Choosing weapons in Barrett’s esophagus

Ablative therapy for Barrett’s esophagus has heralded a new era in therapeutic endoscopy. The foundation of this approach rests on the now decades-old observation that controlled injury to the metaplastic epithelium, when combined with aggressive acid suppression, results in the regeneration of squamous, not columnar, lining [1] [2] [3]. Although this lining may be somewhat lacking with respect to mucosal barrier function [4], it expresses no cancer markers [5] and appears otherwise to be phenotypically similar to native squamous mucosa. Most importantly, successful eradication appears to be associated with a marked decrement in cancer risk, in the limited data available on this issue [6] [7].

A plethora of techniques have demonstrated efficacy in inducing reversion to squamous epithelium in patients with Barrett’s esophagus. Investigators have demonstrated that electrocautery [2] [8], radiofrequency ablation (RFA) [9] [10], laser ablation [11] [12], photodynamic therapy (PDT) [13] [14], and cryotherapy [15] [16] may all be effective in inducing at least transient reversion to squamous epithelium. Most of these studies are prospective or retrospective cohort studies or case series. Many of them lack long-term follow-up, or have cursory documentation of adverse events or disease progression.

On this background, in this issue of Endoscopy, Sie and colleagues from Australia report the late outcomes from two randomized controlled trials (RCTs) of argon plasma coagulation in the setting of Barrett’s esophagus with either no dysplasia or low grade dysplasia (LGD) [17]. These studies enrolled patients who had either undergone a surgical antireflux procedure or had been managed medically with proton pump inhibitors (PPIs). In both studies, patients were randomized in a 1:1 fashion to either treatment with APC or endoscopic surveillance. While the short- and midterm results of these studies have been previously reported [18] [19] [20], the current study reports on outcomes as long as 7 – 11 years in a large proportion of patients. The outcomes quantified include the percent regression of Barrett’s esophagus, the length of the Barrett’s esophagus (Prague “M” criterion), and the rate of progression of disease.

The main finding of the study is that, while there was some degradation of the effect of APC, the majority of patients retained a good response to therapy. While 97 % (61 /63) of patients had > 95 % of their Barrett’s revert to squamous epithelium immediately following therapy, in 66 % of evaluable patients (21 /32) the > 95 % reversion was maintained in long-term follow-up (> 84 months). Among those who did have residual disease, the amount of residual disease on average was small (< 1 cm Prague M length), regardless of whether their gastroesophageal reflux disease (GERD) had received medical or surgical management. There was a trend toward more dysplasia developing in the surveillance group compared with the APC group in mid- to long-term follow-up (9 vs. 2 patients), but this did not reach statistical significance (P = 0.054). In general, there were no differences in efficacy or complication outcomes between those managed with a surgical antireflux procedure and those managed medically with PPI therapy.

These data are a valuable contribution to the literature primarily because of the length of follow-up involved in the study. Because almost half (59 /129) of the participants originally allocated in these studies underwent endoscopic follow-up at greater than 84 months after randomization, this study represents one of the few in the Barrett’s ablation literature which assesses outcomes at intervals of longer than 5 years. Additionally, because the investigators tracked progression rates to cancer or more severe dysplasia, clinically relevant outcomes were assessed. Also, the investigators assiduously tracked the whereabouts and outcomes of this group, making it unlikely that poor outcomes due to disease progression were missed in these patients. Finally, because two studies with parallel structure were performed in medically and surgically managed patients, some inference regarding the relative benefits of these modes of managing reflux for the outcomes of ablative therapy may be gained.

While these factors make the current study notable, some limitations exist. First, the outcomes measured in these trials would not be considered to be adequately rigorous for ablation trials in 2013. While percent regression of Barrett’s esophagus is an easily assessable outcome endoscopically, it is subjective and may not correlate with histological eradication of Barrett’s. While we assume that, with respect to their cancer risk, patients with a lesser extent of Barrett’s esophagus are qualitatively better off than those with a greater extent, the true value of 50 % eradication of one’s baseline Barrett’s esophagus is unclear, and may not translate into a 50 % decrease in cancer risk. Similarly, decreases in overall length of the Barrett’s segment are also subjective and may not correlate with cancer risk. The most commonly used outcomes in current trials, complete eradication of intestinal metaplasia (complete endoscopic and histologic clearance of intestinal metaplasia from the tubular esophagus), and complete eradication of dysplasia (complete endoscopic and histologic clearance of dysplasia from the tubular esophagus), are higher hurdles for ablation, and recognize the potential importance of subsquamous intestinal metaplasia or intestinal metaplasia that underlies seemingly normal squamous epithelium.

Also, the study was performed in patients with Barrett’s esophagus and either no dysplasia or LGD. While the original report of the medical RCT does not note the proportion of patients in the study with Barrett’s esophagus and LGD [20], in the surgical RCT [18], only 2 out of 40 patients randomized had LGD, meaning that almost all patients in this trial had nondysplastic Barrett’s esophagus. Currently, many clinicians would consider that in such patients the risk of cancer progression would be too low to warrant ablative therapy. Not surprisingly, the study demonstrates relatively low numbers of patients with disease progression, and no one went on to develop cancer, making it impossible to know whether the ablative therapy truly influenced the course of the disease. In the absence of such knowledge, it is difficult to know whether ablative therapy really improved clinically relevant outcomes, or merely resulted in a change in the color of the mucosal lining.

Of course, the authors are to be forgiven if certain aspects of these studies, designed 10 or more years ago, would not meet the current standards for ablation trials. Despite these concerns, these investigations provide useful data regarding durability and long-term outcomes with an ablative modality which is widely available but less commonly reported in the literature in recent years. Data such as these beg the question: “Which modality should I be using for my patients?”

