Hello everyone, and welcome to our presentation on Barrett's Esophagus, What Every Senior Fellow Needs to Know webinar, number two in our three-part webinar series sponsored by the American Society for Gastrointestinal Endocrinology Medtronic. My name is Dr. Samuel Han, and I will be your moderator for today's call. The presenters for today's call are Dr. Stuart Speckler and Dr. Sachin Wan. Stuart Speckler, MD, is Chief of the Division of Gastroenterology and Co-Director of the Center for Esophageal Diseases at Baylor University Medical Center at Dallas, Co-Director of the Center for Esophageal Research at the Baylor Scott and White Research Institute, and Adjunct Professor of Medicine at Texas A&M Health Science Center, College of Medicine, and at Sun Yat-Sen University in Guangzhou, China. Sachin Wan, MD, is an Associate Professor of Medicine at the University of Colorado Anschutz Medical Campus. He is the Medical Director of the Esophageal and Gastric Multidisciplinary Clinic at the University of Colorado. Before we get started, just a few housekeeping items. There will be a question and answer session at the close of the presentation. Questions can be submitted at any time online by using the question box on the right-hand side of your screen. If you do not see the question box, please click the white arrow in the orange box located on the right side of your screen. Please note that this webinar is being recorded and will be posted on GILeaf, ASGE's learning management platform in approximately one week. As a registrant for this webinar, you will have access to the recording. The presentation slides are included in GILeaf at this time. At this time, I would like to turn the webinar over to Dr. Wan. Thanks so much, Sam. I wanna start off by thanking the ASGE for organizing this webinar, and especially thank Liz and the organizing committee for all their hard work. Thank you to Sam for moderating this webinar, and finally to all of you for attending this and making education a priority. What Dr. Speckler and I hope to do in the next 50 minutes or so and ensure that you have enough time for question and answers is the following. We wanna discuss the current guidelines and the indications for screening for Barrett's esophagus and esophageal cancer. We hope to highlight the best practices in surveillance for patients with Barrett's esophagus, to discuss the appropriate management of Barrett's esophagus, including patients with Barrett's related neoplasia, and then finally provide an update on the recently published guidelines on endoscopic eradication therapy. Now I'm gonna hand it over to Dr. Speckler. Thank you, Sachin. So we're discussing Barrett's esophagus, the condition named for this distinguished-looking gentleman, Mr. Norman Rupert Barrett. Barrett was a thoracic surgeon. He was born in Adelaide, Australia, and he spent most of his career practicing in London. Now today we can define Barrett's esophagus as the condition in which a metaplastic columnar mucosa that predisposes to cancer replaces the stratified squamous mucosa that normally lines the esophagus. And this condition is extremely common. It's been estimated to affect as many as 5.6% of adult Americans. Now Barrett's esophagus is the result of metaplasia. That's the process in which one adult type of tissue replaces another, and usually as a response to chronic tissue injury. In the esophagus, the stratified squamous mucosa that normally lines the organ in the setting of GERD and the chronic tissue injury of reflux esophagitis gets replaced by this columnar intestinal-type metaplastic mucosa. Presumably this metaplastic columnar lining is better able to resist damage from GERD than the native squamous lining. Unfortunately, it's also predisposed to malignancy. To diagnose Barrett's esophagus, you need to do an endoscopy, and you need to identify two landmarks, the Z-line, which is the junction between squamous and columnar epithelium, and the GEJ, the gastroesophageal junction. The Z-line is formed by the juxtaposition of that pale squamous epithelium and reddish columnar epithelium. The GEJ is the level at which the esophagus ends and the stomach begins. In Western countries, we identify the GEJ endoscopically as the most proximal extent of the gastric folds. When the Z-line is located above the GEJ, as it is in this drawing, then you have a columnar-lined esophagus. If that columnar-lined esophagus is at least one centimeter long, and biopsy specimens show specialized intestinal metaplasia with goblet cells, then you can make a diagnosis of Barrett's esophagus. Now, we worry about Barrett's because it's the major risk factor for esophageal adenocarcinoma. And in this endoscopic photo in the background, you can see the Barrett's metaplasia that spawned this deadly esophageal adenocarcinoma. The incidence of adenocarcinoma in the United States has been rising dramatically from decades, from 3.6 per million in 1973 to 25.6 per million in 2006. That's more than a sevenfold increase over the course of only three decades. Now, ironically, during this same period, our estimates of cancer risk for individual patients with nondisplastic Barrett's have been falling. In the 1990s, we thought that one in every 100 patients with Barrett's developed cancer each year. In the year 2000, we learned that the old estimate was exaggerated because it was based on reports suffering from publication bias. And over the past 10 years, a number of high-quality studies have suggested that even that estimate of risk was exaggerated. So in 2019, it appears that the incidence of cancer in Barrett's esophagus, somewhere between 0.1 and 0.3% per year, meaning roughly one in every 400 patients with nondisplastic Barrett's esophagus develops a cancer each year. For the past 40 years, our primary strategy to prevent deaths from this cancer has been endoscopic screening and surveillance. Now, let's just be clear what we mean by these terms. To screen for Barrett's esophagus, we use a test to identify individuals with Barrett's in a large population. For example, the large population of people with current symptoms. For surveillance, we use the test to identify curable neoplasia in the form of dysplasia or early cancer in patients who we already know have Barrett's esophagus. And presently, we use endoscopy as the test both for screening and surveillance. And one major problem with this strategy is that we have no proof that it works. What we do have are a bunch of non-definitive and often contradictory studies. For example, in this study from 2013, the investigators identified more than 8,000 patients treated in the Kaiser Permanente system, 351 had an esophageal adenocarcinoma, and 70 of those cancers occurred in patients who had a prior diagnosis of Barrett's, and so they were eligible for surveillance. 