Abbreviations:
BE (Barrett’s esophagus), CbFAS (Cryoballoon focal ablation system), CR-D (complete regression of dysplasia), CR-IM (complete regression of intestinal metaplasia), RFA (radiofrequency ablation)The cryoballoon focal ablation system (CbFAS) is the most recent tool added to the therapeutic repertoire for early Barrett’s neoplasia. On the basis of current robust evidence, radiofrequency ablation (RFA) is the treatment of choice for ablating Barrett’s epithelium, whereas the role of cryoablation is undetermined. In this issue of Gastrointestinal Endoscopy, van Munster et al
1
present the first study comparing the efficacy of the CbFAS device with that of RFA in treating early Barrett’s neoplasia.The use of chilling, or “kryeros” (Latinized Greek), in medicine is not new; cold temperatures were already used in ancient Greece and Egypt to treat inflammation and pain. Cryoablation is defined by the use of freezing temperatures to destroy tissue and was used for the first time back in 1845 to 1851 in England, when James Arnott used a combination of ice and salt to produce tissue necrosis at about −20° C and achieved reduction in tumor size and palliation of pain.
2
The ablative techniques have greatly evolved in the past decade, and we have witnessed progressive improvement in the eradication and recurrence rates, safety profiles, and the development of more user-friendly and less operator-dependent devices.
RFA has been extensively evaluated in high-quality clinical trials, including multicenter randomized studies, high-volume registries, and a large meta-analysis showing complete regression of intestinal metaplasia (CR-IM) in 78% to 88% of patients and complete regression of dysplasia (CR-D) 87% to 91%. Recently published real-world data from the U.K. National RFA registry reports a CR-D of 81% and CR-IM 62% at 12 months and a recurrence rate of IM at 19 months’ follow-up around 5%.
3
RFA has also demonstrated a good safety profile, with a pooled adverse event rate of 8.8%.4
All of this strong evidence supports RFA as the ablative technique of choice for early Barrett’s neoplasia. The current trial by van Munster et al
1
sheds some light on the future role of cryoablation, presenting the first study comparing focal RFA with the new CbFAS device in treating patients with flat dysplasia or residual Barrett’s after previous endoscopic resection (ER).The principle of cryotherapy is that tissue necrosis is induced by the application of a cryogen. The 2 potential advantages are a lower risk of structuring and perforation because collagen and elastin fibers are more resistant to the effects of cryogen, and the tissue structure remains intact. Cryotherapy also has the well-established anesthetic effect of cold, potentially leading to less pain during and after the procedure.
5
The first 2 cryotherapy systems developed for endoscopy were noncontact spray catheters delivering liquid nitrogen and carbon dioxide, respectively. Both liquid cryogens rapidly expand into a gas, and thus a decompression tube needs to be placed alongside the endoscope for gas venting and to prevent perforation.
5
The CbFAS device consists of a balloon catheter attached to a battery-powered handle with a trigger. By pressing the trigger once, the 3-cm balloon self-inflates to the size of the esophagus (20-35 mm), and continued activation of the trigger delivers liquid nitrous oxide that focally ablates the area in contact with the balloon. Each cartridge allows treating 2 to 3 sites and can be replaced without removing the catheter.
5
Compared with other cryoablation devices, the CbFAS overcomes the drawbacks of the need for aspiration tubes and imprecise dosing. The costs for CbFAS are also lower because there is no need for expensive consoles or processors. The only required equipment is the single-use ablation catheter, the handle, and a nitrous oxide cartridge.
5
Data on the use of cryoablation in treating early Barrett’s neoplasia are limited. Two multicenter retrospective cohort studies (n = 87) using liquid nitrogen spray reported rates of CR-D of 82% and 97% and CR-IM of 70% and 87%, respectively,
6
, 7
Results from the National Cryospray Registry are suggesting an excellent safety profile,
8
and a recent comparative study, still in press, shows that after liquid nitrogen cryotherapy the patients had less postprocedural pain than did RFA patients.9
The new CbFAS has been assessed in 2 feasibility, safety, and dose-finding studies in animal models and subsequently validated in a multicenter prospective nonrandomized feasibility and safety trial in humans. A total of 39 patients were treated with 1 or 2 ablations for 6, 8, or 10 seconds. No major adverse events and mild pain were reported by 27% of patients immediately after treatment and by 14% after 2 days. At follow-up endoscopy, there was complete neosquamous regeneration in 100% of the 10-second areas compared with 62% of the 6-second areas.
10
The same Dutch group assessed in a single-center study the efficacy of the 10-second cryoablation regimen in a cohort of 30 patients with dysplastic Barrett’s islands. A total of 94 % islands were adequately targeted, and CR-IM and CR-D was achieved in 100 %.11
The first study assessing eradication of early Barrett’s neoplasia with the CbFAS device is now available.
