Cryotherapy is a noncontact ablation method that has long been used clinically in the treatment of a wide variety of malignant and premalignant diseases. The relative ease of use and unique mechanisms of cellular destruction make cryotherapy particularly attractive for the eradication of dysplastic Barrett’s esophagus. Currently, liquid nitrogen and carbon dioxide are the most common cryogens used. Preliminary data with these agents have shown high efficacy in the reversal of dysplastic Barrett mucosa and excellent safety profiles. Intense investigation on cryotherapy ablation of Barrett’s esophagus is ongoing.
Approximately 16,500 Americans are diagnosed with esophageal cancer and 14,500 die of this malignancy each year. The incidence of esophageal adenocarcinoma has continued to rise dramatically over the past 4 decades and is growing at a rate faster than that of any other cancer in the United States. Barrett’s esophagus (BE) is a well-known risk factor in the development of esophageal adenocarcinoma. In the absence of dysplasia, BE is associated with an increased esophageal cancer risk of approximately 0.5% per patient-year. With the presence of high-grade dysplasia (HGD), however, the risk of progression to cancer may be as high as 10% per patient-year. Traditionally, surgery with esophagectomy has been the mainstay of treatment for patients found with HGD; however, many patients are elderly and deemed to be poor surgical candidates. In addition, esophagectomy is associated with significant morbidity and mortality and recent reports have shown recurrence of Barrett metaplasia in as high as 18% of patients after “curative” esophagectomy despite high-dose acid suppressive medications. Therefore, there is increasing interest and research in endoscopic treatments of BE. Cryoablation has long been used to treat a wide variety of dermatologic and gynecologic conditions for more than half a century. Not until recently, however, was the application of cryotherapy in gastroenterology seriously investigated, particularly in the treatment of dysplastic BE and early esophageal cancer. This article focuses on current understanding and results of cryotherapy in the treatment of BE.
Principles and mechanisms of cryotherapy ablation
Cryotherapy is the application of exceptionally cold temperatures to destroy targeted tissue. Tissue destruction from repeated cycles of rapid freezing followed by slow thawing occurs on a cellular and molecular level. At temperatures between –76°C and –158°C, cryotherapy can induce cellular apoptosis. The exact mechanism and biology underlying tissue injury is complex and incompletely understood. As the temperature drops to the freezing point, water in the extracellular matrix forms ice crystals and creates a hypertonic environment causing water to leave the cells by osmosis. Intracellular dehydration and shrinkage ensue. With further freezing, intracellular ice crystallization also occurs, leading to protein denaturation and shearing of the organelles and cytoskeleton. During the thawing process, a brief period of extracellular hypotonicity results in a reverse osmotic gradient, which causes water to rush into the cells rapidly leading to cellular swelling and eventual rupture of the cell membrane. Effects of cryotherapy on cellular injury are dependent on several factors, including the rate of cooling and thawing, the lowest tissue temperature achieved, the water content of the cells, and the number of freeze-thaw cycles. The drop in tissue temperature occurs more quickly with each freeze-thaw cycle and leads to increased depth and volume of the area affected.
Delayed injurious effects of cryotherapy are as important in tissue destruction as the immediate effects and occur hours to days after treatment. Freezing causes vasoconstriction and modification of vascular endothelium, resulting in a cascade of events including increased vascular wall permeability, decreased blood flow, platelet aggregation, and formation of microthrombi. With the loss of microcirculation, a wide area of progressive cellular anoxia and hemorrhagic necrosis results in apoptosis of even cells that may have survived the initial freezing. Furthermore, immune-related processes also may contribute to the success of delayed effects of cryotherapy on malignant tumors. Cancer cells outside of the ablation area have been shown to undergo apoptosis by cryotherapy-induced antitumor response. It has been proposed that cryoimmunity may be achieved via increases in tumor antigens against a backdrop of a significant inflammatory microenvironment created during the cryoablative process, which then results in cytotoxic T-cell proliferation and enhanced Th1 response. Although cryoimmunity has not been specifically studied in gastrointestinal cancers, the possibility of enhanced antitumor immunogenicity makes cryotherapy particularly attractive compared with other endoscopic ablation therapies.
