Cryotherapy in the Management of Esophageal Dysplasia and Malignancy

Accumulating evidence highlights the promising results seen with endoscopic spray cryotherapy in the treatment of dysplasia associated with Barrett esophagus and esophageal carcinoma. Published studies show that the success of spray cryotherapy to eradicate Barrett high-grade dysplasia is comparable to that for other therapies, with a favourable safety profile and high levels of patient comfort. For patients with untreatable esophageal cancer, spray cryotherapy offers a therapeutic option with the potential for complete eradication in early-stage disease and palliation in advanced cases. The mechanism of tissue injury in cryotherapy is unique, with direct cytotoxic effects and ischemic effects from vascular injury. Increased tumor cell death through induction of apoptosis and immunologic effects require further study.

Barrett esophagus is a premalignant condition in which normal stratified squamous epithelium of the esophagus is replaced by metaplastic columnar epithelium. Chronic esophageal reflux is believed to be responsible for this mucosal transformation. Dysplasia arising within metaplastic epithelium is recognized as the major risk factor leading to the development of adenocarcinoma. Dysplasia is believed to progress from low-grade dysplasia to high-grade dysplasia (HGD), and ultimately transform into esophageal adenocarcinoma. Esophageal cancer remains relatively uncommon, yet its incidence has continued to rise steadily over the last 3 decades. In 2008, approximately 16,000 patients (12,500 men and 3500 women) were diagnosed with esophageal cancer and nearly 14,000 died from the disease. These patients generally have a poor prognosis with an overall 5-year survival rate of 10% to 15%.

Healthy patients with biopsy-proven HGD typically have been treated with esophagectomy because of a 5% to 6% annual risk of developing esophageal adenocarcinoma. Many patients are determined to be poor surgical candidates, making it difficult to justify the morbidity and mortality associated with esophagectomy. This has led to the development of several methods of controlled mucosal ablation with the goal of preventing the development of esophageal adenocarcinoma. Currently, endoscopic ablation of Barrett esophagus with HGD and intramucosal carcinoma (IMCA) is accepted therapy for those patients considered inoperable or who decline surgical therapy, and studies have shown that elimination of HGD significantly lessens the risk of developing esophageal adenocarcinoma.

Current ablative techniques include endoscopic resection, photodynamic therapy (PDT), argon plasma coagulation (APC), Nd:YAG (neodymium:yttrium-aluminum-garnet) laser, multipolar electrocoagulation, balloon- and catheter-based radiofrequency ablation (RFA), and cryotherapy. These techniques have achieved mucosal ablation with variable success and each has unique advantages and disadvantages. This article highlights the cumulative findings on the efficacy and safety of cryotherapy in the treatment of esophageal dysplasia and carcinoma.

Mechanism of action

Cryotherapy is the application of extreme cold to biologic tissues for medical treatment. Studies have shown it is most effective when administered as repeated cycles of rapid freezing followed by slow thawing. This process destroys tissue through a combination of immediate and delayed effects while also preserving the cryoresistant structures of the extracellular matrix. Initial cooling causes hypothermia, which stresses cell proteins and lipids. Ultimately, this can lead to cell death even if freezing temperatures are not reached. When tissue temperatures reach freezing, extracellular water freezes, forming ice crystals. These extracellular ice crystals create a hyperosmotic environment, drawing water from intracellular compartments. As the temperature continues to fall, crystallization accelerates, amplifying fluid shifts and resulting in cellular shrinkage and destruction of cellular membranes and organelles (solution-effect injury). Rapid freezing and lower temperatures favor formation of intracellular ice, increasing the likelihood of cell death. Colder temperatures appear to be needed to reliably destroy cancer cells and increase the likelihood of destroying all cells in the treated area.

During the thawing portion of the treatment cycle, large crystals form and disrupt cellular membranes through mechanical and shearing forces. Further membrane disruption occurs as ice crystals melt, producing a hypotonic extracellular environment that shifts water back into cells and ruptures cell membranes. Tissue hypothermia remains for minutes following complete thawing, subjecting tissues to continued metabolic injury.

Vascular stasis, with tissue ischemia and anoxia, is instrumental in cryotherapy-induced tissue destruction. Initial cooling results in vasoconstriction and decreased blood flow, and freezing produces cessation of blood flow. Thawing produces vasodilation and increased vascular permeability through endothelial damage. This damage results in edema, platelet aggregation, and formation of microthrombi, leading to further circulatory collapse. Continued microcirculatory occlusion results in uniform cell death in the affected area, including cells that may have survived the initial insult.

