Ablation of Barrett’s Esophagus via Endoscopic Methods

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Ablation of Barrett’s Esophagus (BE) has been a continuously changing field of study over the past two decades. Radiofrequency ablation (RFA) is the dominant technology for ablation as of this writing. Spray cryotherapies and older techniques including argon plasma coagulation (APC) continue to undergo scientific review to determine their place in the current landscape of tools and techniques for the ablation of BE. This article will review available technologies for performing ablation of Barrett’s esophagus.

Who to Ablate?

Non-Dysplastic Barrett’s Esophagus (NDBE)

The American Gastroenterology Association (AGA), American College of Gastroenterology (ACG), and The British Society of Gastroenterology (BSG) clinical guidelines recommend against routine endoscopic ablation for NDBE due to low risk of annual progression (0.2-0.5%) to esophageal adenocarcinoma (EAC).1,2,3 There are valid concerns about the cost-effectiveness and safety of ablating NDBE. A comparative study published in Gastroenterology found it was more cost effective to perform endoscopic surveillance supplemented with RFA upon biopsy confirmation of HGD than to perform RFA before surveillance.1 Adverse events following ablation of BE are usually mild. Serious complications are infrequent.1 In clinical practice, some endoscopists will still ablate NDBE as it has been shown to be effective in reducing risk for progression to EAC.6,7 Patients with NDBE often ask to undergo ablation if they have significant concerns about progression of their underlying Barrett’s esophagus.

Low-Grade Dysplasia (LGD)

Patients with Barrett’s esophagus (BE) and LGD have an annual risk of progression to EAC of approximately 0.7%.1 There is high interobserver variability when making a histopathologic diagnosis of LGD, and frequent downgrading of LGD to NDBE by expert pathologists. When biopsies showing LGD are confirmed by expert pathologists, the annual risk of progression from LGD to EAC is substantially higher than 0.7%.6 Guidelines from the AGA and ACG recommend that patients with BE and LGD undergo ablative therapy or surveillance.1,2 Current guidelines from the AGA recommend endoscopic surveillance intervals for BE with LGD at 3-6 month intervals if not ablated.2 When the endoscopist encounters a patient >3 months from initial diagnosis of LGD, it would be logical to repeat biopsies before proceeding with ablation to rule out progression.

High-Grade Dysplasia (HGD)

The management of HGD in the setting of BE is probably the least controversial. There is no question of whether to ablate these patients as data accumulated over the past decade strongly support ablation for BE with HGD. The AIM-dysplasia trial in 2011 found an 8-fold risk of progression of BE with HGD to EAC if patients did not undergo RFA.5 Given the efficacy of ablation in treatment of BE with HGD and the high rate of annual progression of BE with HGD (5-8%) to EAC, endoscopic ablation is recommended by the AGA, ACG, and BSG over endoscopic surveillance or esophagectomy.1,2,3

Esophageal Adenocarcinoma T1a

EAC T1a is an intramucosal cancer and has a low propensity for metastatic spread to lymph nodes (<2%).2 The AGA, ACG, and BSG all recommend endoscopic therapy over esophagectomy for EAC T1a.1,2,3 Endoscopic therapy includes EMR of the lesion followed by ablation. One prospective case series looking at long term outcomes of patients treated with endoscopic therapy found that onethird of all patients with EAC T1a treated with EMR alone develop recurrence.9 Given such a high rate of EAC recurrence with EMR alone, ablation is a critical component in the treatment of EAC T1a following resection.  Esophageal Adenocarcinoma T1b EAC T1b is a submucosal cancer and has a higher risk of lymph node metastasis (45%) compared to T1a.2 The AGA, ACG, and BSG are consistent in recommending that patients with EAC T1b and low risk features can be treated with endoscopic therapy.1,2,3 As with EAC T1a, EAC T1b treated endoscopically involves EMR or ESD followed by ablation. To aid the endoscopist in determining which patients are “low risk” EAC T1b amenable to endoscopic therapy, it is recommended to have a multidisciplinary discussion with surgery and oncology.3 If locoregional lymph nodes are shown to have tumor involvement, endoscopic therapy can still be considered as part of a broader treatment strategy.2

Principles of Ablation

The goal of endoscopic ablative therapy in BE is to remove the esophageal mucosal layer and completely eradicate intestinal metaplasia (CEIM), dysplasia (CE-D), or cancer. The depth of injury must be carefully controlled to avoid transmural injury, preserve the deeper layers of the esophagus, and achieve the desired effect of ablation. Superficial damage and retention of the deeper layers allows for re-epithelialization of the esophageal mucosa with a layer of neo-squamous tissue. Ablative therapies produce tissue destruction through thermal or freezing methods.10

Methods for Ablation Radiofrequency Ablation (RFA)

