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Cryoablation in the management of Barrett's esophagus

Overwater, Anouka,b; Weusten, Bas L.A.M.a,b

Current Opinion in Gastroenterology: July 2017 - Volume 33 - Issue 4 - p 261–269
doi: 10.1097/MOG.0000000000000372
ESOPHAGUS: Edited by Stuart J. Spechler

Purpose of review: Providing an overview on types of cryotherapy for esophageal application and their role in the management of Barrett's esophagus.

Recent findings: Recent studies have involved multiple types of cryotherapy including cryospray techniques that use either liquid nitrogen or carbon dioxide as the cryogenic fluid, and the CryoBalloon focal ablation device that uses nitrous oxide. Overall, studies report cryotherapy to be safe and effective in eradicating Barrett's epithelium. However, substantial variations among these studies in design and outcomes preclude direct comparisons of the results. Moreover, little is known of the long-term outcomes of cryotherapy, with only one report describing 5-year follow-up of patients treated with liquid nitrogen cryospray.

Summary: The concept of cryotherapy is appealing. By preserving the extracellular matrix and inducing anesthetic effects, cryotherapy has the potential to enable deeper ablations with less pain and a lower rate of stricture formation than radiofrequency ablation. To date, however, these potential benefits remain unproved. Prospective studies with clearly defined endpoints and longer follow-up are necessary to determine the role of cryotherapy in the management of patients with Barrett's esophagus.

aDepartment of Gastroenterology & Hepatology, St. Antonius Hospital, Nieuwegein

bDepartment of Gastroenterology & Hepatology, University Medical Center, Utrecht, The Netherlands

Correspondence to Bas L.A.M. Weusten, MD, PhD, Department of Gastroenterology & Hepatology, St. Antonius Hospital, Nieuwegein, Postbus 2500 3430 EM Nieuwegein, The Netherlands. Tel: +31 88 320 5600; e-mail: b.weusten@antoniusziekenhuis.nl

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INTRODUCTION

Esophageal adenocarcinoma is among the most rapidly rising cancers in the Western World [1]. Barrett's epithelium (BE) is a premalignant condition occurring secondary to gastroesophageal reflux disease. Patients with BE are at increased risk for the development of esophageal adenocarcinoma, with an estimated risk of 0.3% per year. Therefore, current medical society guidelines advise endoscopic surveillance of patients with BE in order to identify early neoplastic lesions that can be cured with endoscopic therapies [2].

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MANAGEMENT OF BARRETT'S ESOPHAGUS–RELATED NEOPLASIA

There are basically two types of endoscopic treatment for BE related neoplasia: endoscopic resection and ablative therapy. Endoscopic resection is the cornerstone in treatment of BE-related neoplasia. Removal of all visible lesions, no matter how subtle, with endoscopic resection is essential for adequate histological evaluation and staging.

There are two major indications for ablative therapy of BE. The first is flat dysplasia in BE, high-grade dysplasia (HGD) or low-grade dysplasia (LGD), provided that the histologic diagnosis is confirmed by expert pathologists with biopsies from at least two successive endoscopies. The second indication is residual BE after endoscopic resection of visible dysplastic lesions, since there is a chance of up to 30% of developing metachronous lesions during follow-up [3,4]. The risk of recurrence of carcinoma and intestinal metaplasia are reduced to 4 and 8%, respectively, after ablation [5].

Ablation can be performed with either heat-based techniques such as radiofrequency ablation (RFA) or argon plasma coagulation, or cold-based techniques (cryotherapy). At this moment, RFA is the most established ablation technique for BE with high efficacy and a good safety profile [5,6]. Moreover, treatment with RFA improves disease-specific, health-related quality of life [7].

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PRINCIPLES AND BACKGROUND OF CRYOTHERAPY

Cryotherapy has been used for several decades in a variety of oncological conditions in the fields of dermatology, urology, and gynecology. Application methods include inserting a needle, spraying, and local application, and depend on the targeted tissue.

The mechanism of cryotherapy comprises a complex cascade of destructive stresses. It starts with immediate physical events, including extracellular and intracellular ice crystal formation. After hours to days, this leads to cellular damage and postthaw necrosis. At the same time, an apoptotic response is induced by activation of a rapid, membrane-based apoptotic response within the core of a cryogenic lesion (extrinsic), and a delayed mitochondrial-based apoptotic response in the periphery of the cryogenic lesion, partly because of severe oxidative stress (intrinsic). In the last phase, within days to weeks, secondary necrosis occurs due to hypoxia and coagulation necrosis from vascular stasis [8]. Freezing of the tissue should be performed rapidly, while thawing should be slow and complete: the freeze-thaw cycle. The severity of injury is dependent on the target temperature, duration of freezing and the number of freeze-thaw cycles. Repeated freeze-thaw cycles are often used clinically. Repetition of the freeze-thaw cycle might amplify the injurious events that destroy the diseased tissue, although studies have shown that at tissue temperatures of below −50°C cells are sufficiently damaged in a single freeze-thaw cycle [9]. Precise dosimetry in cryotherapy remains difficult due to diversity in procedural implementation, device types, and thermal gradients in frozen tissue and variations in regional blood flow [8].