Repetition of the freeze-thaw cycle results in greater cellular destruction. Tissue cooling is more rapid with each cycle, and the volume of frozen tissue is increased as the cryoeffect further penetrates the target tissue. This results in greater extent, depth, and volume of destroyed tissue in a dose-dependent manner. Relative resistance of stromal components to freezing injury (including collagen fibers) leads to favorable healing because preservation of the extracellular matrix results in a more controlled wound response with less potential for fibrosis and scarring.

Induction of an immunologic reaction is one of the most intriguing aspects of cryotherapy. This technique has been shown to induce cellular apoptosis in cancer cells and may lead to death of malignant cells outside of the original treatment area. This characteristic, unique to cryotherapy, makes cryotherapy particularly useful and attractive in the treatment of Barrett-associated HGD and cancer, as inhibition of apoptosis is one element involved in pathogenesis. Apoptosis-induced immunogenicity can lead hypothetically to an established cellular immunity within esophageal mucosa capable of killing malignant cells that develop long after cryotherapy has been completed.

Cryotherapy systems

Different agents, known as cryogens, have undergone clinical investigation to assess their success at tissue destruction. Liquid nitrogen is inert, inexpensive, and readily available, and it has been used successfully as a cryogen for over 5 decades, given its reliability and known effects. It can cool tissues to approximately −196°C. Carbon dioxide (CO ₂) is another cryogen used for gastrointestinal indications. CO ₂-based cryotherapy uses the rapid high-pressure expansion of CO ₂to induce rapid cooling of tissues to approximately −78°C (the Joule-Thompson effect).

Two separate noncontact catheter-based systems have been developed for spraying cryogen through the working channel of an endoscope. In both, the operator uses the duration of cryogen application and time of tissue freezing to control the depth of esophageal injury. The Cryospray Ablation System (CSA Medical, Inc, Baltimore, Maryland) is a low–ambient pressure system using liquid nitrogen ( Fig. 1 ). A 7F catheter is passed through the working channel of a standard upper endoscope, and the pressure exiting the distal tip of the catheter is approximately 2 to 4 psi. The console consists of a holding tank for liquid nitrogen and the electronic controls necessary to control flow of the cryogen. The console contains a timer with visual and auditory cues to monitor spray time and counters to track the number of freeze-thaw cycles and sites treated. A heating circuit warms the catheter at the end of the procedure to ease removal from the scope. External suction from a pump or wall suction is controlled within the console and connected to an orogastric decompression tube (described below). A two-pedal foot switch is provided with the system—one to activate the spray and the other to engage and disengage suction. Treatment is performed under direct endoscopic visualization and the extent of therapy is controlled by the operator using the foot pedal to control duration of spray.

The Polar Wand cryotherapy device (GI Supply, Camp Hill, Pennsylvania) is a delivery system using CO ₂to generate a cryogen. Rapidly expanding high-pressure CO ₂gas produces cooling, known as the Joule-Thompson effect. A catheter is passed through the working channel of an upper endoscope, and a suction catheter is attached to the tip of the endoscope for decompression throughout the procedure.

Cryotherapy systems

Different agents, known as cryogens, have undergone clinical investigation to assess their success at tissue destruction. Liquid nitrogen is inert, inexpensive, and readily available, and it has been used successfully as a cryogen for over 5 decades, given its reliability and known effects. It can cool tissues to approximately −196°C. Carbon dioxide (CO ₂) is another cryogen used for gastrointestinal indications. CO ₂-based cryotherapy uses the rapid high-pressure expansion of CO ₂to induce rapid cooling of tissues to approximately −78°C (the Joule-Thompson effect).

Two separate noncontact catheter-based systems have been developed for spraying cryogen through the working channel of an endoscope. In both, the operator uses the duration of cryogen application and time of tissue freezing to control the depth of esophageal injury. The Cryospray Ablation System (CSA Medical, Inc, Baltimore, Maryland) is a low–ambient pressure system using liquid nitrogen ( Fig. 1 ). A 7F catheter is passed through the working channel of a standard upper endoscope, and the pressure exiting the distal tip of the catheter is approximately 2 to 4 psi. The console consists of a holding tank for liquid nitrogen and the electronic controls necessary to control flow of the cryogen. The console contains a timer with visual and auditory cues to monitor spray time and counters to track the number of freeze-thaw cycles and sites treated. A heating circuit warms the catheter at the end of the procedure to ease removal from the scope. External suction from a pump or wall suction is controlled within the console and connected to an orogastric decompression tube (described below). A two-pedal foot switch is provided with the system—one to activate the spray and the other to engage and disengage suction. Treatment is performed under direct endoscopic visualization and the extent of therapy is controlled by the operator using the foot pedal to control duration of spray.

