Society: ASGE

Background
Focal cryoballoon ablation (FCBA) is a relatively new ablation modality for the treatment of Barrett’s esophagus (BE) related neoplasia. This prospective, European multicenter study (Euro-Coldplay, NTR NL7253) aimed to evaluate the efficacy and safety of FCBA for the treatment of limited BE.

Method
In eight European Barrett referral centers, patients with C≤2M≤5 BE with an indication for ablation therapy were eligible for inclusion. Before entry, any visible lesion had to be removed by endoscopic resection (max. 2cm in length and 50% of circumference). FCBA was performed by experienced and trained endoscopists at 3 month intervals until complete endoscopic eradication of BE (max. 5 sessions). During every session, the esophagogastric junction was treated circumferentially followed by all visible BE using side-by-side ablations with a dose of 8 seconds per ablation. After at least two FCBA sessions, add-on treatment was allowed with either argon plasma coagulation (APC) for BE lesions of <5mm (max. 2 sessions) or a single endoscopic mucosal resection for lesions of >5mm. Outcomes included complete eradication of intestinal metaplasia (CE-IM) and dysplasia (CE-D), and adverse event rate.

Results
107 patients (91 males; mean age 65) with a median BE length of C0M2 were included, containing low-grade dysplasia (32%), high-grade dysplasia (32%) or early cancer (39%) as worst baseline histology. Currently, 84/107 (79%) patients have finished the treatment phase of which the results are reported hereafter. 57/84 (68%) patients underwent endoscopic resection at entry followed by a median of 2 (IQR 2-2) FCBA treatments with a median of 7 (IQR 6-9) ablations per treatment session. Only one patient (1/84; 1%) could not be treated with FCBA owing to a device malfunction requiring a switch to radiofrequency ablation. During the treatment phase, 3/84 (4%) patients developed a new visible, neoplastic lesion amenable for endoscopic resection (high-grade dysplasia n=2, low-risk T1 cancer n=1). Add-on treatment after at least two FCBA sessions was performed in 32/84 (38%) patients, of whom the most were treated with APC (31/32; 97%). CE-D was achieved in 95% (80/84) and CE-IM in 93% (78/84), per intention-to-treat analysis. Per-protocol analysis, CE-D and CE-IM were achieved in 100% (80/80) and 98% (78/80), respectively. Esophageal stricture was the most common adverse event in 13/84 (15%) patients, which resolved after a median of 2 (IQR 1-4) dilations. No perforation or bleeding were observed, while buried BE glands were seen in 1/84 (1%).

Conclusion
In expert hands, endoscopic eradication therapy with FCBA seems to be highly effective with an acceptable safety profile for patients with limited BE. Long-term follow-up is warranted to evaluate the durability of the treatment response.

Introduction
Endoscopic resection (ER) including endoscopic submucosal dissection (ESD) is widely accepted as a minimally invasive treatment for superficial esophageal squamous cell carcinoma (SESCC). However, there is a risk for developing metachronous SESCC in the preserved esophagus after ER. ER for SESCC on the post-ER scar is generally difficult to achieve en bloc resection even with ESD. Recently, the efficacy of the cryoballoon ablation system (CBAS) has been demonstrated in the management of dysplastic and neoplastic Barrett’s esophagus. On the other hand, there is little evidence for CBAS treatment of SESCC. We aimed to evaluate the efficacy and safety of CBAS for SESCC on the post-ER scar.
Methods
This prospective single-arm study included patients with clinically T1a SESCC on the post-ER scar from two tertiary referral centers in Japan (JapicCTI-205427). The key exclusion criteria were lesions at cervical esophagus, lesions of >5 cm in size and/or involving whole circumferential, and 4 lesions or more. Cryoablation was performed using the focal CBAS (Pentax Medical, HOYA) with 8 or 10-second cryogen dose. No upper limit was set for number of ablation cycles. One repeat-cryoablation was allowed if there was residual disease within 4 months after the initial treatment. The primary endpoint was local complete response (L-CR) rate of the primary lesion (A largest lesion of all lesions) at 48 weeks after first cryoablation as judged by an independent committee. L-CR was defined as no histological and endoscopic recurrence findings. Secondary endpoints were L-CR rate judged by the investigators, L-CR rate for all lesions, technical success rate, procedure time, pain score (scored 0 to 10 within 7 days), recurrence free survival (RFS), overall survival (OS), and incidence of adverse event (AE). Planned sample size was set at 15, with threshold L-CR rate of 55%, expected one of 90%, one-sided alpha of 5% and power of 85%.
Results
From October 2020 to October 2021, 15 patients with 17 lesions were enrolled all of whom completed protocol treatment. Two patients underwent repeat-cryoablation. L-CR rate of the primary lesion judged by the independent committee was 100% (90%CI 81.9-100%). L-CR rate for all lesions was also 100% (17/17). The endoscopic assessment of L-CR by the principal and sub-investigators was consistent in all cases. Median treatment time was 15 min (8-28). For the pain score, 8 patients did not report any pain, and the maximum score was 3 in one patient. The technical success rate was 94.7% (18/19). No recurrence and death were occurred with a median follow-up of 14.3 months. There was no grade 3 or higher treatment-related AEs, one of grade 2 esophageal pain, two of grade 1 esophageal stricture, and one case of grade 1 vomiting.
Conclusion
CBAS is safe and effective for the treatment of patients with SESCC on the scar after ER.

