Haidry

In my opinion at present, we do not have a technology or procedure that is robust enough to accommodate the scale and scope required for screening an at-risk population. Furthermore, I am still uncertain that we as an endoscopic community have defined fully what this at-risk population is.

Bisschops

Eighty percent of cases of Barrett’s related adenocarcinoma are not diagnosed in patients who are under surveillance for known Barrett’s esophagus. Therefore, it is important to better screen patients at risk. In this effort, the focus should be in the first place on high-risk individuals: patients with longstanding reflux, smoking habits, male patients, and a family history of esophageal cancer. The advent of noninvasive screening methods, like for instance Endosponge, should facilitate this effort and help to better select individuals for a more invasive gastroscopy.

Rath

Currently, screening strategies for Barrett’s esophagus (BE) are based on the identification of patients at risk for developing BE. Firstly, patients with a family history of esophageal adenocarcinoma (EAC) or BE are considered at high risk for developing BE themselves and should be included in screening programs. Secondly, patients with gastroesophageal reflux disease (GERD) are also at increased risk for development of BE and hence, in the presence of other coexisting risk factors such as age >50 years, obesity, current or past smoking, and male gender, these patients should also be included in screening programs. So yes, we already have screening programs to identify Barrett’s esophagus patients, and the majority of guidelines advocate and suggest to screen patients with risk factors as outlined above.

At the same time, however, it needs to be pointed out that we currently have no screening programs for low-risk patients and that screening of low-risk patients is currently not advocated in European and US guidelines. This is mainly based on the fact that broadening of screening criteria would considerably increase the number of patients eligible for BE screening and would be associated with a drastic increase in resource use and costs for the healthcare system. However, the future will show whether other less-invasive and resource-intense modalities for BE screening become available for screening also of low-risk patients.

Gisbertz

We are getting there, but not yet. The cytosponge is an exciting new method that will be very suitable to screen high-risk patients for the presence of Barrett’s esophagus. For the general population, breath test examining exhaled volatile organic compounds may become available to screen for GI cancers but specifically early stages and Barrett’s.

Haidry

We will be able to predefine surveillance intervals based on demographic, biomarker, and endoscopic criteria to reduce the intensity of surveillance on some patients whilst increasing it for others.

Bisschops

…that we finally abandon the Seattle biopsy protocol. The incorporation of a biomarker risk panel to better risk stratify patients in order to better select patients that need further surveillance and/or would benefit from early treatment before they develop dysplasia, could be based on brushing methods rather than biopsies. In addition, incorporation of artificial intelligence will help to improve detection of neoplasia. The combination of these will eventually lead to abandoning the tedious Seattle biopsy protocol, just like we did for surveillance of longstanding colitis patients.

Rath

Currently, endoscopic surveillance intervals are mainly determined by the grade of dysplasia and the length of the Barrett’s segment during the last endoscopy. One of the major problems with BE surveillance in its current form that it is both time-consuming and costly. This cost is at least in part caused by a low absolute risk of progression and large numbers of patients in surveillance programs that will likely never develop advanced lesions requiring treatment. Therefore, we need an individualized risk assessment for progression of BE. That this is feasible was just recently shown in a study in which multiple parameters were assessed including, grade of dysplasia, immunohistochemical markers such as p53 or SOX2, patent gender and age, the length of the BE and others to for calculation the risk of neoplastic progression in individual BE patients. In a simulation of this model, it was shown that the majority of patients could be safely discharged from surveillance after two surveillance endoscopies, while effectiveness for timely detection of neoplastic progression was still guaranteed.

Further, artificial intelligence (AI) is a rapidly evolving field and it can be expected that AI will facilitate detection, characterization, and delineation of lesions during BE surveillance and provide an automated, and hence from the experience of the endoscopists independent, diagnosis during endoscopy. Secondly, by identifying suspicious areas, AI will allow to increase the diagnostic yield from biopsies and holds the potential to also increase cost-effectiveness. Lastly, we might see non-endoscopic techniques for surveillance in BE patients such as biomarkers or biomarker panels, sponge techniques, or a combination thereof.