The Polar Wand cryotherapy device (GI Supply, Camp Hill, Pennsylvania) is a delivery system using CO ₂to generate a cryogen. Rapidly expanding high-pressure CO ₂gas produces cooling, known as the Joule-Thompson effect. A catheter is passed through the working channel of an upper endoscope, and a suction catheter is attached to the tip of the endoscope for decompression throughout the procedure.

Treatment technique

There are several contraindications to spray cryotherapy, including pregnancy, anatomic alterations of the esophagus or stomach, breaks in the esophageal mucosa, diminished elasticity of the gastrointestinal tract, and the presence of food in the stomach or duodenum that cannot be removed. Cryotherapy has not been studied in pregnancy, so the effects of treatment in this setting are unknown. Anatomic alterations that preclude cryotherapy include esophageal narrowing that may block passage of the endoscope and decompression tube and gastric alterations that may reduce or restrict the volume of the stomach, potentially increasing the risk of perforation. Such alterations include those related to gastrojejunostomy and many gastric bariatric procedures. Cryotherapy is contraindicated in the setting of esophageal ulceration or when mucosal breaks are evident. These breaks can be due to esophageal inflammation, dilation, endoscopic resection, or an aggressive biopsy. These mucosal breaks may allow the passage of cryogen through the esophageal wall, resulting in pneumomediastinum or pneumoperitoneum. Marfan syndrome is the prototypical condition that diminishes elasticity of the stomach. A single case of gastric perforation has been reported in a patient with Marfan syndrome after cryotherapy. Eosinophilic esophagitis can cause stiffening and narrowing of the esophagus, and cryotherapy should not be performed in advanced disease. Food residue in the stomach or duodenum may block the suction ports in the cryo-decompression tube and prevent adequate venting of gas. If removal of this food cannot be accomplished, the procedure must be rescheduled.

Spray cryotherapy is performed during routine outpatient upper gastrointestinal endoscopy. No specific preparation is needed for cryotherapy. For esophageal ablation, high-dose proton pump inhibitor therapy (twice daily) is initiated 1 week before treatment to maximize acid suppression. Standard sedation is used, either a combination of midazolam and fentanyl/meperidine or monitored anesthesia care with propofol.

Treatment sessions begin with routine endoscopic evaluation. Before scope removal, a guidewire (typically a Savary-Gilliard wire [Cook Medical, Bloomington, Indiana]) is inserted through the scope and left with the distal tip in the stomach. After scope removal, the cryo-decompression tube is lubricated and inserted over the wire into the stomach. Liquid nitrogen spray generates 6 to 8 L of nitrogen gas during a 20-second treatment as the expelled liquid expands into a gas. This tube allows rapid gastric decompression and removal of sprayed nitrogen during treatment cycles. The tube itself contains multiple side holes for luminal decompression. Active suction occurs in the distal tube, demarcated by a double black line on the tube itself. Side holes in the proximal tube open in the esophagus and passively vent to the air for esophageal decompression. Before scope reinsertion, a soft clear friction-fit cap (eg, D-201-11804 [Olympus America, Center Valley, Pennsylvania]) is inserted over the tip of the endoscope to optimize visualization and prevent the cryocatheter tip from contacting the mucosa. The endoscope is reinserted and advanced to the distal esophagus. The decompression tube is withdrawn until the black line on the tube approximates the gastroesophageal junction. The scope is then positioned to the treatment area and the cryocatheter is passed through the biopsy channel and advanced just distal to the tip of the endoscope, allowing for enough clearance to avoid frosting of the lens on the end of the endoscope.

Suction is activated before each cryogen application via the foot pedal. Targeted tissue is frozen for the appropriate length of time (typically 10–20 seconds) and allowed to thaw, thus completing one cycle of treatment. Typically, a targeted area is treated for two to four cycles. If the entire area of interest has not been treated, the next site is selected and the freeze-thaw cycles are repeated. While spraying, the patient is monitored by endoscopy personnel for abdominal distension by placing a hand on the patient’s abdomen. The procedure is temporarily halted if abdominal distension is noted or if suction is compromised.

The surface area of the esophagus that can be kept frozen during a treatment cycle is variable and is determined by the physician. An area 3 cm across can easily be kept frozen for the needed time. Hemicircumferential or circumferential freezing is also possible, especially in later treatment cycles and sites, where the area is already hypothermic ( Fig. 2 ). Overlap areas between two treatment sites occur routinely. Once treatment is complete, the scope and cryo-decompression tube are removed from the patient. Removal of the catheter from the scope is aided by using the heat cycle provided on the console to warm the catheter and scope. Cryotherapy has been used extensively at some centers since 2006, and no damage to endoscopes has been reported despite multiple uses.