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Cryoablation for managing Barrett’s esophagus refractory to radiofrequency ablation? Don’t embrace the cold too soon!

2015; Elsevier BV; Volume: 82; Issue: 3 Linguagem: Inglês

10.1016/j.gie.2015.03.1965

1097-6779

Bas L. Weusten, Jacques Bergman,

Gastric Cancer Management and Outcomes

Barrett’s esophagus (BE) is a premalignant condition predisposing to the development of esophageal adenocarcinoma. In the care of patients with BE with early neoplasia (ie, high-grade dysplasia [HGD] or mucosal cancer), it is of paramount importance to remove all visible lesions in by endoscopic resection. The rationale behind resecting all visible lesions is that proper histopathologic staging can only be done on an endoscopic resection specimen: biopsy specimens from lesions in BE tend to be misclassified as to the degree of dysplasia or the depth of invasion in approximately 30% of cases.1Peters F.P. Brakenhoff K.P.M. Curvers W.L. et al.Histologic evaluation of resection specimens obtained at 293 endoscopic resections in Barrett’s esophagus.Gastrointest Endosc. 2008; 67: 604-609Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar BE with early neoplasia can also be treated by endoscopic ablation therapy. Basically, there are 2 generally accepted indications for ablation therapy in BE. First, ablation is indicated in patients with BE containing flat-type HGD or low-grade dysplasia. As mentioned, a prerequisite is that no visible abnormalities are present before ablation therapy is used as monotherapy. Second, ablation is indicated after previous endoscopic resection of lesions containing HGD or mucosal cancer, even if the residual Barrett’s epithelium is apparently free of dysplasia. Currently, radiofrequency ablation (RFA) is the most established ablation technique for BE. Its efficacy, safety, and durability have been documented in many studies from both the United States and Europe.2Shaheen N.J. Sharma P. Overholt B.F. et al.Radiofrequency ablation in Barrett’s esophagus with dysplasia.N Engl J Med. 2009; 360: 2277-2288Crossref PubMed Scopus (1116) Google Scholar, 3Phoa 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.JAMA. 2014; 311: 1209-1217Crossref PubMed Scopus (449) Google Scholar, 4Phoa K.N. Pouw R.E. Bisschops R. et al.Multimodality endoscopic eradication for neoplastic Barrett oesophagus: results of an European multicentre study (EURO-II).Gut. Epub. 2015 Mar 2; Google Scholar In recent years, cryoablation has gained interest. Cryoablation uses cycles of freezing and thawing and causes cell death by intra- and extracellular ice formation, secondary vascular injury, and cryoablation-induced apoptosis.5Baust J.G. Gage A.A. Johansen T.E.B. et al.Cryobiology mechanisms of cryoablation: clinical consequences on malignant tumors.Cryobiology. 2014; 68: 1-11Crossref PubMed Scopus (108) Google Scholar Whereas heat-based ablation techniques cause extracellular molecules to denaturate, cryoablation is believed to preserve extracellular molecules such as the collagen matrix architecture. Theoretically, cryoablation might therefore allow for deeper tissue ablation while preserving esophageal wall integrity. These properties might make cryoablation an attractive treatment option for RFA-refractory BE because increased Barrett’s mucosal thickness might be a factor involved in decreased sensitivity to RFA. In the current issue of GIE, Sengupta et al6Sengupta 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: 443-448Abstract Full Text Full Text PDF Scopus (33) Google Scholar report on the use of cryoablation in patients with persistent or recurrent dysplasia after RFA. In this retrospective cohort, 121 patients with varying degrees of dysplasia, ranging from “indefinite for dysplasia” to intramucosal cancer, were treated with RFA. Of these, complete eradication of dysplasia (CE-D) was reached in 91 patients (75%) after a median of 3 RFA sessions, whereas dysplasia persisted in 30 patients (25%). Of these 30 patients in whom RFA was considered to have failed, 19 were included in this case series, together with 2 additional patients in whom dysplasia recurred after initially successful RFA. Of these 21 patients, the authors report on 16 patients with adequate follow-up. Of these 16 patients, CE-D was achieved in 12 (75%). Complete eradication of intestinal metaplasia (CE-IM) was achieved in only 5 patients (31%). The authors conclude that salvage cryotherapy is a safe and effective treatment modality for patients in whom RFA previously failed. In our opinion, these conclusions may be a bit too optimistic for a small series