RFA ablation of BE tissue occurs through the generation of an alternating electrical current from a bipolar electrode array and an electrosurgical generator. The electrical current released causes a controlled thermal injury to esophageal tissue. Thermal injury leads to water vaporization, coagulation of proteins, and cell necrosis. (Figure 1) Desiccated tissue serves as an insulator and protective barrier to deeper tissues due to higher electrical resistance.11 A precise dose of thermal radiofrequency energy in the 450-500kHz range provides a consistent depth of ablation, typically down to the level of the muscularis mucosae (700-800µm).11 There are multiple catheter types available for RFA including circumferential ablation catheters (Barrx 360 Express Balloon Catheter), non-circumferential focal over-thescope ablation catheters (Barrx 60, 90, and Ultra Long RFA Focal catheters where number denotes the degrees of non-circumferential contact with mucosa), and focal through-the-scope catheters (Barrx Channel RFA Endoscopic Catheter).

Argon Plasma Coagulation (APC)

APC is an ablative method where thermal injury to BE tissue occurs by releasing argon gas from a catheter probe and igniting it with a high voltage spark, generating a stream of plasma (matter in a high energy state, wherein the electrons are very excited and are not tightly bound to individual nuclei). As the plasma contact target tissue, energy is released in the form of heat, resulting in a reliable area and depth of thermal tissue destruction. In 2016 Manner et al. introduced the method of hybrid-APC to preserve the efficacy of traditional APC but reduce adverse effects. The hybrid-APC approach involves the submucosal injection of an NaCl 0.9% solution using a flexible water-jet probe before thermal ablation with APC.

Cryotherapy Ablation

Cryotherapy ablation creates tissue destruction via alternating freeze and thaw cycles. Immediate tissue destruction occurs from ice crystal formation as water in the intracellular and extracellular tissues freezes.15 Ice crystal formation disrupts cellular membranes and denatures proteins, creating an osmotic gradient favoring water movement extracellularly, leading to cell dehydration and destruction. The extracellular matrix and architecture are maintained as they are not affected by the freezing process, which reduces scar formation. During the thawing process, intracellular ice crystals fuse together with a maximum effect reached at temperatures between -20°C to -50°C. Indirect injury to the vasculature occurs during ice crystal fusion leading to tissue necrosis and ischemia from platelet aggregation, thrombus formation, and regional hyperemia. Three forms of cryoablation have been studied for use in patients with Barrett’s Esophagus: Carbon dioxide (CO2), liquid nitrogen (LN2), and nitrous oxide (NO) based therapies.

CO2 Cryotherapy

Compressed CO2 gas is delivered to tissue via a 7F through-the-scope catheter at a rate of 6-8L/ min and a high pressure of 450-750psi. The JouleThomson effect is exploited with cryotherapy, whereby the rapid expansion of CO2 gas leads to a cooling effect with temperatures down to -78°C. The rapid expansion of CO2 gas at room temperature leads to increased intraluminal pressure inside the esophagus and stomach which can cause perforation. The catheter system for CO2 cryotherapy (Polar Wand cryotherapy device [GI Supply, Camp Hill, PA, USA]) allows for simultaneous delivery of cryogen and venting of waste CO2 gas through a cap and suction system. Delivery of CO2 cryogen at a temperature of -78°C (compared to -196°C for LN2 based cryogen) does not freeze the catheter and no heating circuit is needed to keep the catheter malleable. No FDA approved CO2 cryotherapy device is available in the USA since the Polar Wand was discontinued in 2016 by the manufacturer.

Cryotherapy with Liquid Nitrogen

Liquid nitrogen (LN2) cryogen is delivered by a through-the-scope, contact-free, low pressure (2-4 psi) catheter-based system that reaches a temperature of -196°C.6 Such a low temperature comes with challenges as the catheter can freeze, losing malleability. There is a heater circuit built into the LN2 system (truFreeze, STERIS, Mentor, OH) that allows for warm air to be delivered through the catheter and maintain catheter pliability.17 Unlike CO2 -based systems, LN2 does not have a gas ventilation system. The JouleThomson effect is a principle whereby a highly compressed gas undergoing rapid expansion at a low pressure causes a cooling effect. This is the basis for how LN2 cools tissues, but the rapid expansion of LN2 gas results in high intraluminal pressures and risks perforation. To reduce the risk of luminal perforations, a nasogastric or orogastric tube (OGT) is placed and connected to active suction for decompression. After a patient with Marfan syndrome developed a gastric perforation following three freeze-thaw cycles at 20 s duration, it is suggested to use four freeze-thaw cycles at 10 s.6

Multifocal Nitrous Oxide Cryoballoon

The multifocal nitrous oxide cryoballoon ablation system (cryoballoon focal ablation system [CbFAS]; C2 Therapeutics, Inc, Redwood City, Calif) is a novel way to deliver cryotherapy. This is a portable battery-powered contact cryotherapy system.6 A small hand-held device with an attached liquid nitrous oxide capsule is used to deliver nitrous oxide (NO) gas inside of a cryoballoon. The balloon is inflated to a pressure precisely regulated to a maximum of 3.5 psi. Once the balloon is in contact with tissues, the internal diffuser component sprays NO onto the tissues freezing the mucosa to -85°C. The diffuser system can be rotated and allows the endoscopist to target specific mucosal tissues. Dosimetry data confirmed that 10 s treatments allow for eradication of BE and subsequent squamous regeneration.

