Cryotherapy for Barrett’s esophagus: A cool alternative?

Endoscopic eradication therapies for Barrett’s esophagus (BE) have evolved and improved in the last 20 years. We excise nodular disease using endoscopic mucosal resection (EMR) and treat flat BE with radiofrequency ablation (RFA) based on accumulated, abundant and high-quality scientific evidence that shows pooled RFA eradication rates of 91 and 78 percent for dysplasia and BE, respectively.1 Why should we even think about cryotherapy in this era of RFA success?

How does cryotherapy work? The effects of cryotherapy begin with rapid intracellular and extracellular freezing, resulting in cell necrosis. Freezing causes cell membrane interruption, protein denaturation and changes in vascular flow, leading to the cessation of blood flow. Delayed effects of freezing include self-induced apoptosis. Unlike burning heat, the tissue injury continues over several days.

Up until 20 years ago, we used devices for the endoscopic delivery of compressed carbon dioxide gas (Polar Wand, GI Supply, Camp Hill, PA) or liquid nitrogen (the Cryospray system, truFreeze, CSA Medical, Lexington, MA) developed to treat BE and mucosal bleeding. In 2011, we became interested in a new form of cryoablation involving a disposable compliant balloon containing cryogen and nitrous oxide that would freeze mucosa on contact. It was called the cryoballoon focal ablation system (CbFAS; CryoBalloon Ablation System, C2 Therapeutics, Redwood City, CA). After years of repeated freeze–thaw cycles and tank changing with cryotherapy via carbon dioxide, we were ready for something different.

Why might we consider cryotherapy if we already use RFA, argon plasma coagulation, or both methods in our endoscopy units? Cryotherapy can be part of a multimodality approach when standard “burning” treatments have failed.2,3 The pooled success rate for eliminating dysplasia after unsuccessful RFA in a recent meta-analysis involving nearly 3,800 patients treated with liquid nitrogen Cryospray was approximately 76 percent (95 percent confidence interval, 57 to 88).4 Using CbFAS, our early experience also suggested a high success rate for dysplasia eradication (95 percent) in patients previously ablated.3

What about first-line treatment for neoplastic BE? In several retrospective and some prospective, nonrandomized studies using liquid nitrogen Cryospray, the success rate for eliminating high-grade dysplasia (HGD) in the setting of BE is between 81 and 94 percent, with a five-year durability rate of 93 percent.5,6 Recently, we reported the results of the Coldplay 2 trial,3 a prospective clinical study in which we used multifocal CbFAS in 41 patients with intramucosal cancer, HGD and low-grade dysplasia (LGD). We demonstrated complete eradication of dysplasia and intestinal metaplasia in 95 and 88 percent of study patients after one year and following an average of two procedures (for a BE length of at least 8 cm). Its safety profile appears to compare favorably with RFA. The stricture rate (9.7 percent) in the Coldplay 2 trial was comparable with that reported in other RFA trials with similar high rates of EMR (9 percent in the U.K. RFA registry7 and 11.8 percent in the SURF trial8). Moreover, BE within pre-existing strictures following EMR/RFA may also be successfully treated without causing wall disruption or worsening of the stenosis.3 This early experience with CbFAS is encouraging, but more research is needed. Large, multicenter trials are ongoing.

Cryotherapy can be part of a multimodality approach when standard “burning” treatments have failed.

We could consider cryotherapy for other reasons. It seems to be a “gentler,” less-painful ablative therapy than RFA. A small number (1.5 to 3.0 percent) of patients with RFA are hospitalized for severe pain. Pain is more common with RFA than cryotherapy.9 Similarly, in the cryoballoon ablation trial, pain was mild following the procedure and was generally absent the following postoperative day.3 Results from a Dutch study demonstrated that severe pain occurred in 46 percent of patients undergoing RFA after 48 hours compared with 18 percent of patients following cryoballoon ablation; the results also demonstrated significantly lower pain scores and the need for pain management (narcotic analgesics) for two weeks following cryotherapy.10 We have used carbon dioxide cryotherapy for many years at our hospital, but we shifted to CbFAS because of the research, as well as for its several user-friendly features: no need for tank changing or tube decompression, short procedure times (no more than 30 minutes), no need for freeze–thaw cycling, and the lightweight, portable, lower-cost, handheld controller and disposable balloons that occupy a small storage space.