38 of those patients died from esophageal cancer, and they became the cases in this case control study. For controls, they identified 101 living Barrett's patients who were matched with the cases for age, sex, and duration of follow-up. Now, 55% of the cases who died of cancer had a surveillance endoscopy performed within three years of the cancer diagnosis. Well, if surveillance was effective at preventing death from cancer, then you would expect that the controls who did not die of cancer would have a much higher frequency of surveillance in the cases, but that's not what they found. 60% of the controls had a surveillance endoscopy performed within three years, not significantly different from 55% in the controls. So in this study, surveillance endoscopy within three years was not associated with a decreased risk of death from cancer. Now, in contrast, this more recent study used the National VA Database to identify more than 29,000 veteran patients with Barrett's and 424 of them developed esophageal adenocarcinoma during mean follow-up of five years. In 209 of those cases, the cancer was diagnosed during an endoscopy performed for surveillance of Barrett's, while in 215, the cancer was diagnosed by endoscopy performed from some reason other than surveillance. The patients whose cancers were diagnosed by surveillance had tumors in an earlier stage, so 75% were diagnosed in cancers by the non-surveillance and they had longer median survivals. They had less cancer-related mortality. So unlike that previous study, this study found that surveillance endoscopy was associated with decreased risk of death from esophageal cancer here with a hazard ratio of 0.47. Well, because of these contradictory data from non-definitive studies, there have been endless debates about whether we ought to recommend endoscopic screening and surveillance. The opponents argue that endoscopy is expensive, is associated with small but real risks. There are disadvantages associated with a diagnosis of Barrett's. It creates anxiety, can raise the cost of life insurance policies, and all of that without proof that these procedures prevent deaths from cancer. The advocates argue that no definitive study is likely to become available in the near future, so waiting for that study is not a viable option. In the meantime, we have computer models suggesting that the practices can be beneficial. Most observational studies suggest that there is benefit and no study has documented physical harm as a result of screening and surveillance. And after considering all of these arguments, RGI societies have come down in favor of the procedures, generally concluding it's better to perform unnecessary endoscopy than to miscurable esophageal neoplasm. So who is at risk for Barrett's? Well, this fellow is the poster child for the patient at risk. He has chronic GERD. Barrett's is common in people with heartburn, especially if they also have hiatal hernia. This patient is above age 50, and the frequency of Barrett's esophagus increases with age. It's very uncommon in children. It's two to three times more common in men than in women, and Barrett's has a special predilection for white men, and it's much less common in African-Americans and Asians. And obesity is associated with Barrett's, especially central obesity with that predominantly intra-abdominal distribution of fat. Cigarette smoking is a risk factor, and so is the family history of Barrett's or esophageal adenocarcinoma. And since Barrett's is the precursor of esophageal adenocarcinoma, all these same risk factors apply to esophageal adenocarcinoma. Now, the most recent American College of Gastroenterology clinical guideline on endoscopic screening for Barrett's states specifically that endoscopic screening is not recommended for the general population. And because esophageal adenocarcinoma is so uncommon in women, they specifically recommend against screening women. The odds of a woman developing esophageal adenocarcinoma are similar to the odds of a man developing breast cancer. It happens, but probably not frequently enough to justify screening. The ACG goes on to recommend that screening may be considered in men with chronic or frequent GERD symptoms, chronic meaning more than five years, frequent meaning at least weekly symptoms of heartburn and acid regurgitation. In addition, they require at least two risk factors, and those include age 50 years or greater, white race, central obesity, a history of smoking, or a confirmed history of Barrett's esophagus or esophageal adenocarcinoma in a first degree relative. And although they do generally recommend against screening for women, they do say that screening for women may be considered in individual cases as determined by the presence of multiple risk factors. So high definition white light endoscopy presently is our screening and surveillance procedure of choice. This slide is adapted from a table in a recent review published in Gastroenterology, and it lists other tests that have been proposed to screen for Barrett's and how they stack up in terms of convenience, accuracy, cost, and patient acceptance. So the alternative tests include transnasal and capsule endoscopy techniques, liquid biopsy, which uses blood samples to detect circulating Barrett's cells or cell components like DNA or micro RNA, serum adipokine markers, the electronic nose that detects volatile organic compounds in the breath, and they can indicate the presence of Barrett's, and the cytosponge or also called sponge on a string that's swallowed and then drawn back through the Barrett's esophagus to scrape off cells that can be tested for TRIP oil factor three, which is the marker of Barrett's metaplasia. And among these tests, standard high definition white light endoscopy is the least convenient and most expensive, but although the other techniques have shown some promise, the authors of this recent review article stated that we do not recommend the use of any alternative tests other than endoscopy to screen for Barrett's at this time. So these alternative tests are not quite ready for prime time use. Screening and surveillance for Barrett's means doing high definition endoscopy at least for now. And I think it's important to appreciate the shortcomings of these practices. First, the number of studies have found that more than 90% of patients diagnosed with esophageal adenocarcinoma were not known to have Barrett's prior to the cancer diagnosis. So that's clear evidence that our screening practices just aren't doing the job. We identify fewer than 10% of patients at risk for this deadly cancer. Next, you need to have GERD symptoms to get screened for Barrett's esophagus, but studies have found that approximately 40% of patients with esophageal adenocarcinoma have no prior GERD symptoms. So our current screening practice automatically misses 40% of the patients who develop cancer. Another shortcoming is related to our current guideline that requires at least one centimeter of intestinal metaplasia for a diagnosis of Barrett's. That one centimeter rule is entirely arbitrary and based on a very limited data that suggests that cancer risk for patients with shorter segments is negligible. While cancers clearly can develop from shorter segments of Barrett's. And finally, screening