• References

• 1 Sampliner RE, Hixson LJ, Fennerty MB et al. Regression of Barrett’s esophagus by laser ablation in an anacid environment. Dig Dis Sci 1993; 38: 365-368
• 2 Sampliner RE, Fennerty B, Garewal HS. Reversal of Barrett’s esophagus with acid suppression and multipolar electrocoagulation: preliminary results. Gastrointest Endosc 1996; 44: 532-535
• 3 Berenson MM, Johnson TD, Markowitz NR et al. Restoration of squamous mucosa after ablation of Barrett’s esophageal epithelium. Gastroenterology 1993; 104: 1686-1691
• 4 Jovov B, Shaheen NJ, Orlando GS et al. Defective barrier function in neosquamous epithelium. Am J Gastroenterol 2013; 108: 386-391
• 5 Pouw RE, Gondrie JJ, Rygiel AM et al. Properties of the neosquamous epithelium after radiofrequency ablation of Barrett’s esophagus containing neoplasia. Am J Gastroenterol 2009; 104: 1366-1373
• 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 Overholt BF, Lightdale CJ, Wang KK et al. Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Barrett’s esophagus: international, partially blinded, randomized phase III trial. Gastrointest Endosc 2005; 62: 488-498
• 8 Dulai GS, Jensen DM, Cortina G et al. Randomized trial of argon plasma coagulation vs. multipolar electrocoagulation for ablation of Barrett’s esophagus. Gastrointest Endosc 2005; 61: 232-240
• 9 Fleischer DE, Overholt BF, Sharma VK et al. Endoscopic radiofrequency ablation for Barrett’s esophagus: 5-year outcomes from a prospective multicenter trial. Endoscopy 2010; 42: 781-789
• 10 Ganz RA, Overholt BF, Sharma VK et al. Circumferential ablation of Barrett’s esophagus that contains high-grade dysplasia: a U.S. Multicenter Registry. Gastrointest Endosc 2008; 68: 35-40
• 11 Barham CP, Jones RL, Biddlestone LR et al. Photothermal laser ablation of Barrett’s oesophagus: endoscopic and histological evidence of squamous re-epithelialisation. Gut 1997; 41: 281-284
• 12 Weston AP, Sharma P. Neodymium:yttrium-aluminum garnet contact laser ablation of Barrett’s high grade dysplasia and early adenocarcinoma. Am J Gastroenterol 2002; 97: 2998-3006
• 13 Overholt BF, Panjehpour M, Halberg DL. Photodynamic therapy for Barrett’s esophagus with dysplasia and/or early stage carcinoma: Long-term results. Gastrointest Endosc 2003; 58: 183-188
• 14 Ackroyd R, Kelty CJ, Brown NJ et al. Eradication of dysplastic Barrett’s oesophagus using photodynamic therapy: long-term follow-up. Endoscopy 2003; 35: 496-501
• 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 Dumot JA, Vargo JJ, Falk GW et al. An open-label, prospective trial of cryospray ablation for Barrett’s esophagus high-grade dysplasia and early esophageal cancer in high-risk patients. Gastrointest Endosc 2009; 70: 635-644
• 17 Sie C, Bright T, Schoeman M et al. Argon plasma coagulation ablation versus endoscopic surveillance of Barrett’s esophagus: late outcomes from two randomized trials. Endoscopy 2013; 45: 859-865
• 18 Ackroyd R, Tam W, Schoeman M et al. Prospective randomized controlled trial of argon plasma coagulation ablation vs. endoscopic surveillance of patients with Barrett’s esophagus after antireflux surgery. Gastrointest Endosc 2004; 59: 1-7
• 19 Bright T, Watson DI, Tam W et al. Randomized trial of argon plasma coagulation versus endoscopic surveillance for barrett esophagus after antireflux surgery: late results. Ann Surg 2007; 246: 1016-1020
• 20 Bright T, Watson DI, Tam W et al. Prospective randomized trial of argon plasma coagulation ablation versus endoscopic surveillance of Barrett’s esophagus in patients treated with antisecretory medication. Dig Dis Sci 2009; 54: 2606-2611
• 21 Sharma P, Wani S, Weston AP et al. A randomised controlled trial of ablation of Barrett’s oesophagus with multipolar electrocoagulation versus argon plasma coagulation in combination with acid suppression: long term results. Gut 2006; 55: 1233-1239
• 22 Ragunath K, Krasner N, Raman VS et al. Endoscopic ablation of dysplastic Barrett’s oesophagus comparing argon plasma coagulation and photodynamic therapy: a randomized prospective trial assessing efficacy and cost-effectiveness. Scand J Gastroenterol 2005; 40: 750-758
• 23 Hage M, Siersema PD, van Dekken H et al. 5-aminolevulinic acid photodynamic therapy versus argon plasma coagulation for ablation of Barrett’s oesophagus: a randomised trial. Gut 2004; 53: 785-790
• 24 Kelty CJ, Ackroyd R, Brown NJ et al. Endoscopic ablation of Barrett’s oesophagus: a randomized-controlled trial of photodynamic therapy vs. argon plasma coagulation. Aliment Pharmacol Ther 2004; 20: 1289-1296
• 25 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 2009; 23: 13-19
• 26 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
• 27 Van Vilsteren FG, Pouw RE, Seewald S et al. Stepwise radical endoscopic resection versus radiofrequency ablation for Barrett’s oesophagus with high-grade dysplasia or early cancer: a multicentre randomised trial. Gut 2011; 60: 765-773