RFA for Dysplasia in Barrett’s Esophagus: A Slam-Dunk Decision

The primary goal of ablation in Barrett’s esophagus is to reduce progression to high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). The decision to perform endoscopic therapy (with the goal to eliminate intestinal metaplasia), is based on the principles of: 1. documenting an elevated risk of progression, 2. demonstrating reduction in risk of progression using robust clinical studies, and 3. proving the cost effectiveness of this approach when compared to the competing strategy. All three of these criteria have been met for patients with HGD.

The risk of progression in HGD has been estimated to be high at 7 percent a year (compared to 0.2-0.3 percent a year in those without dysplasia). Endoscopic therapy (combining endoscopic resection and ablation to eradicate intestinal metaplasia) has been shown to be successful in reducing the risk of progression to adenocarcinoma in those with HGD in two multicenter randomized trials with results of endoscopic therapy also being shown to be comparable to esophagectomy.1,2 Lastly, this approach has been shown to be cost effective when compared to esophagectomy in multiple modeling studies.

Low-grade dysplasia (LGD), on the other hand, has been somewhat of a challenge given limitations in making a robust histopathological diagnosis. Community pathologists may over call a LGD diagnosis and even academic pathologists have poor inter-observer agreement in making this diagnosis. This has led to varying reports of natural history and estimates of progression, with some studies estimating the risk of progression in LGD to be similar to that of no dysplasia.


Read the other side of this debate by Dr. Stuart Spechler


However, recent studies have shed more light on this situation. A meta-analysis including 24 studies with 2,694 cases, estimated the annual risk of progression in LGD to EAC to be 0.7 percent, and risk of progression to HGD or EAC to be 1.5 percent.3 The study also shed some light on the possibility of “non- LGD” cases diluting the risk of progression, by stratifying studies into two categories: those where the diagnosis of LGD was less than 15 percent of all Barrett’s esophagus diagnoses and those where the diagnosis of LGD was more than 15 percent of all Barrett’s diagnoses (indicating the possibility of over diagnosis). The rate of progression in the former group was higher at 0.7 percent a year compared to 0.32 percent a year in the latter group. Additionally, several recent population-based studies from Europe have demonstrated that those diagnosed with LGD have a substantially higher risk of progression to EAC compared to those with no dysplasia.4,5

Indeed, studies have shown that while the vast majority (greater than 70 percent) of those diagnosed with LGD in the community are down-staged to no dysplasia upon review by gastrointestinal pathologists with the risk of progression in those with confirmed LGD being substantially higher than those who are down-staged to no dysplasia.6 Confirmation of the LGD diagnosis by additional pathologists has also been associated with a higher risk of progression.

Most importantly we now have level one evidence from a multicenter, randomized controlled trial showing substantially reduced risk of progression to HGD or EAC in those with confirmed LGD when randomized to ablation versus endoscopic surveillance.

Indeed, radiofrequency ablation (RFA) was successful in eliminating dysplasia and intestinal metaplasia in 93 percent and 88 percent respectively, proving the efficacy of this technique.7 While one of the drawbacks of this European trial was the high risk of progression in those diagnosed with LGD (11 percent per year, compared to lower conventional estimates), another nonrandomized multicenter study from the U.S. also demonstrated a substantially reduced risk of progression to HGD/EAC (94 percent) in those treated with ablation compared to those under endoscopic surveillance.8 Endoscopic therapy with RFA is also a safe and well-tolerated technique as shown in a recent systematic review and meta-analysis reporting a 5 percent stricture rate as the most common adverse event.9 Lastly, ablation in LGD (modeled as confirmed by a GI pathologist and stable defined as presence of LGD on at least two endoscopies) was deemed to be more cost effective than surveillance in a modeling study, which accounted for not only the costs of RFA but also the risk of recurrent Barrett’s esophagus following ablation.10

Taking into account all the recent evidence, it is not surprising that recent societal guidelines are recommending the consideration of endoscopic therapy in those with confirmed LGD as the preferred approach. Given the variation in the rates of progression, endoscopic surveillance can be offered as an option for those opting against endoscopic therapy. My approach to those presenting with confirmed LGD is to perform a careful endoscopic examination to exclude prevalent HGD or carcinoma and discuss both options (endoscopic therapy versus surveillance) with the patient. This involves explaining the need for multiple treatments, potential adverse effects, possibility of recurrence and need for continuing endoscopic surveillance. Evaluation should also focus on factors predicting a higher risk of progression: longer Barrett’s segments, prevalent LGD, multifocal LGD (LGD present at multiple levels of the Barrett’s segment) and those with nodularity. In those with potential risk factors predicting higher risk of progression and those with a diagnosis of LGD, ablation is certainly a reasonable therapeutic option given the accumulation of evidence supporting this strategy.

Dr. Iyer has received research support from Exact Sciences, C2 Therapeutics and Intromedic Inc.