is performed primarily to identify patients to enter into endoscopic surveillance programs that as we just discussed, it's not clear that the patients benefit from surveillance. So with all of those caveats in mind, let's hear from Dr. Wani on how best to perform endoscopic screening and surveillance session. Thank you so much too. So we know that Barrett's esophagus progresses in a stepwise and a probabilistic manner from Barrett's esophagus to invasive esophageal adenocarcinoma. The steps are as follows. Patients progress from non-displastic Barrett's esophagus to low grade dysplasia, to high grade dysplasia, intramucosal cancer and to invasive cancer. And despite all the advances that we've made in the field of biomarkers, as of now in 2019, the degree of dysplasia within the Barrett's segment is still the best biomarker we have to predict progression in patients with Barrett's esophagus and to determine the optimal management. Whether that patient with Barrett's should undergo surveillance endoscopies or should that patient be referred to an endoscopist for endoscopic eradication therapy. What our guidelines categorically state is the following. If you have a patient with Barrett's esophagus who's undergoing surveillance endoscopy, you need to obtain biopsies using the Seattle Protocol. And that entails obtaining biopsies every one to two centimeters in a four quadrant fashion throughout the extent of the endoscopically involved Barrett's segment. You should also be obtaining biopsies from any visible lesion, no matter how subtle that visible lesion may be. This should be obtained and processed separately from your systematic biopsies. And there are obvious issues with these surveillance practices. We know that dysplasia and early cancer can be indistinguishable from non-dysplastic Barrett's esophagus. We know that the distribution of dysplasia and early cancer is patchy. And when we obtain these surveillance biopsies, we're really sampling a small fraction of the entire Barrett's segment. Less than 5% of the entire Barrett's segment actually gets sampled when we perform biopsies using the Seattle Biopsy Protocol. And hence the issue of sampling errors. We know this practice is time consuming and expensive. And finally, despite all these guidelines that have been established and published, we have good data that endoscopists don't necessarily follow these published guidelines with regards to obtaining biopsies as per Seattle Biopsy Protocol, or bringing patients back appropriately when you've made a diagnosis of non-dysplastic Barrett's esophagus. And I will show you data that proves this point. The other issue is that surveillance endoscopy is not perfect. Just like missing cancers or advanced adenomas when we perform colonoscopies, we can actually miss cancers during surveillance endoscopies for patients with Barrett's esophagus. And this was really demonstrated nicely in a systematic review and meta-analysis from the Mayo Group. And their question was a simple one. What's the proportion of missed cancers? These are cancers diagnosed within one year. And what's the proportion of patients that get diagnosed with incident cancers? What this systematic review showed us was that the missed rate can be as high as 25%. Similar rates were noted when only patients with non-dysplastic Barrett's esophagus were analyzed. Now to address the limitations of our surveillance endoscopies, the AGA came up with these two quality indicators. If you have a patient with Barrett's esophagus undergoing surveillance endoscopies, you should be obtaining biopsies every one to two centimeters in a four quadrant fashion. Once you do make a diagnosis of non-dysplastic Barrett's esophagus, your surveillance endoscopy should not be any sooner than three to five years. Now that we have these quality indicators established, let's try and answer this question. How well do we perform as endoscopists with regards to these two quality indicators? We recently looked at how often are we performing biopsies using the Seattle biopsy protocol in a large national benchmarking registry? We looked at this question using data from the GI quick registry. We looked at data in more than 53,000 patients and close to 59,000 upper endoscopies. What our data clearly showed us was that even if we use the most lenient definition for compliance to the Seattle biopsy protocol, about 25% of our endoscopies for patients with Barrett's undergoing surveillance endoscopies do not obtain biopsies using the Seattle biopsy protocol. Now let's try and answer this question. How often are we bringing patients back appropriately when we do make a diagnosis of non-dysplastic Barrett's esophagus? And again, we looked at these data from the GI quick registry and what our data clearly showed was that 30% of procedures are really non-compliant with the three year threshold. The vast majority are being brought back in the one to two year intervals. And even if we assume that we bring patients back at three to six months for followup of erosive esophagitis, still 27% of patients were non-compliant with the three year threshold. And the reason why I'm bringing up all this data is because we are seeing that overutilization of endoscopy is extremely prevalent. Just take a couple of seconds to digest this information. If these practices continue in a 10 year timeframe with these current practices for overutilization of upper endoscopy, we would perform an excess of close to 43,000 upper endoscopies or an additional 40% endoscopies. And as Dr. Speckler and I are speaking to the next generation of experts or folks who are really going to embark on independent practice, I really would like to spend some time on understanding the factors that drive this overutilization of endoscopy in Barrett's esophagus. I think all of us on this webinar understand that there are obvious reasons why we perform excess endoscopies. Our patients have cancer phobia. We as endoscopists live with this fear of medical malpractice and missing esophageal cancer. I'm sure all of you would agree that we underappreciate the harms of endoscopy. We as clinicians in society always value doing overweighting. It's so much easier to schedule a patient for a repeat endoscopy rather than bringing that patient to our clinic and disawaiting that patient from an unnecessary upper endoscopy. What are the things that we can do? What are the things that are within our grasp to actually move this pendulum towards the appropriate range is to have educational programs like this one where we stress the importance of appropriate utilization of endoscopy. Having educational programs at a medical school level and at a residency level. I'm sure capitalization of care and models will change this practice. And finally, of course, we need better control trials as was highlighted by Dr. Speckler. What are some of the things that you can do in your practice? At the bare minimum, when you're evaluating a patient with Barrett's esophagus in your endoscopy lab, you need to use the best endoscope