Gisbertz

Less invasive surveillance methods and better risk stratification so that many patients will not undergo unnecessary endoscopies.

Haidry

Operator training and optimum use of available technology.

Bisschops

…cleaning the esophagus. Visualization is obviously the first prerequisite to detect and identify subtle lesions in Barrett’s esophagus. Cleaning the esophagus, automatically increases the inspection time, which is related to dysplasia detection and in addition, during cleaning, subtle mucosal friability may become apparent and is often an indicator of neoplasia. In addition, if advanced imaging techniques are applied during surveillance, a thorough cleaning is necessary. Finally, if we want to apply AI in the future for detection, it is obvious and trivial that cleaning the esophagus is necessary to unmask subtle abnormalities and present them for detection by a CAD system.

Rath

To me, performing a high-quality endoscopic examination is the key step to improve detection rates during BE surveillance. For this, I have a very standardized approach: First, I inspect every segment with HD-WLE and although this is not a guideline recommendation, I usually use a distal attachment cap at the tip of the endoscope to improve visualization. An important aspect here is to take enough time for the inspection, and I usually spend at least 1 min for every centimeter of Barrett mucosa. Afterward, I switch to NBI and make a second thorough inspection of the entire Barrett’s mucosa and usually use optical magnification during evaluation of the vascular and mucosal pit pattern. Lastly, I perform dye-based chromoendoscopy with spraying of acetic acid solution over the whole BE. Regarding biopsies, I obtain targeted biopsies of all suspicious lesions in addition to four-quadrant biopsies of the remaining Barrett’s mucosa according to the Seattle protocol.

Gisbertz

Expert pathologists (expert panel) and centralization of care in high-volume Barret centers with expert gastroenterologists.

Haidry

Absolutely not. I think this is a massive overtreatment based on some very indifferent data over the past 10 years. I think a lot of work needs to go into defining whether patients diagnosed with low-grade dysplasia indeed carry the same risk seen in bespoke trials because in the real world this rate of progression has not been replicated.

Bisschops

No. We take several factors in consideration before treating low-grade dysplasia without visible lesions:

  • Low-grade dysplasia should be confirmed on at least two separate endoscopies and by 2–3 pathologists.

  • Length of the Barrett.

  • Multifocality of LGD.

  • Patient’s preference: we always discuss extensively the results of the SURF trial with our patients and a large number of patients are reassured by the fact that there is no progression in 75% of patients over 2 years, and that when progression occurs, they can still be treated by the same modalities.

If a visible lesion is present and contains LGD however, we always perform endoscopic resections.

Rath

Yes, presence of low-grade dysplasia (LGD) is a clear indication for endoscopic resection. Two things are important to keep in mind when considering endoscopic resection in a patient with LGD: Firstly, various studies in the field have shown that there is frequent overdiagnosis of LGD during histopathology by pathologists that are not focused or specialized on BE. Therefore, histopathologic confirmation of the presence of LGD by an expert pathologist seems mandatory and this is also advocated by our guidelines. Secondly, endoscopic resection requires that we have a visible lesion. In case with have a confirmed LGD on biopsy without an endoscopically visible lesion, endoscopic ablation therapy should be performed and here, radiofrequency ablation is most commonly used.

Gisbertz

Yes, based on the SURF study results, it has been shown that progression to neoplasia is very rare after RFA.

Haidry

This question can only be answered where there is a clinical and patient context associated with the histopathological criteria described above. Robust perspective data on the true risk of submucosal can see is lacking in but will evolve in the next 5 years. In my Opinion if this patient is cancelled appropriately they could undergo Vigeant endoscopic, radiological and clinical surveillance to assess for extraluminal disease currents at which stage escape therapy could be offered.

Bisschops

There is no treatment flow chart for such patients. This is always an individual per-patient based decision. We would always perform a full staging with PET-CT and EUS. If negative, we would discuss operability in an MDT discussion and usually discuss the potential risk of metastasis and the risk of surgery with the patient. The more comorbidities in a patient, the more likely the MDT supports follow-up in these cases now. We do this in a multicenter prospective study protocol.

