Argon plasma coagulation for Barrett’s neoplasia: the right hot ingredient for a successful recipe?

Endoscopic resection has been accepted as a safe and effective treatment modality for early neoplasia in Barrett’s esophagus, and a less invasive alternative to the former gold standard of esophagectomy [1] [2] [3]. Endoscopic resection is mostly aimed at resecting focal lesions, leaving residual Barrett’s mucosa in situ. This approach, however, places the patient at risk of developing new neoplastic lesions in the remainder of the Barrett’s segment. Follow-up studies after focal endoscopic resection have demonstrated a risk of up to 30 % for the development of metachronous lesions during follow-up periods of 2 – 5 years [1] [2] [3]. To prevent secondary neoplastic lesions, ablation of the whole Barrett’s segment after focal endoscopic resection has therefore become a treatment adage [4] [5] [6].

In this issue of Endoscopy, Manner et al. report on the first randomized study to evaluate whether the ablation of residual Barrett’s mucosa after focal endoscopic resection indeed reduces the risk of secondary neoplasia compared with endoscopic surveillance of the residual Barrett’s segment [7]. For this study, patients who had residual Barrett’s mucosa after endoscopic resection for high-grade dysplasia (HGD) or early cancer were included. Based on an expectation of a 30 % risk of secondary neoplasia in the surveillance group during 3-year follow-up and 15 % in the ablation group, it was calculated that 105 patients were required in both the surveillance and ablation groups. However, when the authors performed an interim analysis in 2010, almost 4 years after the start of the study in 2006, the outcomes made them stop the study prematurely in order to offer thermal ablation of residual Barrett’s mucosa to all study patients. At that time, 63 patients were included, of whom 33 were randomized to receive argon plasma coagulation (APC) treatment, and 30 were kept under 6-monthly endoscopic surveillance. In the ablation group, complete remission of the residual Barrett’s mucosa was reached in 26 /33 patients (78.8 %) after a mean of 4 APC sessions. In the ablation group, recurrence was diagnosed in one patient (3 %) during a mean follow-up of 28.2 months. In the surveillance group, 11 /30 patients (36.7 %) were diagnosed with recurrent disease during a mean follow-up of 24.7 months. All recurrences in the study could be treated by repeat endoscopic resection. Kaplan – Meier analysis showed a significantly higher recurrence-free survival in the ablation group compared with the surveillance group (P = 0.005) [7]. Therefore, the results of this randomized study by Manner et al. strengthen the role of additional ablation treatment after endoscopic resection in order to prevent recurrent disease, and the Wiesbaden group has to be congratulated for yet another relevant study in the field of Barrett’s management.

A variety of ablative tools have been studied for ablation of Barrett’s mucosa over the past years. Ideally, the ultimate ablative tool should achieve complete and sustained endoscopic and histological eradication of all Barrett’s mucosa, and it should be safe and easy to apply. Until recently, the techniques most studied did not tick these boxes. Photodynamic therapy showed disappointing results in achieving complete eradication of intestinal metaplasia, and was overshadowed by significant complications, mainly esophageal stenosis and photosensitivity [8] [9] [10]. Stepwise radical endoscopic resection of all Barrett’s mucosa proved very effective, but was technically difficult and resulted in an unacceptable high rate of esophageal stenosis [11] [12]. Radiofrequency ablation (RFA) has shown favorable outcomes, with eradication of all residual neoplasia and intestinal metaplasia in the majority of patients after endoscopic resection, an effect that appears to be sustained at 5-year follow-up [12] [13] [14] [15] [16] [17] [18]. Furthermore, RFA is safe, relatively easy to apply, and success is not operator dependent [12] [13] [14] [15] [16] [17] [18].

