Cryotherapy for Barrett's esophagus: does the gas really matter?

 

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Endoscopic spray cryotherapy is a unique advancement in the endoscopist's toolbox. Not long ago, the technology of cryotherapy in spray form was limited to dermatology, where it still enjoys frequent use and efficacy for the elimination of epithelial neoplasia and other unwanted tissue. Non-contact endoscopic ablation modalities include laser, photodynamic therapy (PDT), argon plasma coagulation (APC), and spray cryotherapy. Cryotherapy is distinguished from these other technologies by the use of intensely cold temperatures to disrupt cellular and extracellular functions and to induce apoptosis. Two very different systems are commercially available for endoscopic cryotherapy: liquid nitrogen (CryoSpray Ablation, CSA Medical, Baltimore, Maryland, USA) and carbon dioxide (CO₂; Polar Wand, GI Supply, Camp Hill, Pennsylvania, USA). The CO₂ system relies on the Joule–Thompson effect, whereby rapid expansion of CO₂ freezes the tissue to –78 ° C as it exits the specialized catheter. The liquid nitrogen system delivers actual liquid nitrogen at a temperature of –196 ° C to the target tissue. It is not hard to imagine that the difference of –100 ° C would translate into differences in the technical application, efficacy, and risk profile of each method of endoscopic cryotherapy.

The liquid nitrogen system has been shown to be effective in eradicating Barrett's esophagus with high grade dysplasia and intramucosal carcinoma even for patients in whom other ablation modalities have failed, according to early reports [1] [2]. The liquid nitrogen system gained acceptance in academic centers with experience in the ablation of Barrett's esophagus after retrospective studies demonstrated efficacy rates comparable to radiofrequency ablation (RFA), as reported in a multicenter registry study by Ganz et al. [3] [4] [5]. In this issue of Endoscopy, Xue et al. present a prospective nonrandomized, case series of CO₂ cryotherapy for Barrett's esophagus, with the primary outcome measure of complete eradication of specialized intestinal metaplasia [6]. Previously, the CO₂ system was marketed primarily for the treatment of vascular lesions of the gastrointestinal tract [7], with reports in Barrett's esophagus limited to abstract form. The current study, although involving Barrett's esophagus, is not comparable to liquid nitrogen ablation studies. The two primary liquid nitrogen studies [4] [5] included only those with high grade dysplasia and intramucosal carcinoma, whereas the current study by Xue et al. specifically excluded these histologies. Most experts agree that nondysplastic Barrett's mucosa is easier to ablate than Barrett's with neoplasia. Trials also show a decline in ablation success rates when moving along the spectrum from nondysplastic Barrett's and low grade dysplasia to high grade dysplasia and intramucosal carcinoma. Whether endoscopic ablation of nondysplastic Barrett's esophagus should be performed at all outside of the research setting remains debated.

There are similarities between the current study and the previous liquid nitrogen studies. The authors in both allowed enrollment of patients in whom prior ablation had failed (in Xue et al. this was APC), unlike other more rigorous trials of RFA and PDT. And like Dumot et al. [1], a prospective cohort design was used. However, there are major limitations to the data presented by Xue et al. The authors' choice of ablating nondysplastic epithelium is probably based on the low incidence of Barrett's esophagus with dysplasia in their population. The sample size is small, treatment dosimetry is vague, the dose of proton pump inhibitor is low by Western standards, follow-up is limited to the 6-month exam, and the biopsy protocol was less than rigorous in the surveillance period. The durability of CO₂ ablation remains unclear. Three of nine patients with long-segment Barrett's esophagus had recurrent specialized intestinal metaplasia on 6-month follow-up, and an overall recurrence rate of 15 % was reported at that time point, even with the less intense biopsy protocol.

An advantage of spray cryotherapy is the “no touch” application of the cryogen on the target tissues. This is particularly important for uneven surfaces due to nodular mucosa, strictures, and other luminal irregularities. The increased depth of injury in liquid nitrogen cryotherapy has afforded some success in the treatment of malignant disease in the esophagus. Direct comparison of cryotherapy with RFA or PDT for long segments of flat Barrett's esophagus is necessary to make firm recommendations about the superiority of either in that setting. There is an impression that cryotherapy is less painful than RFA and PDT and less likely to induce strictures than PDT. These claims must be supported by prospective studies and a comparison of the number of treatment sessions required to achieve complete eradication of Barrett's esophagus.

The major limitation of endoscopic spray cryotherapy is distention in the gastrointestinal tract as a result of the phase change from liquid to gas for liquid nitrogen and rapid expansion of gas in the CO₂ system. Distention during treatment of the esophagus and stomach does not appear to be a major problem with the CO₂ system, which uses a low profile catheter attached to the endoscope to evacuate the excessive CO₂ gas. Other advantages of the CO₂ system are a smaller footprint, lower cost, and pliability of the endoscope during treatment. The liquid nitrogen system has a larger profile, higher cost, and tends to cause stiffness of the endoscope due to intensely low temperature of the insertion tube. However, this colder temperature may allow the liquid nitrogen to ablate larger areas and can achieve greater depth of therapy when desired (such as for submucosal lesions). Although the liquid nitrogen system delivers the cryogen at low pressures (2 – 4 psi), gaseous distention can occur rapidly, as the phase transfer generates 6 – 7 L/minute of nitrogen gas during a 20-second treatment cycle. An orogastric decompression tube must be placed prior to treatment to evacuate this nitrogen gas. The liquid nitrogen and CO₂ systems have not been compared in an in vivo or ex vivo study. Each system must be evaluated in terms of dosimetry, technique, and efficacy before trials can ethically compare these two novel treatment methods.

The undisputed role of liquid nitrogen cryotherapy in centers active in ablation of Barrett's esophagus seems focused on segments with nodular high grade dysplasia or mucosal carcinoma in mucosa with irregularities or fibrosis not amenable to mucosal resection. The role of cryotherapy in flat Barrett's esophagus, either with or without dysplasia, remains to be defined by further study. Experience with spray cryotherapy is accumulating and technologic improvements are underway in the liquid nitrogen system, which will lead to broader application of these devices. It is possible that both cryotherapy technologies will survive the economic challenges of medical device development, and physicians will be able to tailor their treatment by choosing the right tool from their endoscopic toolbox for the job at hand.

References

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B. D. GreenwaldMD 

University of Maryland School of Medicine and Greenebaum Cancer Center

22 South Greene Street
N3W62 Baltimore
MD 21201–1595
USA

Fax: +1-410-328-8315

Email: Bgreenwa@medicine.umaryland.edu