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CRYOTHERAPY DEVICES FOR ESOPHAGEAL APPLICATION

For intraesophageal use, there are currently two ways to apply cryotherapy. The first is cryospray therapy, which can be performed with either carbon dioxide (CO2) or liquid nitrogen. The CryoSpray ablation system (Fig. 1[10▪▪]; 2nd generation, CSA Medical, Baltimore, MD, USA) uses a generator that delivers cold liquid nitrogen at −196°C through a flexible spray catheter with low-flow continuous delivery in a noncontact method. Because of the potential of rapid expansion of the liquid nitrogen into 4–6 L of gas during 20-s treatments, a multiport orogastric decompression catheter is placed with constant suction [11]. The Polar Wand ablation technology (Figs. 2 and 3[12▪]; GI Supply, Camp Hill, Pennsylvania, United States) uses a through-the-scope spray catheter to deliver compressed liquid CO2 that rapidly expands during spraying and reaches −78°C as it exits the catheter. Because of the lower flow volume compared with liquid nitrogen, a separate decompression catheter is not required. A suction channel is directly connected to the spray catheter, as it requires 6–8 L/min CO2 to achieve a temperature of less than −70°C [11]. Both techniques are typically used in freeze-thaw cycles; the most frequently used dosimetry is either two applications of 20 s or four applications of 10 s.

A novel technology for delivering intraesophageal cryotherapy is the CryoBalloon focal ablation system (Fig. 4[13▪]; C2 Therapeutics, Redwood City, California, USA). The system comprises a battery-powered handle with a trigger mechanism, a cartridge containing liquid nitrous oxide, and a catheter with a single spray hole in the shaft covered by a compliant balloon. This through-the-scope device allows for focal ablation (approximately 2 cm2) by the release of nitrous oxide (−85°C) in the balloon that adapts to the diameter of the esophageal lumen. When applying cryotherapy, the gas is contained within the balloon and immediately vented back through the catheter into the handle where it condenses into a sponge (Fig. 5[13▪]).

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DIFFERENCES BETWEEN HEAT-BASED ABLATION AND CRYOTHERAPY

Heat-based ablation techniques with temperatures above 42°C induce denaturation of proteins; an irreversible process with a permanent change in the structure of vital cellular proteins. In contrast, cryoablation induces ice crystal formation, but does not lead to permanent changes in protein structure after thawing. This is a potential advantage since it might preserve the extracellular collagen matrix architecture and enable deeper ablation without increasing stricture rates [8]. In addition, cryotherapy might result in less pain due to an anesthetic effect of cooling of the tissue and its surrounding nerves [14]. These potential advantages of cryotherapy, however, need to be proven relevant in clinical practice. It must be emphasized that current data on safety and efficacy of RFA as an ablation tool for Barrett's esophagus are much more robust than those for any form of cryotherapy.

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REVIEW OF LITERATURE ON CRYOTHERAPY

Cryotherapy is mostly performed in patients with flat-type dysplastic BE. A recent multicenter, prospective, open-label registry reports cryospray therapy with liquid nitrogen to be safe and effective in treating BE patients with LGD and HGD [10▪▪]. Complete eradication of HGD (CE-HGD) and LGD (CE-LGD) was seen in 81 and 91%, respectively, and complete eradication of intestinal metaplasia (CE-IM) in 65% and 61% with an average of 3.5 and 2.9 treatment sessions. With 96 patients included in this registry, this is the largest prospective series reported on this subject thus far. Patients with Barrett's segments up to 14 cm were included, and about one-third of the patients had received previous treatments. These results are in accordance with two multicenter, retrospective studies in 2010 with liquid nitrogen cryospray therapy reporting CE-HGD in 94–97% and CE-IM in 53–57% [15,16]. As a reference: a recent prospective UK registry study on RFA including 508 patients showed complete eradication of dysplasia (CE-D) and CE-IM in 92% and 83%, respectively [17]. In a controlled, prospective, multicenter study of 124 patients treated with RFA, CE-D and CE-IM were achieved in 98% and 93% of patients [18].