available in your lab. And you have to use high resolution endoscopy. That really is the D factor standard of care for evaluating patients with Barrett's esophagus so that you can identify these visible lesions within the Barrett segment. We obviously don't have time to review all the advanced imaging techniques that have been investigated to improve our ability to detect dysplasia within the Barrett segment. Suffice to say that the technique that has really gained the maximum amount of attention is the use of narrow band imaging. It's a push button technology. It uses blue light to highlight the mucosal and vascular pattern within the Barrett segment. These are patterns that you should be familiar with. These are classic examples of what non-dysplastic Barrett's esophagus looks like. And you can appreciate the regular mucosal pattern at the top and the regular vascular pattern in the bottom images. Now contrast those images to the ones that you're seeing on the screen right now. You can appreciate that the mucosal pattern is clearly disrupted and so is the vascular pattern. These changes sometimes can be extremely subtle or a walk in the park as seen in the image to the right bottom. What I will recommend to all the senior fellows is to really spend time learning the patterns that are consistently seen in patients with non-dysplastic Barrett's esophagus and those seen in patients with high-grade dysplasia and mucosal cancer. Advanced imaging techniques can actually guide us when we perform endoscopic eradication therapy. To me personally, this really has the highest level of interest but unfortunately also the least amount of data. We routinely use narrow band imaging to actually mark the area that looks suspicious on endoscopy and which guides our endoscopic mucosal resection. There's also research that's being done for the use of advanced sampling techniques. Wide area transepithelial sampling or WATS is one such approach. This actually provides wide area tissue sampling using minimally invasive brush biopsies. This is an abrasive technique that samples deeper layers and then the samples get analyzed by high-speed computer scans. It identifies abnormal cells, cell clusters and abnormal glandular cells. The pathologists then review these flagged or suspicious cells on a high resolution video monitor and they use the same classification system that our pathologists use for classifying patients with varicose esophagus i.e. non-displastic varicose, low-grade, high-grade or cancer. These are some of the images that our pathologists see with these WATS specimens and the images are not too different from what our pathologists get to see when we submit our biopsy specimens. This was a randomized control trial that really brought this technology to the forefront. This really investigated what is the adjunctive role of WATS in addition to our Seattle biopsy protocol. And what the study showed us was that the use of WATS increased the yield of dysplasia by 15%. This was an absolute increase of 15%. Similar results were seen in a systematic review and meta-analysis which showed us that overall the absolute increase is about 2.4% and for the high-risk population, it's about 6.5%. So what are some of the things that you can take to your practice to improve your ability to detect dysplasia within the bare segment? At the bare minimum, you should be spending adequate time inspecting the bare segment. These are technical factors that are within our grasp and control. You should have a systematic and a meticulous approach during inspection. Get into the habit of photo-documenting landmarks and use standardized grading systems such as the Prague criteria for determining the length of the bare segment and the Paris classification for any visible lesion that you may see within the bare segment. And you should be at the very least obtaining biopsies using the Seattle protocol. From a cognitive standpoint, I think it's critical that you're aware of the grading systems and you have adequate training for the use of high-resolution white light endoscopy and narrowband imaging for detecting early neoplasia. And finally, at an institutional level, when you do embark on independent practice, whatever practice you join, ensure that that endoscopy lab has at the bare minimum high-definition white light endoscopy. With that, I'm gonna hand it over to Dr. Speckler to tell us who are the patients who are candidates for endoscopic eradication therapy. Stu. Thanks, Ajan. Well, as you just heard from Dr. Wadhi, dysplasia and barrens is a serious condition. Patients with high-grade dysplasia develop cancer at the rate of at least 6% per year. Before 2011, we used to argue a lot about how best to treat patients with high-grade dysplasia with arguments focusing primarily on whether or not to recommend esophagectomy. But in 2011, the AGA flatly recommended endoscopic eradication therapy as the treatment of choice for patients with confirmed high-grade dysplasia in barrens. And since then, all of the major GI societies have taken a similar position. Endoscopic eradication therapy now is clearly the preferred treatment for patients with dysplasia in barrens. Now, before we discuss this any further, you have to consider the histology of the esophagus. Remember that the muscularis mucosae is that thin muscle layer that separates the mucosa from the submucosa. The mucosa is further subdivided by the basement membrane. The epithelium sits on top of the basement membrane, and the lamina propria is that layer of connective tissue that sits under the epithelium and on top of the muscularis mucosae. Endoscopic therapy is appropriate only for neoplasms that are confined to the mucosa, like this one, high-grade dysplasia, which involves only the epithelium. And endoscopically, we might cure this tumor that's broken through the basement membrane to involve the lamina propria, but it has not reached the submucosa. And that's what we call an intramucosal carcinoma or a T1A lesion. Now, these are the lesions that are potentially curable with endoscopic therapy. But we don't try to cure this T1B tumor endoscopically because it's penetrated deeply into the submucosa and lymph node metastases are found in considerably more than 10% of these T1B tumors. But there's one more feature that this cartoon illustrates that I think is important, because unlike the colon, the esophagus has lymphatics that regularly extend into the mucosa, and so even mucosal neoplasms have the potential to metastasize. Now, how often does that happen? To answer that question, Kerry Dunbar and I performed a systematic review on the risk of lymph node mets for high-grade dysplasia or intramucosal cancer in Barrett's. We reviewed medical literature for studies that included patients who had esophagectomies for high-grade dysplasia or intramucosal carcinoma, and who had final surgical pathology results reported, including lymph node status. We found 70 relevant articles with more than 1,800 patients who had esophagectomy for these mucosal neoplasms, and