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 . In addition, cryotherapy might result in less pain due to an anesthetic effect of cooling of the tissue and its surrounding nerves . 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.
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 . 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 .
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 . 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 . 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 . 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 . 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 , but the hidden nature of subsquamous BE hampers adequate surveillance. A systematic review on this subject reports subsquamous IM after RFA in 0.9% . 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.
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.
Financial support and sponsorship
Conflicts of interest
Prof. Dr. Weusten has received financial support for IRB approved studies by C2Therapeutics. For A. Overwater none were declared.
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
1. Thrift AP, Whiteman DC. The incidence of esophageal adenocarcinoma continues to rise: analysis of period and birth cohort effects on recent trends. Ann Oncol 2012; 23:3155–3162.
2. Weusten B, Bisschops R, Coron E, et al. Endoscopic management of Barrett's esophagus: European Society of Gastrointestinal Endoscopy (ESGE) Position Statement. Endoscopy 2017; 49:191–198.
3. May A, Gossner L, Pech O, et al. Local endoscopic therapy for intraepithelial high-grade neoplasia and early adenocarcinoma in Barrett's oesophagus: acute-phase and intermediate results of a new treatment approach. Eur J Gastroenterol Hepatol 2002; 14:1085–1091.
4. Pech O, Behrens A, May A, et al. Long-term results and risk factor analysis for recurrence after curative endoscopic therapy in 349 patients with high-grade intraepithelial neoplasia and mucosal adenocarcinoma in Barrett's oesophagus. Gut 2008; 57:1200–1206.
5. Phoa KN, Pouw RE, Bisschops R, et al. Multimodality endoscopic eradication for neoplastic Barrett oesophagus: results of an European multicentre study (EURO-II). Gut 2016; 65:555–562.
6. Shaheen NJ, Sharma P, Overholt BF, et al. Radiofrequency ablation in Barrett's esophagus with dysplasia. N Engl J Med 2009; 360:2277–2288.
7. Shaheen NJ, Peery AF, Hawes RH, et al. Quality of life following radiofrequency ablation of dysplastic Barrett's esophagus. Endoscopy 2010; 42:790–799.
8. Baust JG, Gage AA, Bjerklund Johansen TE, Baust JM. Mechanisms of cryoablation: clinical consequences on malignant tumors. Cryobiology 2014; 68:1–11.
9. Gage AA, Baust JM, Baust JG. Experimental cryosurgery investigations in vivo. Cryobiology 2009; 59:229–243.
10▪▪. Ghorbani S, Tsai FC, Greenwald BD, et al. Safety and efficacy of endoscopic spray cryotherapy for Barrett's dysplasia: results of the National Cryospray Registry. Dis Esophagus 2016; 29:241–247.
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.
11. Sreenarasimhaiah J. Endoscopic applications of cryospray ablation therapy-from Barrett's esophagus and beyond. World J Gastrointest Endosc 2016; 8:546.
12▪. Verbeek RE, Vleggaar FP, Ten Kate FJ, et al. Cryospray ablation using pressurized CO2
for ablation of Barrett's esophagus with early neoplasia: early termination of a prospective series. Endosc Int open 2015; 3:E107–E112.
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.
13▪. Künzli H, Schölvinck D, Meijer S, et al. Efficacy of the CryoBalloon Focal Ablation System for the eradication of dysplastic Barrett's esophagus islands. Endoscopy 2016; 49:169–175.
Barrett's esophagus islands were adequately targeted with the CryoBallon Focal Ablation System and adequately targeted islands showed complete eradication of Barrett's epithelium.
14. Erinjeri JP, Clark TWI. Cryoablation: mechanism of action and devices. J Vasc Interv Radiol 2010; 21:S187–S191.
15. Shaheen NJ, Greenwald BD, Peery AF, et al. Safety and efficacy of endoscopic spray cryotherapy for Barrett's esophagus with high-grade dysplasia. Gastrointest Endosc 2010; 71:680–685.