Background:
Endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR) are minimally invasive procedures to remove the dysplastic Barrett’s esophagus (BE) lesion. The optimal resection technique for dysplastic BE lesions remains unclear as while EMR is safe, effective and easy to perform, recurrence rates are lower with ESD. We aim to compare the cost-effectiveness of EMR and ESD for resection of BE neoplasia.

Methods:
An incremental cost-effectiveness analysis was performed using a Markov decision tree model including parameters available from the literature review (including 1267 patients who underwent ESD and 4410 who underwent EMR) for BE neoplasia. Monte Carlo simulations were conducted for randomly sampled values for each model estimate to predict the probability of cost-effectiveness at various willingness-to-pay (WTP) thresholds. The base case was a patient with high-risk BE lesions (high-grade dysplasia (HGD) or T1a esophageal adenocarcinoma (EAC)). Outcomes data for BE patients with HGD or T1a esophageal adenocarcinoma were analyzed. The median follow-up period was 31 months (18 months to 5 years). The average lesion size before intervention was higher for ESD compared to EMR (22.7mm vs 13.6mm). The probability of overall post-resection recurrence was analyzed, and the incremental cost of the ESD was compared to that of EMR. Effectiveness was defined as the number of esophagectomies or repeat endoscopic procedures avoided per 1000 cases in the simulation. The costs of EMR and esophagectomy were derived through CPT codes and the existing literature, and the cost of ESD was derived through the billing department of our institution. The incremental cost of esophagectomy or repeated endoscopic intervention for recurrence following ESD or EMR was derived from the model.

Results:
ESD resulted in higher rates of R0 resection (74.5% vs 40.82%, p=0.001) but higher rates of periprocedural adverse events such as bleeding (2.79% vs 1.13%, p=0.01) and perforation (0.46% vs 0.04%, p=0.01) compared to EMR. ESD yielded a significantly lower overall local recurrence compared EMR (2.92% vs 11.27%, p=0.01). The proportion of recurrence requiring repeat endoscopic treatment following ESD or EMR was 1.84% and 8.96%, respectively. ESD prevented an additional 71.21 per 1000 cases of repeat endoscopic resection compared to EMR. ESD would prevent approximately 12 additional esophagectomies compared to EMR for every 1000 patients undergoing the procedure at an incremental cost per surgery avoided of $5362. At WTP estimate of $25000, ESD is more cost-effective than EMR in preventing endoscopic reintervention and esophagectomies (p=0.001).

Conclusion:
ESD is associated with higher upfront costs for the patient, but is more cost-effective in the long term by lower overall recurrence and lower probability of repeat endoscopic or surgical treatment.