lymph node metastases were identified in the resection specimen in 1.39%. So the risk of lymph node metastases for mucosal neoplasms in Barrett's is in the range of 1% to 2%. I think this is a point that's not stressed as often as it should be. I think it's important to appreciate that endoscopic therapy can't be 100% successful. There's a 1% to 2% failure rate built in here related to these undetected lymph node metastases, and once a tumor has spread to the lymph nodes, it's unlikely to be cured with endoscopic therapy that just removes mucosa. And all of this means that accurate T-staging is crucial to determine if curative endoscopic therapy is feasible for patients with high-grade dysplasia and intramucosal carcinoma, whose risk of lymph node metastases is only 1% to 2%. Curative endoscopic therapy is feasible, but if there's submucosal invasion, then the risk of lymph node involvement is at least 10% and probably higher. So accurate T-staging is crucial. And endoscopic mucosal resection, EMR, is the best procedure that we have for T-staging these early cancers in Barrett's esophagus. Dr. Wani will discuss the technique of EMR in detail in a few minutes, but with this technique, the endoscopist removes a large sample of mucosa and submucosa, a sample much larger and deeper than a typical endoscopic pinch biopsy. Now, initially, we used EMR as a therapeutic procedure to remove neoplasms in Barrett's, but today EMR is at least as much a staging procedure as it is a therapeutic procedure. If your EMR specimen shows submucosal invasion, then endoscopic therapy is not advised. Now, that brings us to endoscopic ablation. A number of endoscopic modalities have been used to ablate Barrett's. There have been modalities that deliver heat, cryotherapy that freezes tissue with cold nitrogen nitrous oxide or carbon dioxide gas, and photochemical energy delivered by photodynamic therapy. But presently, the generally preferred endoscopic technique is this radiofrequency ablation that uses a generator to deliver radiofrequency energy, which are microwaves, to the esophagus through a balloon-based arrangement of closely spaced electrodes. And here's a cartoon of the inflated RFA balloon positioned in the distal esophagus, and here's what the esophagus looks like after the radiofrequency energy is applied. And Dr. Wani will discuss this technique soon. In a randomized sham-controlled trial of radiofrequency ablation for dysplasia in Barrett's, 64 patients with low-grade dysplasia and 63 with high-grade dysplasia were randomized two-to-one to get either real ablation or sham ablation. And radiofrequency ablation clearly prevented the progression of neoplasia. Only 3.6% of the ablated patients progressed to a higher grade of neoplasia by one year compared to 16.3% of the sham group. And only 1.2% of the ablated patients progressed to cancer compared to 9.3% of the sham group. We also have a randomized trial of radiofrequency ablation versus endoscopic surveillance for patients with low-grade dysplasia. In this European study, 136 patients with low-grade dysplasia confirmed by expert pathologists were randomized to either ablation or endoscopic surveillance. Progression to high-grade dysplasia or cancer was observed at three years in 1.5% of the RFA group and in 26.5% of the surveillance group. That means that RFA decreased the risk of neoplastic progression by 25%. If you focus only on progression to cancer, that was observed in 1.5% of the RFA group and 8.8% of the surveillance group. So RFA decreased the risk of cancer by 7.4%, highly significant. And noting these results, the Data and Safety Monitoring Board for this study determined that they should terminate the study early on the grounds that RFA was clearly superior to surveillance for preventing neoplastic progression and because they felt there was potential for patient safety issues if they continue the trial. Now, it's important to appreciate that there are high rates of metachronous neoplasms that develop after endoscopic therapy. In this study of 349 patients who had mucosal neoplasms in parents, the investigators performed endoscopic therapy with endoscopic mucosal resection or photodynamic therapy that was focused on the neoplasm. So they didn't always ablate the remaining parent's metaplasia. 337 patients had a complete response with apparent eradication of the neoplasm, but during a follow-up of 64 months, 22% of those patients were found to have metachronous neoplasms. Those developed in 17% of 200 patients who had their Barrett's epithelium ablated after they took out the primary neoplasm, but in almost twice as many, 30% of the 137 patients whose Barrett's epithelium was not ablated. So today, endoscopic therapy for mucosal neoplasia in Barrett's, and that includes low-grade dysplasia, high-grade, and intramucosal carcinoma. It starts with EMR of any visible mucosal irregularities. That gives you crucial staging information, and the EMR can be therapeutic as well. In fact, that EMR is so important that the recent ACG guideline says specifically that endoscopists who plan to practice endoscopic ablative procedures should additionally offer EMR. And available data that you should all, suggests you should also ablate the remaining Barrett's metaplasia, usually with RFA to minimize the development of metacritous neoplasms. And this combination of EMR and ablation is what's meant by endoscopic eradication therapy. Now, this is a treatment not without risk. A recent systematic review and meta-analysis of 37 articles, more than 9,000 patients found an 8.8% pooled rate of adverse events, including esophageal strictures, bleeding, and perforation. And when we perform endoscopic eradication, we and our patients have to appreciate that we're making a long-term commitment to follow-up because recurrences of neoplasia and metaplasia are frequent. For example, in this study from the University of Pennsylvania, the investigators completely eradicated intestinal metaplasia in 197 patients with high-grade dysplasia or intramucosal carcinoma. And neoplasia, meaning dysplasia or even cancer, recurred frequently with a rate approaching 25% after 60 to 120 months of follow-up. And metaplasia recurred even more frequently at a rate approaching 50% by 48 months. And other studies suggest that after RFA, intestinal metaplasia recurs in 7.5 to 10% of patients per year. So these worries and recurrence rates suggest that patients must have surveillance endoscopy after complete eradication of their Barrett's metaplasia. At this point, let me once again turn the program over to Dr. Wani, who will discuss the fine points of endoscopic eradication therapy. Seshan. Excellent, thank you so much, Stu. So in these last few minutes, what I hope to do is to really just highlight some of the recent documents that talk about endoscopic eradication therapy and the quality indicators for folks who actually perform endoscopic eradication therapy. You should be familiar with this most recent guideline document on endoscopic therapy for patients with