of 16 patients. One may argue that a stenosis rate of 19% (3 of 16) is not insignificant, and persistence of intestinal metaplasia in 69% (11 of 16) may also question its effectiveness. A more conservative conclusion would be that cryoablation is feasible for RFA-refractory cases. In the Sengupta et al study,6Sengupta 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: 443-448Abstract Full Text Full Text PDF Scopus (33) Google Scholar 25% of the patients were considered to have RFA-refractory dysplasia, defined as persistence of dysplastic Barrett’s epithelium after a median of 3 RFA sessions. This failure rate contrasts with previously published papers on RFA. In a recently reported prospective European multicenter series of 124 patients with HGD or mucosal Barrett’s cancer, CE-D was achieved in 98%, and CE-IM was reported in 93% of patients.4Phoa K.N. Pouw R.E. Bisschops R. et al.Multimodality endoscopic eradication for neoplastic Barrett oesophagus: results of an European multicentre study (EURO-II).Gut. Epub. 2015 Mar 2; Google Scholar How can we explain the discrepancy between these reported success rates of RFA? To answer this, we first need to agree on the ultimate goal of endotherapy in these patients. In our opinion, eradication of dysplasia only is not an adequate endpoint. Studies have shown that striving only for eradication of dysplasia while leaving residual, apparently nondysplastic, BE untreated will lead to recurrent neoplasia in 20% to 30% of patients within 3 years of follow-up.7Pech 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: 1200-1206Crossref PubMed Scopus (573) Google Scholar, 8Peters F.P. Kara M.A. Rosmolen W.D. et al.Endoscopic treatment of high-grade dysplasia and early stage cancer in Barrett’s esophagus.Gastrointest Endosc. 2005; 61: 506-514Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar In addition, in the presence of residual Barrett’s mucosa, eradication of dysplasia may not be a reliable endpoint because of sampling error and poor interobserver agreement in the histopathologic assessment. The ultimate goal of treating any BE patient with early neoplasia is therefore the complete eradication of all Barrett’s epithelium: CE-IM, and not only CE-D, is the desired endpoint. What is the optimal way to achieve this endpoint? First, as mentioned previously, all visible abnormalities, no matter how subtle, should be resected before embarking on any form of ablative therapy. This is not only to optimize histopathologic diagnosis and risk stratification but also to render the Barrett’s segment flat for subsequent ablation therapy: visible lesions (at least Paris classification type 0-I and 0-IIa lesions) are logically thicker and therefore less responsive to RFA. In our practice, the vast majority of patients referred for early neoplasia in BE are treated with EMR as a first step in the treatment algorithm, even in patients with a referral diagnosis of flat-type dysplasia. In the aforementioned European multicenter study, EMR was performed in 90% of all patients before RFA.4Phoa K.N. Pouw R.E. Bisschops R. et al.Multimodality endoscopic eradication for neoplastic Barrett oesophagus: results of an European multicentre study (EURO-II).Gut. Epub. 2015 Mar 2; Google Scholar Likewise, results from the RFA registry in the United Kingdom show that a higher rate of baseline EMR is associated with an improved success rate of RFA.9Haidry R.J. Butt M. Dunn J.M. 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. Epub. 2014 Dec 24; Google Scholar In the Sengupta et al study, the rate of EMR was only 21%. Although this may partly reflect the patient selection of the study (ie, some patients had indefinite or low-grade dysplasia for which baseline EMR is rarely indicated), it suggests underuse of EMR for visible lesions, which may have contributed to the reported failure rate of RFA in the study. Second, RFA should be performed according to a strict protocol. In the European multicenter study, the protocol consisted of 1 or 2 circumferential RFA sessions, followed by trimonthly focal RFA sessions until complete endoscopic clearance of all BE was achieved. During each focal RFA session for ablation of visible tongues or islands, the area at the top of the gastric folds was treated circumferentially, irrespective of its endoscopic appearance. These trimonthly RFA sessions are repeated until complete endoscopic clearance of all BE appears to be achieved and biopsy samples show the absence of intestinal metaplasia. During the treatment phase, patients are put on aggressive acid-suppression therapy, consisting of high-dose proton pump inhibitor