Comparative Trials

RFA is currently the first-line ablative therapy for BE. A few comparative trials on RFA vs LN2 and RFA vs APC have assessed whether these other modalities have similar efficacy, however, at of the time of writing this article non-inferiority trials against RFA do not exist.

RFA vs LN2 Cryotherapy

In a recent multicenter retrospective cohort study published in 2021, LN2 cryotherapy had similar efficacy to RFA. In the study, 162 patients with BE were treated with either LN2 cryotherapy or RFA. LN2 therapy required overall more treatment sessions, but LN2 and RFA netted similar rates of CE-D (RFA 81%, LN2 71%) and CE-IM (RFA 64%, LN2 66%).6 Another comparative trial of 94 patients undergoing LN2 or RFA for ablation of BE looked at pain intensity scores between treatment groups and found that LN2 therapy was associated with less post-procedural pain than RFA.7


The so-called BRIDE study published in 2018 is the only comparative trial between RFA vs APC for ablation among patients with BE. The BRIDE study was a randomized controlled trial (RCT) of 171 patients randomized 1:1 to receive RFA or APC as ablative therapy. Patients had some form of advanced disease, either HGD or T1a EAC. All patients underwent endoscopic resection prior to ablative therapy. The study found similar efficacy at 24 months between the treatment arms, with CE-D of 93.5% for APC and 88.2% for RFA.

There was a lower retention rate of patients in the APC arm of the study which may have been due to a lower patient acceptability of APC. Buried BE glands were found in 6.1% of patients in the RFA group and 13.3% in the APC groups. Adverse events, including stricture rates, were similar (RFA 8.3%, APC 8.1%). RFA was also more expensive, costing $27,491 more in accumulated medical bills.

Risks and Benefits of Ablation Modalities RFA

Data on the efficacy and safety of RFA is by far more abundant compared to APC and cryotherapies. ACG guidelines from 2022 recommend RFA as the first line ablative therapy of non-nodular dysplastic BE.1 Dosimetry data is well known and a precise amount of tissue destruction occurs due to the nature of balloon-based bipolar radiofrequency energy electrodes., The durability of RFA has been repeatedly proven over the years. A prospective multicenter cohort study known as the AIMdysplasia trial published in 2011 found that RFA provided durable CE-D and CE-IM following treatment as evidenced by a low rate of disease progression over three years. Furthermore, a 2017 follow up of the AIM-dysplasia trial cohort found that among patients with BE and dysplasia who maintained CE-IM at three years, only 32% experienced a recurrence of BE. The SURF trial, a RCT of 136 patients with BE and LGD comparing RFA to surveillance alone, found that RFA reduced the risk of neoplastic progression to HGD or EAC by 25% over three years.

Risks associated with RFA include buried subsquamous BE glands which have a theoretical risk of progression to neoplasia, or adverse events such as post-operative pain, esophageal strictures, bleeding, and rarely, perforation. Rates of buried BE glands after RFA have been variable. The AIM-II trial in 2010 was a prospective, multicenter US trial looking at five year follow-up after RFA ablation of NDBE. Zero cases of buried BE glands were found after five years. The BRIDE study published in 2018 found that among 76 patients with BE treated with RFA, 6.1% had buried BE glands found on biopsy at 12 months.24 None of the patients with buried BE glands developed neoplasia.

Post-procedural pain is a common complaint with all ablative therapies, but RFA is five-times more likely to be associated with post-procedural pain than LN2 cryotherapy. Perhaps one of the best datasets available for safety of RFA is a systematic review and meta-analysis from 2016 that looked at 37 articles comprised of 9200 patients that found an overall rate of adverse events to be 8.8%, with 5.6% developing strictures, 1% bleeding, and 0.6% perforation. If endoscopic resection occurred before RFA, adverse event rates were substantially higher.