Endoscopic cryotherapy devices
The major technical advantage of cryotherapy in comparison with other ablative technologies is the ability to spray the mucosa at will, producing rapid injury of fairly large areas without the need for contact. In contrast, the success of most thermal ablation techniques is dependent on precise close contact between the ablation probe and esophageal mucosa. Although studies are needed, cryotherapy in theory may be the preferred modality to treat lesions in the gastroesophageal junction and in patients with a slightly tortuous esophageal anatomy where precise physical contact between the surface of the ablation probe and the mucosa is very difficult to maintain. The major disadvantage of cryotherapy compared with thermal ablation is the large volume of cryogen gas exiting the catheter, which increases risks of perforation unless adequate venting is established. Pasricha and colleagues first described a through-the-scope probe-based cryotherapeutic device (Cryomedical Sciences Inc, Bethesda, MD, USA) consisting of a long, insulated catheter through which liquid nitrogen is delivered near its saturation temperature of –196°C. Clinical application of the initial prototype was limited because of restricted catheter maneuverability caused by excessive endoscopic rigidity from delivery of liquid nitrogen at very low temperature. The investigators then went on to describe a second prototype that used cryogenic refrigerant at or near ambient temperature, based on the Joule Thomson effect, whereby high-pressured gas, in this case carbon dioxide (CO 2 ), is forced at or near ambient temperature through the catheter and upon reaching the distal tip, a sudden and rapid expansion of the gas from a higher pressure to atmospheric pressure causes a massive drop in temperature. More recently, this invention was incorporated into the Polar Wand cryotherapy device (GI Supply, Camp Hill, PA, USA) using CO 2 gas as a cooling agent ( Fig. 1 ). At flow conditions of 6 to 8 L/min, end effector temperatures of –78°C can be achieved. The ablation catheter is passed though the working channel and a suction catheter is attached to the tip of the endoscope for decompression. In contrast to a liquid nitrogen–based cryoablation system (see the following paragraph), the cryocatheter in the accessory channel remains at ambient temperature, thus preserving normal endoscopic maneuverability. Furthermore, expensive cryogen holding tanks used to contain liquid nitrogen are not necessary when using a CO 2 -based system.
The CryoSpray Ablation System (CSA Medical, Inc, Baltimore, MD, USA) is an alternative method to deliver cryotherapy and consists of a 7F catheter manufactured from a special polymer ( Fig. 2 ). With this system, a dual-lumen orogastric suction tube is inserted into the stomach for active suction and passive luminal decompression. Multiple distal ports and side holes along the cryo decompression tube allow for both gastric and esophageal decompression. Luminal decompression is imperative to prevent perforation because liquid nitrogen can expand into 6 to 8 L of gas during each 20 seconds of treatment. The endoscopist controls the cryoablation and suction decompression with a foot pedal provided with the system.
Endoscopic cryotherapy devices
The major technical advantage of cryotherapy in comparison with other ablative technologies is the ability to spray the mucosa at will, producing rapid injury of fairly large areas without the need for contact. In contrast, the success of most thermal ablation techniques is dependent on precise close contact between the ablation probe and esophageal mucosa. Although studies are needed, cryotherapy in theory may be the preferred modality to treat lesions in the gastroesophageal junction and in patients with a slightly tortuous esophageal anatomy where precise physical contact between the surface of the ablation probe and the mucosa is very difficult to maintain. The major disadvantage of cryotherapy compared with thermal ablation is the large volume of cryogen gas exiting the catheter, which increases risks of perforation unless adequate venting is established. Pasricha and colleagues first described a through-the-scope probe-based cryotherapeutic device (Cryomedical Sciences Inc, Bethesda, MD, USA) consisting of a long, insulated catheter through which liquid nitrogen is delivered near its saturation temperature of –196°C. Clinical application of the initial prototype was limited because of restricted catheter maneuverability caused by excessive endoscopic rigidity from delivery of liquid nitrogen at very low temperature. The investigators then went on to describe a second prototype that used cryogenic refrigerant at or near ambient temperature, based on the Joule Thomson effect, whereby high-pressured gas, in this case carbon dioxide (CO 2 ), is forced at or near ambient temperature through the catheter and upon reaching the distal tip, a sudden and rapid expansion of the gas from a higher pressure to atmospheric pressure causes a massive drop in temperature. More recently, this invention was incorporated into the Polar Wand cryotherapy device (GI Supply, Camp Hill, PA, USA) using CO 2 gas as a cooling agent ( Fig. 1 ). At flow conditions of 6 to 8 L/min, end effector temperatures of –78°C can be achieved. The ablation catheter is passed though the working channel and a suction catheter is attached to the tip of the endoscope for decompression. In contrast to a liquid nitrogen–based cryoablation system (see the following paragraph), the cryocatheter in the accessory channel remains at ambient temperature, thus preserving normal endoscopic maneuverability. Furthermore, expensive cryogen holding tanks used to contain liquid nitrogen are not necessary when using a CO 2 -based system.
Related posts:
Barrett’s Esophagus: Clinical Issues
Barrett’s Esophagus Surveillance: When, How Often, Does It Work?
Biology of Barrett’s Esophagus and Esophageal Adenocarcinoma
The Role of Radiofrequency Ablation in the Management of Barrett’s Esophagus
Endotherapy for Barrett’s Esophagus: Which, How, When, and Who?
Role of Minimally Invasive Surgery in the Modern Treatment of Barrett’s Esophagus
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