12
A total of 41 Barrett’s patients with early neoplasia were treated with a 10-second dose of nitrous oxide at 10- to 12-week intervals. After a median of 3 sessions, CR-IM was achieved in 88% of patients and CR-D in 95% at 21-month follow-up. The results were comparable with those of RFA. No major adverse events were reported.12
There are no previously reported comparative data between RFA and CbFAS. Only a recently published single-center retrospective study has compared RFA with the liquid nitrogen noncontact spray device.
13
Prospectively collected data from a total of 154 patients who underwent previous ablation (RFA = 73 vs Cryospray = 81) were retrospectively analyzed. The rate of CR-D was higher in the RFA group but not statistically significant (87.5% vs 79%) and was comparable with previously reported data. By contrast, there were statistically significant differences in the rate of CR-IM that favored the RFA group: 67% versus 41%.The study from van Munster et al
1
is therefore the first to compare the efficacy and tolerability of CbFAS and RFA in eradicating dysplastic BE. This multicenter retrospective analysis of data includes a total 46 patients with short-segment noncircumferential Barrett’s ≤2 cm. Twenty patients underwent ablation with the new CbFAS device and 26 with the focal RFA catheter. After a single ablation session there were no differences in the Barrett’s regression surface between the 2 modalities (CbFAS 88% vs RFA 90%). These outcome data are comparable with all the previously mentioned studies, both for cryoablation and for RFA, but the limitation must be borne in mind that only patients with short Barrett’s esophagus (BE) were included, and only a single cryoablation session was performed.Van Muster et al
1
also analyzed the presence and severity of pain after the ablation. Cumulative pain, duration of pain, duration of major pain, and peak pain were reported on a numeric scale by all patients up to 14 days after the treatment. The cumulative use of analgesics was also recorded and analyzed. Statistically significant differences were observed for all the analyzed variables and favored the CbFAS group. The reported rates of pain, in terms of both maximum level and duration of pain, were low compared with previously reported data, and this could be explained by the small surface of Barrett’s ablated. These results are in line with those previously reported in a prospective trial including 94 patients (noncontact spray cryoablation = 35, RFA = 59). The odds ratio of pain immediately and 48 hours after RFA were at least 5 times higher.9
So, where does this study leave us with regard to BE ablation? An ideal ablative technique not only should be efficacious but also has to be well tolerated and cost effective. In the context of focal ablation, RFA and CbFAS seem to be equally effective, but CbFAS is better tolerated. We do not have any cost effectiveness analyzed, but this needs to be examined in future studies. Who are potential candidates to undergo CbFAS? Barrett’s patients with a higher risk of stricture formation, such as previous EMR, long Barrett’s segments, or previous peptic strictures, are potential targets for cryoablation. The rationale is that cryoablation destroys the superficial epithelium, not affecting the subepithelial layers including muscle fibers. In theory this should be associated with a lower stricture rate and no perforation risk. The subgroup of patients who do not respond to RFA can also be candidates for cryoablation. This was reported in a recent meta-analysis reporting CE-D in 75% of patients and CE-IM in 50% with persistent BE.
14
The costs of the CbFAS are significantly lower compared with other ablation devices, and cost-effectiveness studies should be conducted. If favorable results on those and the excellent safety profile are also validated in larger cohort prospective trials, the cost and low incidence of side effects may justify the use of cryoablation in selected patients with nondysplastic Barrett’s. It might be the next step in the exciting field of endoscopic therapy for BE.
In conclusion, CbFAS seems to be promising based on the results of this retrospective comparative study. It demonstrates that there is a role for cryotherapy, especially with regard to tolerability, that needs to be established in future studies. This clearly calls for an adequately powered multicenter randomized controlled trial to prospectively compare the efficacy, safety, tolerability, and cost effectiveness of these 2 ablation techniques.
Disclosure
Dr Ragunath is the recipient of an educational grant from Medtronics. The other author disclosed no financial relationships relevant to this publication.
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- Focal cryoballoon versus radiofrequency ablation of dysplastic Barrett’s esophagus: impact on treatment response and postprocedural painGastrointestinal EndoscopyVol. 88Issue 5
- PreviewRadiofrequency ablation (RFA) is safe and effective for eradicating Barrett’s esophagus (BE) but is associated with significant postprocedural pain. Alternatively, balloon-based focal cryoablation (CRYO) has recently been developed, which preserves the extracellular matrix and might therefore be less painful. Although data for CRYO are still limited, uncontrolled studies suggest comparable safety and efficacy to RFA in eradicating limited BE areas. Therefore, secondary endpoints such as pain might become decisive for treatment selection.
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