Despite an initial enthusiasm for APC as an ablative therapy for BE due to the ease of its use and widespread familiarity with the technique for other indications, reports of major complications such as bleeding, strictures, and perforation have led to a decline in use. The APBANEX trial in 2006 was a multicenter prospective study of 60 patients undergoing traditional APC ablation of NDBE in which 10% of patients developed serious adverse events. Although RFA had a rate of 6.1% buried BE glands in the BRIDE study, APC was found to have a rate of 13.3%.24 A RCT from 2021 looking at APC ablation in 107 patients with BE and LGD found that there was a high adverse event rate that was directly proportional to the amount of watts used. For example, the group that underwent treatment at the 90 W level experienced an 83% adverse event rate while the 60 W group had a 48% adverse event rate. The hybrid-APC method where a pillow of 0.9% NaCl is injected prior to APC has remarkably lower rates of adverse events and a reported 2% stricture rate.14

The cost of APC may be more favorable than for RFA. The BRIDE study found that RFA incurred more costs than APC, with accumulated costs of RFA on average $33,170 vs $5,678 for APC. Efficacy of APC may be comparable to RFA, with long-term ablation outcomes after APC available from two RCTs from 2013 where 129 patients with BE underwent APC vs surveillance. A new study out of Europe showed promising results for hybrid-APC. Published in January 2022, the study included 154 patients having neoplastic BE and found that among patients treated with hybrid-APC there was a 97.7% rate of CE-D and 65.9% CE-IM.

CO2 Cryotherapy

CO2 cryotherapy dosimetry is non-existent. Efficacy of CO2 cryotherapy has been variable across studies. A prospective single case series of 30 patients treated with CO2 cryotherapy was terminated early because of low CE-IM rates of 11% and CE-D rates of 44%. One conflicting study in 2015 by Canto et. al reported that among patients undergoing CO2 cryotherapy there was a CE-D rate of 89% and CE-HGD of 94%. CO2 cryotherapy did have some advantages over LN2 cryotherapy, including less freezing of the catheter and the ventilation mechanism built into the Polar Wand reduced risk of perforations. The Polar Wand was discontinued by the manufacturer in 2016.

LN2 Cryotherapy

As with CO2 cryotherapy, there is a lack of dosimetry data surrounding LN2 treatment., Rapid expansion of a highly compressed gas via the Joule-Thompson effect, the principle by which LN2 cryotherapy causes tissue cooling, can lead to perforation. In initial studies a patient with Marfan Syndrome developed gastric perforation.19 To prevent gastric perforation an OGT is utilized during the procedure, but this tube in the esophagus can impair the endoscopists maneuverability during ablation. The ultra-cold temperatures involved (-196°C) in LN2 cryotherapy reduces catheter pliability, but a heater probe built into the catheter does help prevent the catheter from freezing.

A 2010 multicenter prospective trial of LN2 ablation in BE that included 77 patients found that 52% had adverse events including chest pain (17.6%), dysphagia (13.3%), odynophagia (12.1%), sore throat (9.6%), and strictures (4%)., Stricture rates appear to vary substantially across studies, however, and are generally much higher in those who undergo EMR before LN2 cryotherapy. A multicenter 2017 study of 88 patients undergoing LN2 cryotherapy following EMR of esophageal adenocarcinoma T1a or T1b had stricture rates of 12%.

The efficacy of LN2 cryotherapy was examined in a 2019 meta-analysis that included 386 patients. The pooled CE-D rate (83.5%) was comparable to that seen with RFA, but LN2 cryotherapy had a much lower CE-IM rate (56.5%). All patients in the study received LN2 cryotherapy, a subset as a salvage therapy after RFA, and another subset were treatment-naïve patients. It was concluded that RFA may be better as a first-line therapy, with LN2 cryotherapy an acceptable salvage therapy for RFA refractory BE.

Multifocal Nitrous Oxide Cryoballoon

The nitrous oxide cryoballoon (CbFAS system) is a novel therapy still under investigation to determine its role within the current ablation landscape. A prospective clinical trial published in 2020 looked at 120 patients undergoing CbFAS ablation of BE 1-6 cm in length, with either LGD, HGD, or EAC. Findings among the 94 patients in the per-protocol analysis found a pooled CE-D rate of 97% and a CE-IM rate of 91%. Stricture rates were higher than those seen in LN2 cryotherapy (12.5%).


Ablative therapies for BE include RFA, APC, and spray cryotherapy in the form of CO2, LN2, or NO. None of these technologies are perfect. RFA has the best safety profile of all ablative modalities and high rates of CE-D and CE-IM. RFA is more expensive than LN2 cryotherapy and is associated with higher post-operative pain. CO2 cryotherapy had one study terminated early due to poor performance and the Polar Wand was discontinued by the manufacturer in 2016. LN2 cryotherapy lacks dosimetry data and can have significant adverse event rates. LN2 cryotherapy has a similar rate of CE-D as RFA, but lower rates of CE-IM making it more suitable for salvage therapy after RFA failure. The CbFAS cryoballoon system is a novel form of NO spray cryotherapy. RFA remains the first-line treatment.


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