulting from endoscopic resection.

PDT

The goal of PDT is destruction of tissue through a light-sensitizing reaction sequence. A photosensitizer is first administered, which accumulates in esophageal malignant and premalignant tissue before light activation therapy. The most common photosensitizer is porfimer sodium, and this is delivered intravenously 72 hours before the procedure. Available alternatives are oral 5-aminolevulinic acid and intravenous m-tetrahydroxyphenyl chlorine (mTHPC). On exposure to either bare cylinder or balloon-based diffusing light fibers that are placed alongside the target tissue by endoscopic approach, activation of the photosensitizing agent occurs. The resulting molecular excitation reacts with oxygen to facilitate creation of radical oxygen species that cause eventual cell apoptosis.

In a multicenter trial, BE HGD patients were randomized to either receive twice daily oral omeprazole, 20 mg, with or without porfimer sodium PDT administration. At 5 years follow-up time, PDT was significantly more effective than proton pump inhibition alone in elimination of HGD (77% vs 39%; P <.0001). A secondary outcome assessed was prevention of cancer progression that also showed significant difference, with the PDT–proton pump inhibition group demonstrating half the likelihood of developing cancer and longer time to progression to cancer.

Another porfimer PDT study consisted of 103 patients with LGD, HGD, or IMC with a mean follow-up of 50.65 months (range, 2–122 months). Intention-to-treat success rates were 92.9%, 77.5%, and 44.4% for the respective LGD, HGD, and IMC groups. Three patients (4.6%) developed subsquamous adenocarcinoma. Esophageal strictures occurred in 18% with one session of PDT, 50% with two treatments, and 30% in the overall group.

5-Aminolevulinic acid PDT has shown 97% and 100% complete response rates for treatment of BE with HGD and IMC, respectively, in a median follow-up period of 37 months (interquartile range, 23–55). Disease-free survival of HGD patients was 89%, and 68% in patients with IMC. The calculated 5-year survival was 97% for HGD and 80% for IMC, but no deaths were related to Barrett’s neoplasia.

In a pilot study of PDT using mTHPC for HGD or IMC, treatment results were variable based on red versus green light usage. Successful ablation was achieved in four out of six mucosal carcinoma and three out of four HGD patients who received red light. However, exposure to green light failed to achieve successful disease eradication or long-term remission. Significant complication, such as death, occurred after premature biopsy performance after treatment. This limited sample size study demonstrated that although mTHPC can destroy BE epithelium, the optimal light and drug dosimetry are still unknown.

No randomized controlled prospective trials have been conducted to date comparing PDT with surgery for BE neoplasia management. However, a retrospective data analysis of HGD patients who received PDT (N = 129) or esophagectomy (N = 70) revealed no statistically significant differences in mortality or long-term survival based on choice of treatment modality. The management of IMC with PDT seems to have a less efficacious profile, and thus cannot be uniformly recommended.

Major side effects of PDT include photosensitivity that requires patients to avoid postprocedure skin sunlight exposure, noncardiac chest pain, and symptomatic stricture formation. Risk factors for post-PDT stricture development include history of prior esophageal stricture, performance of EMR before PDT, and greater than one PDT treatment in a single session. Development of subsquamous BE glands is another concern regarding PDT, because these glands may harbor neoplastic potential. However, the clinical significance of subsquamous BE glands is presently not fully understood. Reports of adenocarcinoma arising from subsquamous BE glands after PDT therapy have been described. For these significant reasons, PDT usage has gone out of favor in recent years, with the advent of other available endoscopic ablative options.

RFA

Using either a balloon-based catheter or a focal device, RFA of BE tissue can be achieved in either a circumferential or localized fashion. Initially, a sizing balloon is inserted into the esophagus, and the optimal size of circumferential balloon is selected based on various pressure measurements in different esophageal locations. The process of RFA is a series of two separate applications of direct thermal energy with the electrodes imbedded in either the circumferential or focal device. Treated tissue is scraped between the first and second ablation to ensure adequate and uniform thermal contact. The most common complications associated with RFA include noncardiac chest pain, nontransmural lacerations, and a lower stricture rate when compared with EMR.

The efficacy and safety of RFA has been demonstrated in a gradual and progressive fashion. After initial thermal dose-escalation animal testing and preesophagectomy human experiments, the first larger clinical study of RFA involved BE patients without dysplasia in the Ablation of Intestinal Metaplasia study from 2003 to 2005. This multicenter trial demonstrated a 70% complete remission of BE of the circumferentially treated group at 1-year follow up, without subsequent stricture formation or buried BE presence from 4306 biopsy fragments evaluated. The subsequent Ablation of Intestinal Metaplasia II study reported 98% complete remission of IM after stepwise circumferential therapy with additional focal ablative therapy of remaining BE.