The ablative tool used by Manner et al. in their study was APC [7]. Although ablation treatment with APC performed by experienced hands in this study resulted in significantly higher recurrence-free survival compared with surveillance after endoscopic resection, one may question whether APC is the most appropriate tool for this purpose. APC is a widely used, contact-free endoscopic ablation technique using free flow of ionized argon gas. The ablation effect achieved with APC can be quite operator dependent, as there are several factors influencing ablation results such as energy setting, APC mode, the distance between the catheter and the mucosa, and the time during which energy is transmitted. Furthermore, APC treatment is performed spot by spot, making ablation of a larger area of Barrett’s mucosa quite time consuming. Manner et al. report complete remission of Barrett’s mucosa by APC in 26 /33 patients (79 %) [7]. Complete remission was considered to be reached when endoscopic inspection showed regression of > 90 % of the original Barrett’s segment. Care should be taken, therefore, not to compare this 79 % “complete” remission rate with that of recent published ablation studies, which generally have insisted on a complete 100 % endoscopic remission rate and histological removal of all intestinal metaplasia, and often have incorporated the intention-to-treat principle in their reported success rate, which means that procedures in patients who are lost to follow-up or who discontinued treatment for unrelated reasons are considered as failures [11] [12] [13] [14] [15].

The study protocol did not require standard biopsies from the Z line to assess histological eradication of intestinal metaplasia at this level; biopsies were obtained only in case of abnormalities during endoscopic inspection. However, as endoscopic differentiation between intestinal metaplasia and gastric mucosa at the level of the Z line is difficult [19], histological eradication of intestinal metaplasia at this level may be relevant as most recurrences after endoscopic ablation therapy are described in this area [11] [20] [21]. Furthermore, no biopsies from neosquamous mucosa were obtained during follow-up to evaluate for buried Barrett’s glands, whereas buried glands have been reported after APC in 0 to 53 % [10] [22] [23].

Adverse events related to APC in the study by Manner et al. included stricture formation requiring dilation in three patients (9 %), and fever lasting for more than 24 hours for which intravenous antibiotics were started in one patient (3 %). Another patient reported tarry stools (3 %), but no repeat endoscopy was necessary. In addition, a number of minor adverse events such as fever lasting < 24 hours, retrosternal pain, dysphagia, and odynophagia were reported [7]. APC therefore appears to be a safe ablation technique, with a stenosis rate that appears comparable to that reported after RFA [12] [13] [14] [15] [16] [17] [18].

Sustainability of APC treatment cannot be extracted from the Manner study. Mean follow-up after APC was 28.2 months, during which one recurrence was found. The study does not state whether this recurrence occurred in a patient who had previously reached complete eradication of all Barrett’s mucosa, or whether this patient still had residual Barrett’s after APC. Furthermore, no information is provided on the recurrence of Barrett’s mucosa during the available follow-up period.

For treatment of long-segment Barrett’s esophagus measuring over 10 cm in length, one can imagine that APC might be a time-consuming intervention, requiring multiple treatment sessions. In a study by Alvarez Herrero et al. of 26 patients treated with RFA for long-segment Barrett’s esophagus, complete remission of neoplasia and intestinal metaplasia was achieved in 83 % of patients and required a median of three endoscopic ablation sessions [24]. This 83 % clearance rate will most likely be difficult to match using APC for long-segment Barrett’s esophagus. However, APC might be a fast and relatively inexpensive alternative for the treatment of residual short-segment Barrett’s or small remnants at the area of the gastroesophageal junction after endoscopic resection. Also APC could be of additive value as a tool to ablate residual small islands of intestinal metaplasia, once the majority of the Barrett’s mucosa has been eradicated by circumferential RFA. It would be interesting to know whether patients with residual short-segment Barrett’s or small remnants at the gastroesophageal junction were included in the Manner study, and if so, how successful APC was in eradicating intestinal metaplasia in this indication.

In their randomized study, Manner et al. demonstrated that ablation of residual Barrett’s mucosa after focal endoscopic resection of neoplasia significantly reduced recurrence of neoplasia compared with surveillance. With this study they have strengthened the widespread adage that once there is an indication for endoscopic resection of HGD or early cancer in Barrett’s esophagus, not only the focal lesion but the whole Barrett’s segment has to go. However, the results of this study are currently not convincing enough to decide whether APC is the most appropriate tool for this. Future evaluation of APC in a multicenter study that is currently being initiated by the Wiesbaden group is therefore a logical and interesting next step in this field.

• References

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