<b>Table 1: ESD vs EMR: Local recurrence and Cost Comparison</b>

Table 1: ESD vs EMR: Local recurrence and Cost Comparison

Background
While endoscopic submucosal dissection (ESD), enables higher en-bloc and R0 resection compared to cap-assisted endoscopic mucosal resection (cEMR), its comparative impact on achieving complete remission of dysplasia (CRD) and intestinal metaplasia (CRIM) in BE endoscopic eradication therapy is not well defined. We aimed to compare the journey of patients from initial resection with ESD and cEMR to achieving CRD and CRIM using a large multicenter North American cohort.
Methods
A retrospective cohort of patients undergoing ESD or cEMR for BE dysplasia or esophageal adenocarcinoma (EAC) between 2010-2022 at four academic quaternary referral centers in the United States was created. Patients underwent ESD or cEMR by expert endoscopists, at the discretion of the treating provider. Study endpoints included procedural outcomes: percentage of BE area initially removed, en-bloc resection rate, and CRIM journey outcomes: the number of resection and ablative procedure sessions following initial resection, till CRD and CRIM were achieved. The total area of Barrett’s segment was experimentally estimated by the sum of the circumferential BE segment area and 1/3^rd the area of the maximal BE segment. The total area of resected tissue was estimated by calculating the area of the ellipse (πab).
Results
627 patients undergoing cEMR and 284 patients undergoing ESD were included. Baseline characteristics are shown in Table 1. The initial ESD group had significantly higher age and more HGD/EAC tumors than the initial EMR group (table 1). While the initial EMR group had more Caucasians , higher BMI, and largerhiatal hernias (table 1). Total follow-up time was 66.9 months (SD 49.03) and 22.05 months (SD 17.5) after the initial cEMR and ESD. Patients in the ESD group had a similar total BE surface area to those in cEMR group (ESD, 15.79 cm², EMR, 17.42 cm²). ESD group patients had higher en-bloc resection rates (ESD, 92.96%, EMR, 45.4%), and achieved a higher proportion of resected BE mucosa (60.47% with ESD to 14.30% with EMR). Patients undergoing Initial cEMR resection needed more repeat EMRs, and radiofrequency ablation (RFA) sessions compared to those treated with initial ESD. ESD also resulted in a shorter time to CRIM (11.25 vs 23.66 months p<0.001) and CRD (7.03 vs 19.31 months p<0.001). (Table 2)
Conclusion
Patients that had cEMR required more repeat resection and ablative procedures to reach CRIM/CRD compared to ESD. This could be due to ESD removing a greater proportion of the BE segment than cEMR, and less at-risk BE mucosa remaining for treatment with ablation therapy.

<b>Baseline demographic and procedural data between study groups</b>

Baseline demographic and procedural data between study groups

<b>Journey to CRD/CRIM after endoscopic resection therapy</b>

Journey to CRD/CRIM after endoscopic resection therapy

Background: Endoscopic eradication therapy (EET) combining endoscopic resection (ER) either with cap-assisted endoscopic mucosal resection (cEMR) or endoscopic submucosal dissection (ESD) followed by ablation of residual disease is the standard of care for the treatment of dysplastic Barrett’s esophagus (BE) and intramucosal esophageal adenocarcinoma (EAC). We have previously shown comparable rates of complete remission of intestinal metaplasia (CRIM) with both approaches. However, long-term follow up data comparing recurrence between these techniques are lacking. We compared rates of recurrence after CRIM following cEMR+ablation vs. ESD+ablation in a large United States multicenter cohort.

Method: Patients who underwent EET of Barrett’s dysplasia/neoplasia at 4 academic institutions in the United States were included. Demographic, clinical, and histological data were abstracted from medical records. All histology was reviewed by expert GI pathologists. Patients achieving CRIM (defined as the absence of IM on surveillance endoscopy) were included in the recurrence analysis. Outcomes studied included rates of any, dysplastic and high-grade dysplasia (HGD)/EAC recurrence in the two treatment groups. Secondary outcomes included predictors of recurrence. Cox proportional hazards models and inverse probability treatment weighting (IPTW) analysis (to balance the clinical characteristics of patients between the two treatment cohorts) were utilized for comparing outcomes.