RFA was also evaluated in 142 patients with BE HGD who demonstrated at 12-month follow-up complete remission of HGD in 90.2%, complete remission of dysplasia in 80.4%, and complete remission of IM in 54.3%. In a recent landmark multicenter, sham-controlled trial, 127 patients with dysplastic BE were randomly assigned to receive either RFA or a sham procedure. Primary outcomes at 12 months included complete eradication of dysplasia and IM. In an intention-to-treat analyses, in LGD patients, complete eradication of dysplasia occurred in 90.5% from the ablation group, compared with only 22.7% from the control group ( P <.001). In the HGD subgroup, complete eradication occurred in 81% of ablated patients, compared with 19% of the control group ( P <.001). Overall, 77.4% of ablation patients demonstrated complete eradication of IM, in contrast to 2.3% of the control group ( P <.001). There was less disease progression in patients from the ablation group (3.6% vs 16.3%; P = .03) and fewer cancers noted (1.2% vs 9.3%; P = .045). More reports of chest pain occurred after ablation than sham procedures, and a 6% esophageal stricture development rate was noted in the RFA treated group. This markedly lower stricture rate associated with RFA as compared with EMR creates a significant advantage for RFA in the treatment of BE with flat HGD.

In the setting of BE with HGD, performance of EMR of any visible lesions with subsequent RFA of the remaining flat segment has been studied. Complete histologic eradication of all dysplasia and IM was achieved in 43 patients (98%). Postablation complications included mucosal laceration at prior EMR site (N = 3) and transient dysphagia (N = 4). No dysplasia recurred after a 21-month follow-up period. A multicenter European trial involved EMR of visible lesions, followed by serial RFA. Focal escape endoscopic resection was used in cases of BE persistence despite RFA. The study included 24 patients, and eradication of neoplasia and IM was achieved in 95% and 88% of patients, respectively. These rates improved to 100% and 96%, respectively, after escape EMR in two patients. No neoplasia recurred within a median 22-month follow-up period. Of note, neosquamous epithelium rigorous EMR and biopsy evaluation in a group of 22 post-RFA patients with baseline BE with IMC or HGD showed no evidence of persistent genetic abnormalities or buried BE glands. To date, no published studies exist on outcomes of sole RFA therapy of BE with IMC.

Cryotherapy

The latest modality to arrive on the endoscopic horizon is cryotherapy. Sprayed liquid nitrogen is applied to the target area, and freeze-thaw cycles result in tissue destruction by intracellular disruption and tissue ischemia, with relative preservation of the extracellular matrix to promote less fibrosis formation. Placement of an orogastric decompression tube allows for adequate excess nitrogen gas expulsion to help prevent inadvertent gastrointestinal viscus perforation. Repeat treatment sessions may be conducted every 4 to 6 weeks as needed to ensure complete remission of the target area’s neoplasia.

In a prospective open-label trial, patients with BE and HGD or IMC who were deemed inoperable or who refused esophagectomy were enrolled for cryoablation. EMR was performed for pathologic staging of nodules before cryoablation and on focal residual areas during the follow-up period. Patients with prior ablation therapy were not excluded. Of 30 patients, 90% had pathologic downgrading postcryotherapy treatment. After a median follow-up of 1 year, elimination of cancer or downgrading of HGD was achieved in 80% of IMC and 68% of HGD patients, respectively. A perforation occurred in a patient with Marfan syndrome with a prototype system. Of six patients who showed a complete response, three had recurrence of dysplasia or cancer in the gastric cardia.

Liquid nitrogen cryotherapy efficacy and safety profiles have been demonstrated in a four-center study of 24 patients (17 with HGD, 4 with IMC, and 3 with early stage adenocarcinoma). Complete response to HGD was found in 94% with HGD, and 100% with IMC and cancer. Complete response to IM was noted in 53% of HGD, 75% of IMC, and 67% with cancer. No symptoms were reported in 48% of 323 procedures. Three patient developed esophageal strictures, but all were successfully treated by dilation. Other complications included chest pain, dysphagia, sore throat, and the gastric perforation previously noted in the Marfan patient.

In a more recent retrospective nonrandomized study involving nine centers over a 2-year treatment period, 98 patients with BE and HGD underwent 333 treatments. No esophageal perforations occurred, and esophageal strictures developed in three subjects. The efficacy analysis revealed a 97% complete eradication rate for HGD, 87% complete eradication of all dysplasia with persistent nondysplastic IM, and 57% had complete eradication of all IM. Published results on efficacy of cryotherapy in treating BE with IMC are still awaited.