Cryotherapy might have a role in Barrett patients not responsive to other treatment modalities. Sengupta et al.[19▪] reported on the use of cryospray therapy with liquid nitrogen as salvage therapy in RFA refractory cases. RFA failure was defined as progression of dysplasia while on RFA treatment, persistent dysplasia after three RFA sessions, or cases deemed treatment failures by the treating endoscopist. Sixteen RFA refractory patients were treated with cryotherapy: CE-D and CE-IM was achieved in 75 and 31%, respectively. Although these results are promising, data on efficacy of cryotherapy in RFA-refractory cases should be interpreted with caution. Failure of, or incomplete response to RFA might be because of a number of factors that should be considered before switching to another ablation technique [20]. First, ongoing inflammation due to poorly controlled reflux can lead to thickening of the mucosa that renders it less susceptible to RFA, given its limited ablation depth. In these cases, better reflux control might eliminate the mucosal thickening that prevented its eradication by RFA. Moreover, persistence of areas of BE after multiple courses of RFA should raise suspicion for cancer, again with the mucosa being too thick for RFA to achieve an adequate depth of ablation. In these cases, endoscopic resection should be considered rather than an alternative ablation method. In our experience, real RFA refractoriness of nonmalignant Barrett's metaplasia is a rare phenomenon.

Another field of interest for application of cryotherapy is ablation of residual BE after endoscopic resection of visible lesions. Unfortunately, a recent prospective, single-center study with CO2 cryospray therapy was prematurely terminated because of insufficient efficacy, with CE-IM achieved in only 11% of patients [12▪]. A clear explanation for the lack of efficacy in this trial is missing. One might hypothesize that the relatively high cryo temperatures when using CO2 rather than liquid nitrogen might be of influence. However, a retrospective, two-site study using CO2 cryospray therapy in 64 patients showed much better results: CE-IM was achieved in 67% of patients after 3 years or at the last visit [21]. Twenty-eight patients had prior ablations (photodynamic therapy/RFA) and 16 had undergone previous EMR for visible lesions in this study.

The most recently published articles relate to the CryoBalloon focal ablation system. This device was developed to overcome disadvantages of the spraying technique, which include the need for gas venting, operator dependency and possible unequal distribution. First, a safety and feasibility study with the CryoBalloon was performed in 39 patients who received 62 ablations [22▪]. Ninety percentage of ablations were performed successfully, and squamous regeneration was seen in 100% with ablations of 10 s and a mean procedure time of 7 min. Twenty-seven percentage of patients reported pain, but none required analgesics. However, in each patient only one or two ablations of 2 cm2 each were delivered instead of ablation of the full BE segment. Next, the potential of this device for precise targeting of BE islands was investigated [13▪]. BE islands were adequately targeted (44/47) and CE-IM was observed in 100% of the completely ablated areas. Twenty-seven percentage of patients reported chest discomfort without need for analgesics. Again, only one or two focal ablations of about 2 cm2 were applied in each patient. Currently, the efficacy and safety of multiple side-by-side ablations using the CryoBalloon focal ablation system are being investigated. Preliminary results were presented with a median follow-up of 6 months [23▪]. Overall rates of CE-D and CE-IM were 95 and 71%, respectively.

Cryotherapy is safe and well tolerated. The most common complaint is chest pain or discomfort; 17.6% of patients reported chest pain in a retrospective multicenter study with 77 patients [16]. However, the number of patients reporting severe pain requiring analgesics is much lower in most studies (2.6%). Logically, the severity of pain after cryotherapy appears to be related to the area of ablated mucosa [15,23▪]. In general, however, endoscopists performing both RFA and cryotherapy have the impression that patients treated with cryotherapy report less pain than patients treated with RFA. There are, however, no direct comparative studies on this subject.

Strictures occur infrequently after cryotherapy (3–3.8–9%) and can be treated successfully with dilation [15,16,24]. Reported stricture rates in RFA (6–11.8%) appear to be comparable [6,25]. Two studies on cryospray therapy, one with liquid nitrogen and one with CO2, report a patient with a perforation. One of these patients had Marfan syndrome. We endorse the recommendation by the authors not to perform cryospray therapy in patients with limited ability to distend the stomach, as for example patients with connective tissue diseases or altered anatomy after gastrointestinal surgery [16]. The second reported perforation occurred during the first treatment session of the study, and the authors concluded that this was to be attributed to the learning curve [12▪].