Results: A total of 979 patients (680 patients treated with initial cEMR and 299 patients treated with initial ESD) were included. Of these, 639 patients (521 cEMR, 118 ESD) with a median (IQR) follow-up time after CRIM of 3.5 (1.3, 6.4) years in the cEMR group and 1.5 (0.2, 2.4) years in the ESD group were included in the recurrence analysis. Baseline demographics and clinical characteristics are shown in Table 1. The incidence rates of any BE recurrence were 15.9 and 17.5 per 100 patient years in the cEMR and ESD groups, respectively. The incidence rates of dysplastic BE recurrence were 5.9 and 6.3 per 100 patient years in the cEMR and ESD groups, respectively. On multivariable analyses, the chances of developing any Barrett’s recurrence were not influenced by endoscopic resection technique (cEMR vs ESD: HR, 1.14; 95% CI, 0.71-1.82; p= 0.60), which was similar to the IPTW analysis (cEMR vs ESD: HR, 1.1; 95% CI, 0.65-1.85; p= 0.73). BE length was an independent predictor of recurrence. The cumulative probabilities of recurrence were 26% in the cEMR group compared to 21.3% in the ESD group at 1 year after achieving CRIM.

Conclusions: Patients with Barrett’s neoplasia initially treated with cEMR followed by ablation had similar recurrence rate to those treated with ESD followed by ablation. Randomized trials are needed to effectively compare histologic outcomes between the two ER techniques.

Background: Endoscopic management is the standard of care for low-risk T1a esophageal adenocarcinoma (EAC) given comparable outcomes to surgery. Data on outcomes of endoscopic management of high risk T1a EAC are limited. We examine the clinical outcomes after endoscopic management of low-risk vs high-risk T1a EAC including intraluminal recurrence, lymph-node (LN) and distant metastases, and survival (overall and cancer free).
Methods: Patients who underwent endoscopic resection (endoscopic mucosal resection, endoscopic submucosal dissection) revealing T1a EAC at a referral BE endotherapy unit between 1996 and 2022 were included. Patients with submucosal invasion (T1b EAC) and positive deep margins were excluded. High-risk T1a EAC was defined as T1a EAC with poor differentiation and/or lymphovascular invasion (LVI). Low-risk T1a EAC was defined as T1a EAC with well or moderate differentiation without LVI. All pathology was assessed by expert pathologists. Demographic, endoscopic, and pathology data as well as follow-up data on EAC recurrence were obtained from a prospective database. Numerical data were reported as median (interquartile range, IQR). Continuous and categorical variables were compared using 2-sample t-test and Pearson’s Chi-square/Fisher’s Exact Test respectively. Kaplan Meier (KM) curve estimates were used to compare differences in survival and time to local recurrence.
Results: 120 T1a EAC patients were included (low-risk, n=84; high-risk, n=36), 102 (85%) men, with median (IQR) age 71 (65, 77) years. Baseline characteristics and clinical outcomes are shown in Table 1. There were no significant differences in age, sex, tobacco use, BE length, lesion size, and endoscopic resection technique (between groups. Of patients with high-risk T1a EAC, 29 had poor differentiation and 9 had LVI. Rates of local recurrence (19% vs.12%) and LN or distant metastatic disease (11% vs.2%) were higher in the high-risk compared to low-risk T1a EAC group with a trend to significance in the rates of LN/metastatic disease (p=0.07). 94% of patients with local recurrence were successfully treated with endoscopic resection and 1 patient underwent curative esophagectomy. Of those with LN/distant metastatic disease, 1 underwent curative esophagectomy/chemoradiation, 2 palliative chemoradiation, 1 palliative endoscopic therapy, and 1 palliative care (1 missing). There was no difference in overall survival between groups (Figure 1, p=0.17).
Conclusion: We observed a four-fold increase in the rate of LN/distant metastatic disease in those with high risk compared to low risk T1a EAC treated endoscopically, with a trend towards statistical significance. The endoscopic management of T1a EAC should factor risk-stratification to determine clinical outcomes. Further data on high risk T1a EAC treated endoscopically are critically needed and being collected.

Hee Eun Lee

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