Barrett's-associated dysplasia and intramucosal cancer. This is the official guidelines for the ASGE using the GRADE framework. And lastly, the set of documents that established quality indicators for folks performing endoscopic eradication therapy. You should read these documents, not because Stu and I were a part of this whole process, but primarily because whether you like it or not, measuring quality in endoscopy is going to become a part and parcel of our practice. I'll quickly just go over the clip notes for the quality indicators and the guideline documents that I just mentioned. These quality indicators were categorized into these three categories as pre-procedural, intra-procedural, and post-procedural. The first pre-procedural quality indicators really addresses this whole concept of ensuring that any patient referred to your practice with a diagnosis of Barrett's-related dysplasia must have that diagnosis confirmed by an expert GI pathologist or a panel of pathologists. This is a process measure and your performance target needs to be at least 90%. In this good data supporting this quality indicator, we and others have consistently shown that our pathologists really struggle to make a diagnosis or agree on a diagnosis, especially of low-grade dysplasia or indefinite for dysplasia and high-grade dysplasia. I will submit to you that our pathologists agree with each other far more when we provide larger specimens for patients that have undergone endoscopic mucosal resection, but still suboptimal in my mind for us to make a decision on whether that patient should undergo surveillance endoscopies or be referred for endoscopic eradication therapy. This was a systematic review that we did for our guideline document, and we showed that an expert pathology review results in a change in diagnosis, whether it's upstaging or downstaging in nearly 55% of all patients. And using these data, the ASGE have actually put this in their guideline document that before you embark on endoscopic eradication therapy, you need to confirm the diagnosis by at least one expert GI pathologist or a panel of pathologists. The other important pre-procedural quality indicator addresses this concept of discussing the risks, benefits, and alternatives to endoscopic eradication therapy before you begin treatment. And the driving force behind this quality indicator is to really dissuade folks from an open access endoscopy where patients can just be referred to you for endoscopic eradication therapy. These patients really need to be brought to your clinic so that you can discuss the details of what endoscopic eradication therapy entails, talk to them about the risks that Dr. Speckler just mentioned a few minutes ago about endoscopic eradication therapy, explaining to them that they're going to come back every two to three months until you achieve your endpoint of complete eradication of intestinal metaplasia, discussing the importance of being on BID-PPI therapy. And I don't believe you can do that if you actually see these patients in an open access endoscopy system. The other quality indicator in this pre-procedure category was also touched upon earlier. What this really highlights is that if you are going to perform endoscopic eradication therapy in your practice, you need to have the following. You need to have high definition white light endoscopy, and you need to have the expertise in performing ablation and endoscopic mucosal resection. It's not good enough for you to just be an ablator. Now, moving on to our intra-procedural quality indicators, it's important that you document your landmarks and the length of births using the PROC criteria, a process measure, your performance target needs to be at least 90%. And based on all the available data, the ASG guidelines and the ones that Dr. Speckler mentioned earlier, clearly recommend against surgery for patients who get diagnosed with high-grade dysplasia or intramucosal cancer. We gave this a strong recommendation, even though we have no randomized control trial that has compared surgery to endoscopic eradication therapy. Having said this, we have good observational data suggesting that outcomes between these two treatment modalities are comparable. Where EET really stands out is by showing that the risks of adverse events is significantly lower compared to esophagectomy. Another important intra-procedural quality indicator is performing endoscopic mucosal resection for any visible lesion that you see in patients with Barrett's esophagus. This is a process measure and your performance target needs to be 90%. The most commonly used technique for performing mucosal resection in our practice is the use of the multiband mucosectomy technique. This really involves sucking the visible lesion, deploying a band, and then using a five-french hexagonal snare to cut the lesion of interest. This is really an important aspect of obtaining successful endoscopic eradication therapy outcomes in your practice. As Dr. Speckler mentioned earlier, EMR is not only a therapeutic modality, but it's also a staging or a diagnostic modality. When you perform EMR, that results in a change in diagnosis in nearly 40% of patients. So again, critical information to have whether you should refer your patients for an esophagectomy or whether you should continue with endoscopic eradication therapy. Our guidelines also categorically state that you should perform resection on all visible lesions compared to no endoscopic resection of visible lesions. And this was a strong recommendation. With regards to management of patients with confirmed high-grade dysplasia consistent with the previously published guideline documents, the ASGE guidelines also recommend endoscopic eradication therapy compared to surveillance. For low-grade dysplasia, we can spend an entire hour discussing the controversies on low-grade dysplasia, but we really decided to take a patient-centered approach to managing this condition. We suggest endoscopic eradication therapy compared to surveillance. However, patients who place a high value in avoiding adverse events related to endoscopic eradication therapy, choosing surveillance in that patient population is a perfectly fine treatment modality or option. What this quality indicator document also did for the first time was actually set thresholds on how well we should be performing, i.e., how well should we be achieving complete eradication of neoplasia and intestinal metaplasia. And we decided to use a timeframe for effectiveness of complete eradication. We set a boundary or a threshold of 18 months. And from the time you start endoscopic eradication therapy up to 18 months in your practice, you should achieve complete eradication of dysplasia in at least 80% of your patients. With regards to the endpoint of complete eradication of intestinal metaplasia, that threshold was set at 70%. Now, again, I will submit to you that these thresholds are meant to be the floor and not the ceiling. I really truly believe that you can do far better than these thresholds in your