Timelines for successful endoscopic eradication therapy in Barrett’s esophagus-related neoplasia: what are we aiming for?

Just over 10 years ago, endoscopic eradication therapy (EET) for Barrett’s esophagus (BE)-related neoplasia came to the fore. Interventional endoscopists and BE specialists worldwide were excited but still slightly unsure about which patients fitted the treatment criteria and how best to treat them. Patients were excited because historic interventions had poor outcomes, and surgeons remained skeptical about the long-term oncological consequences of local treatment and organ-preserving therapies.

In 2022, EET for BE-related neoplasia is now mandated internationally. The paranoia that we carried in the early days about disease recurrence has been superseded by long-term follow-up data that have put these anxieties to rest. These data have come from multiple prospective studies examining optimum treatment modalities and regimens, and with rigorous patient selection. In addition, studies have extended the boundaries to explore strategies for avoiding the over- or undertreatment of patients.

Over the years as our experience of protocols for EET in BE have improved, we have looked at different treatment modalities but also at how to optimize patient selection and factors that can prognosticate good outcomes at baseline. When counseling patients considering EET for BE, it is important to remember that, unlike surgical intervention, EET involves repeated interventions that range from baseline diagnostics to active treatment sessions with endoscopic resection (ER), as well as subsequent and ongoing follow-up examinations to prove disease clearance and check for recurrence. Therefore, data that can inform decision making based on the number of EET sessions required are vital for patients and healthcare systems.

“… one can see that the number of endoscopic eradication therapy sessions in these studies all vary and the confounding factors are the baseline BE length but also the need for endoscopic resection prior to radiofrequency ablation.”

In this issue of Endoscopy, Mittal et al. examine, in a very elegant study, the threshold of EET sessions required to achieve complete BE eradication, defined as remission of intestinal metaplasia (CE-IM) [1]. The Treatment with Resection and Endoscopic Ablation Techniques for BE (TREAT BE) Consortium has produced some invaluable data and quality indicators over the past 5 years that have shaped practice internationally but also streamlined the care that we deliver to this group of patients. The study is another important output from this highly acclaimed group. Over a 7-year period, the authors collected data from multiple centers to calculate the mean number of sessions required from index intervention to the attainment of CE-IM. The treatment protocol they used is internationally accepted, with meticulous ER for all visible dysplasia followed by sequential radiofrequency ablation (RFA) for the residual Barrett’s mucosa, at intervals of 2–3 months between each intervention. Many large-volume studies internationally have followed the same protocols [2] [3]. Using Kaplan–Meier projections, Mittal et al. concluded that after three EET sessions, 95 % confidence can be reached that the clearance of intestinal metaplasia is between 70 % and 77 %. For every subsequent session, an additional 14 percentage point increment in clearance was observed. In this cohort, the mean length of BE was 4 cm for the entire cohort, and only 3 cm for the cohort who achieved CE-IM after three sessions.

There are some important considerations when trying to interpret the number of EET sessions needed to achieve disease clearance, especially in a diverse subset such as in this study population. First, in patients where there is visible dysplasia and high grade dysplasia (HGD) or intramucosal cancer, ER will be required before embarking on subsequent RFA. This will automatically add an extra session in this cohort of patients. In comparison, patients with flat low grade dysplasia (LGD) or intestinal metaplasia in this cohort would not have undergone ER and instead proceeded straight to ablation, therefore potentially reducing the number of sessions they received to achieve remission. One could argue that extensive ER at baseline will result in a shorter BE segment requiring subsequent RFA, but it is difficult to tease out these data from the study.

Second, the baseline BE length will be an important prognosticator for how many sessions of EET are needed to achieve CE-IM. The mean BE length in this cohort is shorter than in other published series. In the AIM dysplasia trial [4], the mean BE length was longer at 5.3 cm (± 0.3). In the UK Registry [2], the mean BE length was 5.8 cm (± 3.5) and the mean number of RFA sessions was 2.5 (endoscopic mucosal resection was not included). In the EURO II trial [3], the mean BE length was 6 cm and the median number of sessions of RFA alone was 3 (90 % had undergone ER). Therefore, one can see that the number of EET sessions in these studies all vary and the confounding factors are the baseline BE length but also the need for ER prior to RFA. In the study by Mittal et al., even though 53.1 % of the cohort had HGD or cancer, only 23 % had visible lesions. However, the rate of EMR was 50.6 % in the study cohort.

An important discussion point here is that historically all protocols have been designed to look at disease outcomes at a 12-month cutoff. Therefore, we were limiting ourselves to a maximum of four interventions before taking biopsies to sample for eradication success. Clearly, in patients with longer BE segments, this 12-month cutoff is not helpful as it would clearly underreport success outcomes because these patients are still technically undergoing treatment for residual BE. This same group of investigators has therefore looked at quality metrics in the past and suggested that 18 months may be a more realistic cutoff [5].

In this cohort, the authors also showed that when using the threshold of three EET sessions, baseline histology of LGD, HGD, or intramucosal cancer and BE length were significantly associated with lower response rates. We also know from other clinical studies, but also from clinical practice, that patients who have poor acid suppression after EET will require more sessions owing to poor healing. Van Munster et al. developed a prognostic model that identified patients with a BE length of ≥ 9 cm and HGD/esophageal adenocarcinoma and those with poor squamous regeneration as being at high risk for a complex treatment course [6]. These patients have a longer treatment journey as well as more sessions compared with patients with more straightforward disease and patients with a mean BE length of 6 cm [6].

Ultimately, as endoscopists delivering high quality care, we need to take into consideration studies like this to help inform patients but also to plan resources for the likely number of EET sessions that patients will need. We can also use modeling using this and previous studies to inform treatment pathways for patients who are less likely to achieve remission in the timelines we have historically set. This may allow physicians to potentially explore the use of adjunctive treatments, such as more aggressive and baseline ER and other emerging ablation modalities, to ensure successful outcomes.

Publication History

Article published online:
30 August 2022

• References

• 1 Mittal C, Muthusamy VR, Simon VC. et al. Threshold evaluation for optimal number of endoscopic treatment sessions to achieve complete eradication of Barrett’s metaplasia. Endoscopy 2022; 54: 927-933
• 2 Haidry RJ, Dunn JM, Butt MA. et al. Radiofrequency ablation and endoscopic mucosal resection for dysplastic Barrett’s esophagus and early esophageal adenocarcinoma: outcomes of the UK National Halo RFA Registry. Gastroenterology 2013; 145: 87-95
• 3 Phoa KN, Pouw RE, Bisschops R. et al. Multimodality endoscopic eradication for neoplastic Barrett oesophagus: results of an European multicentre study (EURO-II). Gut 2016; 65: 555-562
• 4 Shaheen NJ, Sharma P, Overholt BF. et al. Radiofrequency ablation in Barrett’s esophagus with dysplasia. N Engl J Med 2009; 360: 2277-2288
• 5 Wani S, Muthusamy VR, Shaheen NJ. et al. Development of quality indicators for endoscopic eradication therapies in Barrett’s esophagus: the TREAT-BE (Treatment with Resection and Endoscopic Ablation Techniques for Barrett’s Esophagus) Consortium. Gastrointest Endosc 2017; 86: 1-17
• 6 van Munster SN, Frederiks CN, Nieuwenhuis EA. et al. Incidence and outcomes of poor healing and poor squamous regeneration after radiofrequency ablation therapy for early Barrett’s neoplasia. Endoscopy 2022; 54: 229-240