We might also consider cryotherapy for esophageal cancer. Cryotherapy injury can be applied to deeper levels by increasing the cryogen dose. This cannot be achieved by RFA, which superficially coagulates. Complete eradication of intramucosal adenocarcinoma in BE has been well described. Although endoscopic resection is still preferred for staging purposes and for the removal of nodules and known intramucosal adenocarcinoma, certain patients have recurrent disease, nonlifting lesions, positive deep margins from incomplete resections or disease that is unresponsive to standard therapies. Such patients may be likely to achieve cure without the need for esophagectomy.

Is cryotherapy a cool alternative to RFA? Stay tuned….

Dr. Gutierrez has no conflicts to disclose. Dr. Canto has received a research grant from C2 Therapeutics. Dr. Canto is on the Gastroenterology Editorial Board.

1. Orman, E.S., Li, N., Shaheen, N.J. Efficacy and durability of radiofrequency ablation for Barrett’s Esophagus: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2013;11:1245-5125.
2. Sengupta, N., Ketwaroo, G.A., Bak, D.M., et al, Salvage cryotherapy after failed radiofrequency ablation for Barrett’s esophagus-related dysplasia is safe and effective. Gastrointest Endosc. 2015;82:443-448.
3. Canto, M.I., Shaheen, N.J., Almario, J.A., Voltaggio, L., Montgomery, E. Lightdale, C.J. Multifocal nitrous oxide cryoballoon ablation with or without EMR for treatment of neoplastic Barrett’s esophagus. Gastrointest Endosc. 2018. [Epub ahead of print].
4. Visrodia, K., Zakko, L., Singh, S., Leggett, C.L., Iyer, P.G., Wang, K.K. Cryotherapy for persistent Barrett’s esophagus after radiofrequency ablation: a systematic review and meta-analysis. Gastrointest Endosc. 2018;87:1396-1404.e1.
5. Shaheen, N.J., Greenwald, B.D., Peery, A.F., et al, Safety and efficacy of endoscopic spray cryotherapy for Barrett’s esophagus with high-grade dysplasia. Gastrointest Endosc. 2010;71(4):680-685.
6. Ramay, F.H., Cui, Q., Greenwald, B.D. Outcomes after liquid nitrogen spray cryotherapy in Barrett’s esophagus-associated high-grade dysplasia and intramucosal adenocarcinoma: 5-year follow-up. Gastrointest Endosc. 2017;86:626-632.
7. Haidry, R.J., Dunn, J.M., Butt, M.A., et al, Radiofrequency ablation and endoscopic mucosal resection for dysplastic Barrett’s esophagus and early esophageal adenocarcinoma: outcomes of the UK National Halo RFA Registry. Gastroenterology. 2013;145:87-95.
8. Phoa, K.N., van Vilsteren, F.G., Weusten, B.L., et al, Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized clinical trial. JAMA. 2014;311:1209-1217.
9. Solomon, S.S., Kothari, S., Smallfield, G.B. et al, Liquid nitrogen spray cryotherapy is associated with less postprocedural pain than radiofrequency ablation in Barrett’s esophagus: a multicenter prospective study. J Clin Gastroenterol. 2018. [Epub ahead of print].
10. van Munster, S., Kunzli, H., Bergmann, J., Weusten, B.L. Post-procedural pain associated with endoscopic ablation therapy of Barrett’s esophagus. Gastrointest Endosc. 2017;85. Abstract 568.

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