16. Greenwald BD, Dumot JA, Horwhat JD, et al. Safety, tolerability, and efficacy of endoscopic low-pressure liquid nitrogen spray cryotherapy in the esophagus. Dis Esophagus 2010; 23:13–19.
17. Haidry RJ, Butt MA, Dunn JM, et al. Improvement over time in outcomes for patients undergoing endoscopic therapy for Barrett's oesophagus-related neoplasia: 6-year experience from the first 500 patients treated in the UK patient registry. Gut 2015; 64:1192–1199.
18. Phoa KN, Pouw RE, Bisschops R, et al. Multimodality endoscopic eradication for neoplastic Barrett oesophagus: results of an European multicentre study (EURO-II). Gut 2016; 65:555–562.
19▪. Sengupta N, Ketwaroo GA, Bak DM, et al. Salvage cryotherapy after failed radiofrequency ablation for Barrett's esophagus-related dysplasia is safe and effective. Gastrointest Endosc 2015; 82:443–448.
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.
20. Weusten BLAM, Bergman JJGHM. Cryoablation for managing Barrett's esophagus refractory to radiofrequency ablation? Don’t embrace the cold too soon!. Gastrointest Endosc 2015; 82:449–451.
21. Canto M, Shin E, Khashab M, et al. Safety and efficacy of carbon dioxide cryotherapy for treatment of neoplastic Barrett's esophagus. Endoscopy 2015; 47:582–591.
22▪. Schölvinck D, Künzli H, Kestens C, et al. Treatment of Barrett's esophagus with a novel focal cryoablation device: a safety and feasibility study. Endoscopy 2015; 47:1106–1112.
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.
24. Gosain S, Mercer K, Twaddell WS, et al. Liquid nitrogen spray cryotherapy in Barrett's esophagus with high-grade dysplasia: long-term results. Gastrointest Endosc 2013; 78:260–265.
25. Phoa KN, van Vilsteren FGI, Weusten BLAM, et al. Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia. JAMA 2014; 311:1209.
26. Halsey K, Chang J, Waldt A, Greenwald B. Recurrent disease following endoscopic ablation of Barrett's high-grade dysplasia with spray cryotherapy. Endoscopy 2011; 43:844–848.
27. Xue H, Tan H, Liu W, et al. A pilot study of endoscopic spray cryotherapy by pressurized carbon dioxide gas for Barrett's esophagus. Endoscopy 2011; 43:379–385.
28▪▪. Ramay FH, Cui Q, Greenwald BD. Outcomes after liquid nitrogen spray cryotherapy in Barrett's esophagus-associated high-grade dysplasia and intramucosal adenocarcinoma: 5-year follow-up. Gastrointest Endosc 2017; Feb 21. pii: S0016-5107(17)30108-6. doi: 10/1016/j.gie.2017.02.006.
The is the first study reporting long-term outcomes 5 years after cryospray therapy with liquid nitrogen.
29. Orman ES, Kim HP, Bulsiewicz WJ, et al. Intestinal metaplasia recurs infrequently in patients successfully treated for Barrett's esophagus with radiofrequency ablation. Am J Gastroenterol 2013; 108:187–195.
30. Gupta M, Iyer PG, Lutzke L, et al. Recurrence of esophageal intestinal metaplasia after endoscopic mucosal resection and radiofrequency ablation of Barrett's esophagus: results from a US multicenter consortium. Gastroenterology 2013; 145:79–86. e1.
31. Vaccaro BJ, Gonzalez S, Poneros JM, et al. Detection of intestinal metaplasia after successful eradication of Barrett's esophagus with radiofrequency ablation. Dig Dis Sci 2011; 56:1996–2000.
32. Gray NA, Odze RD, Spechler SJ. Buried metaplasia after endoscopic ablation of Barrett's esophagus: a systematic review. Am J Gastroenterol 2011; 106:1899–1908.
33. Johnston MH, Eastone JA, Horwhat JD, et al. Cryoablation of Barrett's esophagus: a pilot study. Gastrointest Endosc 2005; 62:842–848.
Keywords:Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
ablation techniques; Barrett's epithelium; Barrett's esophagus; cryoablation; cryotherapy