References

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2.Shaheen NJ, Sharma P, Overholt BF, Wolfsen HC, Sampliner RE, Wang KK, Galanko JA, Bronner MP, Goldblum JR, Bennett AE, Jobe BA, Eisen GM, Fennerty MB, Hunter JG, Fleischer DE, Sharma VK, Hawes RH, Hoffman BJ, Rothstein RI, Gordon SR,Mashimo H, Chang KJ, Muthusamy VR, Edmundowicz SA, Spechler SJ, Siddiqui AA,Souza RF, Infantolino A, Falk GW, Kimmey MB, Madanick RD, Chak A, Lightdale CJ.Radiofrequency ablation in Barrett’s esophagus with dysplasia. N Engl J Med. 2009 May 28;360(22):2277-88. doi: 10.1056/NEJMoa0808145. PubMed PMID: 19474425

3.Singh S, Manickam P, Amin AV, Samala N, Schouten LJ, Iyer PG, Desai TK.Incidence of esophageal adenocarcinoma in Barrett’s esophagus with low-grade dysplasia: a systematic review and meta-analysis. Gastrointest Endosc. 2014 Jun;79(6):897-909.e4; quiz 983.e1, 983.e3. doi: 10.1016/j. gie.2014.01.009. Epub 2014 Feb 17. Review. PubMed PMID: 24556051.

4. Sikkema M, Looman CW, Steyerberg EW, Kerkhof M, Kastelein F, van Dekken H, van Vuuren AJ, Bode WA, van der Valk H, Ouwendijk RJ, Giard R, Lesterhuis W, Heinhuis R, Klinkenberg EC, Meijer GA, ter Borg F, Arends JW, Kolkman JJ, van Baarlen J, de Vries RA, Mulder AH, van Tilburg AJ, Offerhaus GJ, ten Kate FJ, Kusters JG, Kuipers EJ, Siersema PD. Predictors for neoplastic progression in patients with Barrett’s Esophagus: a prospective cohort study. Am J Gastroenterol. 2011 Jul;106(7):1231-8. doi: 10.1038/ajg.2011.153. Epub 2011 May 17. PubMed PMID: 21577245.

5. Hvid-Jensen F, Pedersen L, Drewes AM, Sørensen HT, Funch-Jensen P. Incidence of adenocarcinoma among patients with Barrett’s esophagus. N Engl J Med. 2011 Oct 13;365(15):1375-83. doi: 10.1056/NEJMoa1103042. PubMed PMID: 21995385

6.Duits LC, Phoa KN, Curvers WL, Ten Kate FJ, Meijer GA, Seldenrijk CA, Offerhaus GJ, Visser M, Meijer SL, Krishnadath KK, Tijssen JG, Mallant-Hent RC, Bergman JJ. Barrett’s esophagus patients with low-grade dysplasia can be accurately risk-stratified after histological review by an expert pathology panel. Gut. 2015 May;64(5):700-6. doi: 10.1136/gutjnl-2014-307278. Epub 2014 Jul 17. PubMed PMID: 25034523.

7. Phoa KN, van Vilsteren FG, Weusten BL, Bisschops R, Schoon EJ, Ragunath K, Fullarton G, Di Pietro M, Ravi N, Visser M, Offerhaus GJ, Seldenrijk CA, Meijer SL, ten Kate FJ, Tijssen JG, Bergman JJ.Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized clinical trial. JAMA. 2014 Mar 26;311(12):1209-17. doi: 10.1001/jama.2014.2511. PubMed PMID: 24668102.

8.Small AJ, Araujo JL, Leggett CL, Mendelson AH, Agarwalla A, Abrams JA, Lightdale CJ, Wang TC, Iyer PG, Wang KK, Rustgi AK, Ginsberg GG, Forde KA, Gimotty PA, Lewis JD, Falk GW, Bewtra M. Radiofrequency Ablation Is Associated With Decreased Neoplastic Progression in Patients With Barrett’s Esophagus and Confirmed Low-Grade Dysplasia. Gastroenterology. 2015 Sep;149(3):567-76.e3; quiz e13-4. doi: 10.1053/j.gastro.2015.04.013. Epub 2015 Apr 24. PubMed PMID: 25917785; PubMed
Central PMCID: PMC4550488

9. Qumseya BJ, Wani S, Desai M, Qumseya A, Bain P, Sharma P, Wolfsen H. Adverse Events After Radiofrequency Ablation in Patients With Barrett’s Esophagus: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2016 Aug;14(8):1086-1095.e6. doi: 10.1016/j.cgh.2016.04.001. Epub 2016 Apr 9. Review. PubMed PMID: 27068041.

10. Hur C, Choi SE, Rubenstein JH, Kong CY, Nishioka NS, Provenzale DT, Inadomi JM. The cost effectiveness of radiofrequency ablation for Barrett’s esophagus. Gastroenterology. 2012 Sep;143(3):567-75. doi: 10.1053/j. gastro.2012.05.010. Epub 2012 May 21. PubMed PMID: 22626608; PubMed Central PMCID: PMC3429791.

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