twice-daily maintenance therapy combined with ranitidine 300 mg at bedtime and sucralfate after each meal for 2 weeks after each RFA session. Treatment sessions are performed at 3-month intervals to ensure that the mucosa has completely healed at the time of the next RFA session. Treatment sessions are postponed in case the mucosa looks inflamed and swollen; under these circumstances, the RFA will not achieve its maximum effect (the mucosa is too thick for the depth of ablation). In addition, inflammatory changes may mimic neoplasia, causing confusion when these are sampled for histology, or may mask neoplasia, causing delayed diagnosis of disease progression. RFA should therefore only be performed for flat-type mucosa without visible lesions or inflammatory changes. When endoscopists use this strict treatment algorithm, CE-IM will be achieved in the majority of patients, even in BE longer than 10 cm.10Alvarez Herrero L. van Vilsteren F.G.I. Pouw R.E. et al.Endoscopic radiofrequency ablation combined with endoscopic resection for early neoplasia in Barrett’s esophagus longer than 10 cm.Gastrointest Endosc. 2011; 73: 682-690Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar In our experience, patients who are truly RFA refractory will manifest themselves relatively early in the course of the treatment algorithm. These patients have a long BE segment without any squamous islands at baseline and will show virtually no conversion to squamous mucosa after their first circumferential RFA session11Van Vilsteren F.G.I. Alvarez Herrero L. et al.Predictive factors for initial treatment response after circumferential radiofrequency ablation for Barrett’s esophagus with early neoplasia: a prospective multicenter study.Endoscopy. 2013; 45: 516-525Crossref PubMed Scopus (63) Google Scholar and a prolonged healing time. These patients require a tailor-made approach in which surgical options (ie, surgical fundoplication or primary treatment with esophagectomy) should be considered. Some patients may show a gradual conversion to squamous mucosa over the course of RFA treatment sessions yet may be better off with an alternative treatment in the final stages of the treatment algorithm to remove residual Barrett’s mucosa. In the European multicenter study, 18% of patients had some residual Barrett’s epithelium treated with EMR and argon plasma coagulation after completing the maximum number of RFA sessions.4Phoa K.N. Pouw R.E. Bisschops R. et al.Multimodality endoscopic eradication for neoplastic Barrett oesophagus: results of an European multicentre study (EURO-II).Gut. Epub. 2015 Mar 2; Google Scholar Sengupta et al6Sengupta 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: 443-448Abstract Full Text Full Text PDF Scopus (33) Google Scholar suggest that cryoablation might be a valid option in these patients. However, let’s not embrace the cold too soon: there are more alternatives here that might serve the endoscopist. Usually, only minute islands of BE persist at this stage of the treatment algorithm. In the European multicenter study, the majority of “escape treatments” after RFA consisted of argon plasma coagulation ablation for Barrett’s islands (all <5 mm). If larger areas of BE remained, the protocol mandated EMR as escape treatment, and this was required in 7% of patients. The use of endoscopic resection for residual BE after RFA should be strongly considered: persistence of BE after RFA should raise the suspicion of dysplasia or even cancer because these lesions are usually thicker and therefore less responsive to RFA. Cryoablation may have a role in treating larger areas of BE refractory to RFA provided that these are completely flat. The study of Sengupta et al supports a potential role for cryoablation under these circumstances, yet the exact position of cryoablation in the treatment algorithm for BE remains to be determined. Dr Weusten has received research support for Covidien GI Solutions and C2 Therapeutics and is on the Advisory Board of C2 Therapeutics and Boston Scientific. Dr Bergman has received research support from Covidien GI Solutions, ERBE Medical, Boston Scientific, Ninepoint Medical, and C2 Therapeutics and is a consultant for Covidien GI Solutions and Boston Scientific. Salvage cryotherapy after failed radiofrequency ablation for Barrett’s esophagus–related dysplasia is safe and effectiveGastrointestinal EndoscopyVol. 82Issue 3PreviewRadiofrequency ablation (RFA) is an effective treatment for Barrett’s esophagus (BE) dysplasia. For patients with dysplasia refractory to RFA, data are limited regarding efficacy of endoscopic therapy. Full-Text PDF