Rath

This is a challenging question. Although indication for endoscopic therapy has extended to tumors invading the submucosa superficially (less than 500 mm) without pathologic risk factors (G1 or G2 differentiation, no lymphovascular invasion), it has to be stated that the patients with high-risk features (such as presence of lymphovascular invasion) are usually surgical candidates. However, in high-risk T1b patients, also other factors such as comorbidities or age needs to be taken into account. Furthermore, we know from various studies that the risk of metastases in high-risk T1b cancers might lower than originally thought. Therefore, in individual patients with a high-risk T1b cancer that are “unfit” for surgery, close-meshed endoscopic follow-up with regular endoscopic and also endosonographic surveillance for early detection of lymph node metastases at a still curative stage can be taken into consideration as an alternative to surgery.

Gisbertz

I would include this patient in the SNAP-III study: since this patient has substantial risk of lymph node metastases, I would include this patient in this study that investigates the accuracy of sentinel node navigation surgery in high risk T1b adenocarcinoma patients using a dual tracer (technetium and ICG). I would also discuss an esophagectomy and surveillance in the PREFER study, to make shared decision-making possible.

Haidry

Oncological outcomes will be influenced primarily by robust and consistent inclusion criteria. To truly prognosticate the oncological outcome and prognosis it is very important that baseline staging is accurate. Under or over staging the Patient at baseline will influence an indifferent outcome prognostication. Complication rates will be affected by not just surgical technique but also optimizing patient selection in terms of anesthetic and comorbid factors and optimizing the recovery period.

Bisschops

Experience of the center and the surgeons.

Rath

Probably the experience of the center and the surgeon. Having done esophageal surgery in a high-volume center is one of the key aspects here.

Gisbertz

Experience and exposure of the surgeon and the complete postoperative care team (nurses, anesthesists, physiotherapists, dieticians, etc).

Roos E. Pouw: Speaker fee from Medtronic; consultancy for MicroTech. Oliver Pech: Speaker fees from Medtronic, Fujifilm, Olympus, Boston Scientific, and Aohua. Rehan Haidry: No conflicts of interest to declare. Raf Bisschops: Advisory and speaker’s fee from Medtronic, Pentax, Fujifilm. Advisory fee from Cook and Boston Scientific. Timo Rath and Suzanne Giesbertz: No conflicts of interest to declare.

There were no funding sources for this work.

All authors contributed equally.

Dr. Roos E. Pouw

Department of Gastroenterology and Hepatology

Amsterdam Gastroenterology Endocrinology Metabolism

Amsterdam University Medical Centers

De Boelelaan 1118

1081 HZ Amsterdam, The Netherlands

r.e.pouw@amsterdamumc.nl

Prof. Oliver Pech

Department of Gastroenterology and interventional Endoscopy

Krankenhaus Barmherzige Brueder

Pruefeninger Str. 86

93049 Regensburg, Germany

oliver.pech@barmherzige-regensburg.de

Prof. Rehan Haidry

University College Hospital

Cleveland Clinic London

33 Grosvenor Place

London SW1X 7HY, UK

rehan.haidry@nhs.net

Prof. Raf Bisschops

University Hospitals Leuven

Department of Gastroenterology and Hepatology

TARGID 4-27-1

Herestraat 49

3000 Leuven, Belgium

raf.bisschops@uzleuven.be

Prof. Timo Rath

Ludwig Demling Endoscopy Center

University Hospital Erlangen

Ulmenweg 18

91054 Erlangen, Germany

timo.rath@uk-erlangen.de

Prof. Suzanne S. Giesbertz

Amsterdam UMC location University of Amsterdam

Department of Surgery

2. Cancer Center Amsterdam

Meibergdreef 9

1105 Amsterdam, the Netherlands

s.s.gisbertz@amsterdamumc.nl

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