Cryoablation – waiting for the inevitable

 

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After removal of all visible lesions in dysplastic Barrett’s esophagus (BE), radiofrequency ablation (RFA) remains the cornerstone of our ablative endotherapy. RFA is supported by robust evidence demonstrating high efficacy and acceptable safety, but it is associated with certain drawbacks, including post-procedural pain and strictures. Therefore, the search for a less morbid, yet equally effective, alternative continues and cryoablation has been proposed as an alternative. Whether the alternative surpasses our current standard remains as yet to be answered.

Cryoablation is usually performed using liquid nitrogen, delivered via a spray catheter (cryospray) or a balloon catheter (cryoballoon), which induces tissue injury through the formation of intra- and extracellular ice crystals. Cryospray applies nitrogen directly to the mucosa, whereas the cryoballoon ablation (CBA) system administers uniform ablation through its surface, which is thought to offer more consistent results and faster application. Compared with RFA, cryoablation is hypothesized to hold several advantages as it may reach deeper tissue layers while preserving extracellular matrix integrity, without leading to increased stricture risk, although at the moment, the stricture risk for cryoablation is between 1% and 12.5%, so for now it is comparable to RFA (6%–11.8%) [1] [2].

To date, most cryotherapy data have originated from feasibility studies or small retrospective series, often combining primary and rescue (after previous RFA) treatments. A recent meta-analysis of 23 studies reported pooled complete remission rates for dysplasia (CRD) of 84.2% (95%CI 79.1%–89.3%) and for intestinal metaplasia (CRIM) of 64.1% (95%CI 49.2%–79.0%) [3]. In a subset of four comparative studies, CRD and CRIM rates for RFA and cryoablation appeared comparable [3]. However, all the systematic reviews performed so far have been based essentially on low quality evidence consisting of mostly retrospective studies with variable designs and patient populations. High quality RFA trials have demonstrated CRD rates near 90% and CRIM rates around 78% [4], setting a high benchmark and making it hard to surpass these results. One prospective multicenter study has shown more promising results for CBA as a primary ablation mode: in 94 BE patients treated with CBA as primary ablative therapy, high CRIM and CRD rates of 91% and 97% were obtained at 1 year [1].

After achieving CRIM, recurrence remains a clinical reality and we are in need of long-term data for cryoablation to determine its efficacy. Post-RFA annual recurrence rates are acceptable and approximately 2% for any dysplasia and 1.2% for high grade dysplasia/intramucosal cancer (HGD/IMC) following RFA [5]. The current study by Sachdeva et al., published in Endoscopy, provides insights into the efficacy of CBA over a longer period, with a median follow-up of 4.4 years for CBA and 4.1 years for RFA [6].

In this multicenter retrospective study, 610 patients received RFA and 71 received CBA as primary ablative therapy for dysplasia, following previous endoscopic resection in the majority of cases (68.9% vs. 64.8%, respectively). While it seemed that the overall recurrence rate of BE was higher with RFA (hazard ratio [HR] 2.19, 95%CI 1.18–4.06), when the definition of recurrence was limited to recurrence in the tubular esophagus, excluding intestinal metaplasia at the gastroesophageal junction (GEJ), the recurrence rates were not significantly different (HR 1.18, 95%CI 0.61–2.30). When defining recurrence of BE, the debate continues as to whether IM at the GEJ should be considered. While CRIM has been used as the end point in most studies, according to the recent ESGE guideline, recurrence should only be visible Barrett’s in the tubular esophagus [7]. The more clinically relevant end point – the dysplasia recurrence rate – was similar between the two groups (HR 0.88, 95%CI 0.39–1.97), a result maintained in a propensity score-matched analysis (54 RFA cases vs. 54 CBA cases). Annual recurrence rates were also comparable (RFA 3.75 vs. CBA 2.83 per 100 patient-years).

Although promising, these are still small cohorts and previously van Munster and colleagues calculated that a sufficiently powered noninferiority randomized controlled trial (RCT) would require around 1500 patients [8]. Propensity score matching, as used in the study of Sachdeva et al., can be used to partially mimic the randomized design of an RCT, but it cannot compensate for the unknown confounding covariates that are randomly distributed in an RCT, nor compensate for the lack of power.

Why were more patients not allocated to cryoablation? The patients in the study with a ≤6-cm segment were offered a choice of the two modalities, with a shared decision-making process. As length is an issue owing to the focal ablation capacity (2–2.5 cm per application), CBA is challenging in segments of over 6 cm. Therefore, in the current study the RFA group had considerably longer BE segments, with a mean of 4.5 cm compared with 2.7 cm for the CBA group. Moreover, only two patients with a segment longer than 6 cm received CBA. However, over 10 years, of the 527 patients with a segment ≤6 cm, RFA was performed in 458 and CBA in 69, indicating patients and doctors still had a preference for RFA.

So where do we currently stand? CBA is a safe and technically feasible therapy for BE eradication in experienced hands. From heterogeneous studies and small prospective cohort studies, CRIM and CRD seem to be comparable after a short follow-up period. The study of Sachdeva et al. adds to the knowledge that recurrence rates for dysplasia seem comparable between CBA and RFA after longer follow-up too, but the inevitable conclusion would be that we still require that RCT to determine the noninferiority of CBA compared with RFA as primary ablation therapy. While this retrospective matched cohort study suggests that CBA may serve as an alternative to RFA in selected patients, broader adoption should await the results of a well-powered RCT designed to assess its noninferiority. Until then, CBA remains a promising option, potentially as rescue therapy when RFA fails, but not yet a replacement for our standard care.

Publication History

Article published online:
01 July 2025

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