practice. And lastly, you should get into the habit of documenting and tracking your adverse events in your endoscopic eradication therapy practice. I will tell you that this whole guideline in terms of how you should be performing surveillance or how often you should be bringing these patients back is a moving target. We were up until recently bringing patients back based on the surveillance intervals set forth by the AIM dysplasia trial. Most recently, this document actually and the study actually suggests that maybe we're performing far too many endoscopies when we perform surveillance after we've achieved complete eradication of intestinal metaplasia. These are data from the US and UK RFA registry and they suggest that for patients with low-grade dysplasia, once you've achieved complete eradication of intestinal metaplasia, these patients can be brought back at one and three years. For high-grade dysplasia, these patients need to be brought back at three months, six months, one year, and then annually. These have not made their way into any of our guideline documents, but I'm sure will be considered in future guideline documents addressing endoscopic eradication therapy. So I'm gonna end by telling you how we approach patients with Barrett's-related neoplasia. Once a patient is referred, the first thing we do is obtain slides and confirm the diagnosis by our expert GI pathologist. That patient then undergoes a repeat endoscopy and we perform resection of all visible lesions. And what we do next is really dependent on the highest histologic grade based on our above evaluation. If we find submucosal cancer, that patient is discussed in our esophageal multidisciplinary clinic and surgical management is strongly considered unless the patient is a poor candidate for surgery. If we find high-grade dysplasia or intramucosal cancer, we continue with endoscopic eradication therapy with the goal of achieving complete eradication of intestinal metaplasia. For low-grade dysplasia, this is approached on a case-by-case basis. And if we do embark on endoscopic eradication therapy, our goal is the same, to achieve complete eradication of intestinal metaplasia. And then finally, these patients are enrolled in surveillance programs to detect early occurrences. With that, I'll stop here and both Dr. Speckler and I would be happy to answer any questions. Again, we thank you for joining us today for Barrett's Esophagus, what every senior fellow needs to know. At this time, Dr. Speckler and Wani will address questions received from the audience. As a reminder, you can submit a question through the question box. If you do not see the question box, please click the white arrow in the orange box located on the right side of your screen. It'll be towards the bottom. Our first question is, I often get referrals for EGD biopsy negative, but WATS positive for Barrett. What do you do in this case? Do you repeat the EGD with WATS or manage at Barrett? Sure, I can take that question since I spoke about WATS. I don't think we have clear direction on how we should be managing positive WATS specimens. Having talked to several expert pathologists and having them review those slides for patients with positive WATS, they really have felt that these are true positives. But unless you have a study that actually shows us that when you have a WATS positive and you repeat the endoscopy and actually find a visible lesion that looks like dysplasia, or you repeat the endoscopy and confirm the WATS positive, I don't think you can call that a true positive. I know several individuals who actually do treat based on WATS positives results, but I would strongly urge that that patient be brought back at the bare minimum for a repeat endoscopy to confirm the WATS positive result. Great, thank you, Dr. Manoj. I hope that answers. Our next question is, if we encounter an area of nodularity in an area of Barrett that we do not have the skillset to perform EMR, should we just refer to a tertiary care center without biopsy to prevent scarring and making future EMR more difficult, or should we biopsy to help guide future therapy? So I think it's perfectly fine to take a biopsy or two. What makes it really challenging for the endoscopist to perform mucosal resection is if you start using heat or you resect a part of the visible lesion, but obtaining a biopsy or two really does not impact our ability to perform endoscopic mucosal resection. Thank you, Dr. Wani. Our next question is, do you think staging with EUS is less invasive and has a lower risk of complication than EMR? For the T-staging of lesions, EMR is much more accurate than EUS. So EUS may have a role if you're looking for lymph node metastases, but as far as T-staging is concerned, it's just not nearly accurate enough, and we get much better information from EMR. So again, there's some division as to whether or not you should be doing EUS routinely for patients with dysplasia and barits to look for lymph node metastases, but as far as the T-staging of the lesion, that really requires EMR, endoscopic mucosal resection. Great, thank you, Dr. Speckler. Our next question is, does the length of non-dysplastic barit esophagus increase the risk of progressing to high-grade dysplasia slash intramucosal carcinoma, and should we ever consider ablation for long segment non-dysplastic barit esophagus? Okay, yeah, again, these questions come up frequently. It's a great question. Definitely the risk of cancer is related to the length of the barit segment. So the longer the segment, the more likely you are to develop dysplasia and cancer. The problem is that at the moment, we don't have any guideline that states that you should be ablating long segment barits without dysplasia routinely. You can make arguments pro and con, but I personally don't feel that long segment barits by itself is an indication for endoscopic ablation at this time. If there's many other risk factors, like there are multiple areas of dysplasia and things like that, then it's no problem. Generally, things like strong family history in a patient with long segment barits, I might consider ablation. But otherwise, for non-dysplastic barits, at the moment, we're not accepting long segment. Seshan, do you agree? Yeah, I completely agree. Even in our practice, we don't routinely ablate patients with non-dysplastic barits. I would say that I have had a handful number of patients who we have performed ablation, but that has been our practice in patients with a strong family history. And it's really important, in my opinion, to get that family history, because it's not family history of just esophageal cancer. What we're really trying to determine is if that individual has a first-degree relative esophageal adenocarcinoma, remember that patients can have esophageal squamous cell cancer as well. So, completely agree with you, Stu. Thank you. Thank you both. Our next question is, how do you determine the length of the barit segment in cases where there's a hiatal hernia? Sometimes it's confusing where the gastric folds