Little is known about the durability of cryotherapy. Reported recurrence rates after cryotherapy vary widely (0–33%) [19▪,21,24,26–28▪▪]. This might be due to the wide variations among studies in their definition of recurrence and in their biopsy and surveillance protocols. For example, recurrence can be defined as recurrence of visible BE in the original Barrett segment, as intestinal metaplasia found in biopsies taken just below the neosquamocolumnar junction, or as the presence of subsquamous intestinal metaplasia (also known as buried BE). Moreover, recurrence can occur after first achieving complete eradication of all intestinal metaplasia, or BE can remain or extend despite therapy. A single-center, retrospective study with the longest follow-up thus far reports the long-term outcomes after cryospray therapy with liquid nitrogen in 40 patients after 5 years of follow-up [28▪▪]. Initial CE-D and CE-IM was achieved in 90% and 65%, respectively. Of the patients with initial CE-IM, 81% (21/26) had persistent CE-IM after 5 years of follow-up. Overall rates of CE-D and CE-IM after 5 years, when allowing for retreatment, were 88% and 75%, respectively. Of all cases of recurrent dysplasia (both HGD and LGD], more than 75% were found at the area just below the neosquamocolumnar junction. For RFA, in comparison, reported recurrence rates differ widely. Retrospective studies report recurrence rates of 26–33% [29–31]. However, a European multicenter randomized controlled trial and a prospective, multicenter study reported recurrence rates of only 8–10% in patients treated with RFA [18,25]. Persistence of BE covered by regenerated squamous epithelium (subsquamous BE, or buried BE) is a potential risk for all ablative techniques. The risk of progression to malignancy might be less than that of unablated epithelium, as the subsquamous cells have no exposure to acid reflux [32], but the hidden nature of subsquamous BE hampers adequate surveillance. A systematic review on this subject reports subsquamous IM after RFA in 0.9% [32]. Literature on cryospray therapy report much higher percentages of subsquamous IM ranging from 0–9.1% [12▪,13▪,15,26,27,33]. Unequal distribution of cryospray might account for these higher percentages. In theory, by providing a more uniform and more predictable ablation effect, the CryoBalloon system could compare favorably in this respect, but studies on the CryoBalloon system so far are insufficient to draw conclusions on this subject. An overview of all data on efficacy, safety, and durability of cryotherapy is provided in Table 1.

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CONCLUSIONS AND FUTURE PERSPECTIVES

There are multiple types of cryotherapy, multiple ways of applying cryotherapy, and multiple cryogenic fluids. In addition, substantial variation exists in study designs and endpoints. Most studies lack a uniform standard definition of eradication. Efficacy is reported in response, reversal or complete eradication rates. In addition, inclusion and exclusion criteria vary widely among studies, and biopsy protocols and surveillance intervals are often poorly defined. It is therefore hard to make a fair comparison among the various cryoablation techniques, and to compare cryotherapy with RFA.

The conceptual benefits of cryotherapy are appealing. By preserving the extracellular matrix and inducing anesthetic effects, cryotherapy has the potential to enable deeper ablations with less pain and a lower rate of stricture formation than RFA. To date, however, these potential benefits remain unproved. Prospective studies with clearly defined endpoints and longer follow-up are necessary to determine the role of cryotherapy in the management of BE. Ultimately, direct comparative studies on efficacy, safety, durability, costs and quality of life with the most established ablation technique (RFA) are required.

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Acknowledgements

None.

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Financial support and sponsorship

None.

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Conflicts of interest

Prof. Dr. Weusten has received financial support for IRB approved studies by C2Therapeutics. For A. Overwater none were declared.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

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REFERENCES

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This is the largest prospective multicenter study reporting cryotherapy with liquid nitrogen to be safe and effective in eradicating Barrett's epithelium, especially in short Barrett segments.

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This study was early terminated because of low efficacy of cryospray therapy with carbon dioxide. These results are in contrast with previously performed studies with the same technique.

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Barrett's esophagus islands were adequately targeted with the CryoBallon Focal Ablation System and adequately targeted islands showed complete eradication of Barrett's epithelium.

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This study reports cryotherapy to be safe as salvage therapy for refractory dysplasia or recurrent dysplasia after RFA. Caution is warranted, since RFA refractoriness should raise suspicion for reflux esophagitis or malignancy.

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This is a study on a new technology for cryoablation: the CryoBalloon Focal Ablation device. This device is developed because of possible advantages over the spraying technique with no need for gas venting and possibly a more equal distribution of the cryoablation.

23▪. Canto MI, Shin EJ, Khashab MA, et al. 638 Multifocal nitrous oxide CryoBalloon ablation with or without endoscopic mucosal resection (EMR) for treatment of neoplastic Barrett's esophagus (Be): preliminary results of a prospective clinical trial in treatment-naive and previously ablated patients. Gastrointest Endosc 2016; 83:AB159.

Preliminary results of this study are the first data on performing multifocal ablations with the CryoBalloon.

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The is the first study reporting long-term outcomes 5 years after cryospray therapy with liquid nitrogen.

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Keywords:

ablation techniques; Barrett's epithelium; Barrett's esophagus; cryoablation; cryotherapy

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