end and where the distal esophagus starts. Yeah, that's very true. It can be difficult sometimes. The tops of the gastric folds, the position can change with respiration and with the degree of air insufflation. I think in that situation, you just have to do the best you can. Deflate, look for the tops of the gastric folds. And in Western countries, that's what we accept. In Asian countries, especially in Japan, they don't accept the tops of the gastric folds as the end of the esophagus, beginning of the stomach. They look for these peculiar palisade vessels. Many of the fellows I know have not even heard of these things, these palisade vessels, but if you look carefully at the distal esophagus, you can see these longitudinal vessels that are very characteristic and where those longitudinal vessels and the Japanese would hold, that's the end of the esophagus. Again, in Western countries, we still are looking for the tops of the gastric folds. And yes, it can be very difficult to find them and with precision, especially if there's a large hiatal hernia, but we do the best we can. Great, thank you, Dr. Speckler. Our next question is, what is your surveillance interval for patients with nondisplastic esophagus? Yeah, I can answer that. So, our guidelines are not very clear and I'm talking about the American guidelines. I think all guidelines have said that these patients need to be brought back at three to five years. And my practice is slightly skewed. I see predominantly patients with various related neoplasia, but I would say that you should be bringing these patients back no sooner than three years. I think for, I really like the guidelines put forth by the British Society of Gastroenterology that actually makes a distinction between the three to five years based on the length of the Barrett segment. If you have a Barrett less than three centimeters, the BSG guidelines recommend that you bring them back at five years. Greater than three centimeters, bring them back at three years. So, what I'd really like to see in future American guidelines is to actually make that distinction between three to five years. I know we don't follow the BSG guidelines, but I guess the take-home point is that don't bring these patients back any sooner than three years. Way back, I think more than a decade ago, the first set of guidelines actually required that you bring patients back in one year to confirm that there's no dysplasia. You confirm the diagnosis of Barrett esophagus. That practice really needs to be abandoned. It's critical that you perform your best exam during that endoscopy itself, obtain your biopsies that you would as if the patient has been in a surveillance program for a while. Great, thank you, Dr. Wani. Our next question is, if you get a referral for low-grade dysplasia in a one-centimeter segment of Barrett, which technically should not have been biopsied, do you manage those patients as low-grade dysplasia? Barrett? Yeah, I'll take that one. Yeah, generally, we do not recommend biopsying less than one centimeter, although you can argue whether that's a good policy. It is the policy. We generally don't want to just biopsy in a regular Z-line. But once you've found dysplasia there, I think you are obligated to do something very shortly. Now, the question is, is that a short segment of Barrett's or might you be biopsying a segment of dysplasia in the stomach? In general, I think that these short segments are almost never dysplasia in the stomach, just in the gastric cardia. I think what we call the gastric cardia is often confused anyway. Personally, I would look, I would go back, I would endoscope that patient, make sure that we're not dealing with a diffuse H. pylori gastritis with intestinal metablasia and dysplasia. And once I've excluded that, I think I would go in and ablate that area. Seshan, do you agree? Yeah, absolutely. And I think what I would add to that is bringing the patient back and discussing the merits of surveillance for low-grade, true low-grade dysplasia within the Barrett's. And if you decide on ablation being the treatment modality that you wanna go down on, I think that's perfectly fine. But just remember that you have the option, even if it is too low-grade, to enroll that patient in a surveillance program. Great, thank you. Our next question is, can you perform EMR on a nasal lesion without performing the biopsy beforehand? I can answer that. So absolutely, it's not required that you've biopsied it before. Very often, patients that get sent to our practice, they recognize the need for mucosal resection and no biopsy has been performed. So obtaining a biopsy is not critical for performing mucosal resection. What is important is really taking a good look. And identifying any visible lesion and if performing EMR is not a part of your practice, then you need to refer that patient to someone who does perform mucosal resection. Great, thank you, Dr. Warner. We have time for one last question, which is, how do you feel about the debate between using ESD versus EMR for lesions that can be treated with EMR? Stu, are you okay if I take this? Yeah, absolutely. Go ahead. I will tell you that the available data suggests that EMR is just as good as ESD. Now, when you think about the advantages of ESD, what's being often touted is the ability to perform on-block resection and the ability to get R0 resection. Now, in contrast, when you perform endoscopic mucosal resection, you may land up performing a piecemeal resection so you don't obtain an on-block resection. And by that, I mean, you really can't determine the lateral margins. But with both techniques, you can determine what the deep margins look like. We unfortunately don't have any data to suggest that outcomes in patients who have undergone ESD are superior to patients who have undergone endoscopic mucosal resection. So, and I'm not going to deny that there may be candidates who are better suited for ESD, especially if there has been prior treatment. There is a concern that the patient may have invasive cancer extending up into the submucosa and is not a surgical candidate. I think you can consider performing ESD, but I strongly believe that if the patient can undergo EMR, that really needs to be the approach that you adopt in your clinical practice. Stu, would you agree with that? Oh, absolutely. Absolutely. Great. Thank you both, Dr. Wang and Dr. Zuckler. So I think that concludes our session for today. I want to thank all of you for joining us today. We hope this information is useful to you in your practice. If you have any questions regarding today's webinar, please contact the staff listed on the slide. And please take a moment to complete the evaluation after the webinar concludes in GIE. Your input will help us in improving our future webinars. The recording of this webinar will be available in approximately one week on ASU's GIE. This concludes our webinar. Please stay tuned for future educational opportunities from ASU and have a great day.

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