Barrett’s Esophagus Dr. Robert Osterhoff, MD Palo Alto Medical Foundation Mills Peninsula Hospital March 19th 2016

Objectives Background Examples and images Screening and Surveillance Definitions: Learn the definition of Barrett's esophagus and gain some understanding of its pathophysiology and relationship to esophageal cancer History of Barrett’s esophagus The scope of the problem Examples and images What does Barrett’s look like Prague classification Short vs. Long segment Screening and Surveillance Understand the current indications and guidelines for Barrett's screening and surveillance Explore some of the controversies Treatment Gain an understanding of methods of treatment for Barrett's esophagus and current standards of care, including risks of treatment and the impact on patients

Background…why do we care The real issue is Esophageal cancer (EAC) Accounts for approximately 1% of all cancers and 6% of cancers involving the gastrointestinal tract By some estimates the incidence has grown 400% in the last 10-20 years The one year mortality is >85% Barrett’s esophagus is a premalignant condition for EAC It has been estimated that 5.6% of adults in the United States have Barrett’s esophagus. Follows progression from metaplasiadysplasiacancer

Before we begin…Definitions Metaplasia (Greek /(met″ah-pla´zhah)  change in type A change or adaptation of one type of epithelium to another that is more likely to be able to withstand the stresses it is faced with Dysplasia (Greek /(dis″pla´zhah) δυσ- dys-, "bad" or "difficult" and πλάσις plasis, "formation") Abnormal growth or development of cells, tissue, bone, or an organ. Replacement of normal cells with those of another type, often maladaptive or premalignant Low-grade vs. High-grade dysplasia Carcinoma(Greek[kahr″sĭno´mah]  malignant new growth made up of epithelial cells tending to infiltrate surrounding tissues and give rise to metastatses  Johns Hopkins Pathology Atlas. http://pathology2.jhu.edu/beweb/cancer.cfm © 2000-2016 Johns Hopkins University.

Barrett’s esophagus: simple definition Barrett’s esophagus is a condition in which the lining of the esophagus changes, becoming more like the lining of the intestine. It is a “precancerous condition”

True Definition: Barrett’s esophagus Barrett’s esophagus: The replacement of the normal stratified squamous epithelium of the esophagus by simple columnar epithelium with goblet cells . Barrett's esophagus and esophageal cancer: An overview, Vincenza C. et. al Published online: May 17, 2012 Pages: 414-424 DOI: 10.3892/ijo.2012.1481

History Norman Rupert Barrett Allison and Johnstone Esophageal surgeon who was born in Adelaide, Australia in 1903 Worked for most of his career as a surgeon at St. Thomas’ Hospital in London First described the columnar metaplasia in 1950. Allison and Johnstone In 1953 described 7 patients who had reflux esophagitis involving an “esophagus lined with gastric mucous membrane associated with gastroesophageal reflux An association with adenocarcinoma was made in 1975.

History (continued) By the 1980s, it was well established that adenocarcinoma was associated with Barrett’s esophagus Multiple strategies for diagnosis and treatment emerged in the 1990s RFA developed and became widespread in early 200os along with some clinical guidelines

EAC: Scope of the Problem 1% of all cancer in the US In 2012, there were an estimated 35,781 people living with esophageal cancer in the United States. Rates are rising National Cancer Institute; SEER database http://seer.cancer.gov/statfacts/html/esoph.html

Esophageal cancer represents 1.0% of all new cancer cases in the U.S. EAC (continued) Common Types of Cancer Estimated New Cases 2015 Estimated Deaths 2015 1. Breast Cancer (Female) 231,840 40,290 2. Lung Cancer 221,200 158,040 3. Prostate Cancer 220,800 27,540 4. Colon Cancer 132,700 49,700 5. Bladder Cancer 74,000 16,000 6. Melanoma of the Skin 73,870 9,940 7. NHL 71,850 19,790 8. Thyroid Cancer 62,450 1,950 9. Renal Cancer 61,560 14,080 10. Endometrial Cancer 54,870 10,170 - 18. Esophageal Cancer 16,980 15,590 Mean age at diagnosis=67 National Cancer Institute; SEER database http://seer.cancer.gov/statfacts/html/esoph.html

Barretts: Risk of progression The risk of developing EAC in patients with NDBE was considered to be in the range of 0.1–3.5% per year Several studies suggesting a risk of ~0.5% per year A recent large study has shown that the risk may be as low as 0.1 - 0.3% per year A cohort study of 11,028 patients from Denmark published in 2011 showed an incidence of only 1.2 per 1000 person-years 5.1 per 1000 person-years in patients with dysplasia. 1.0 per 1000 person-years in patients without dysplasia.

Diagnosis Upper endoscopy identifies “salmon-colored mucosa” at the GE junction Four quadrant random biopsies every 1-2cm with cold forceps from the abnormal area Nodules or clearly abnormal areas should be targeted and removed by biopsy or EMR Chromoendoscopy or narrow-band imaging used when available to enhance detection

Barrett’s examples Atlas of Gastrointestinal endoscopy . http://www.gastrointestinalatlas.com/english/barrett_s_esophagus.html

Prague classification Developed by the Barrett’s Esophagus Subgroup of the International Working Group for the Classification of Reflux Oesophagitis (IWGCO) Sharma, P. et al. The development and validation of an endoscopic grading system for Barrett's esophagus: the Prague C & M criteria. Gastroenterology 131, 1392-1399 (2006).

Short segment vs. Long segment Short segment = <3cm Long segment = >3cm New ACG Guideline: Diagnosis & Management of Barrett’s Esophagus November 2015 AJG Nicholas J. Shaheen, MD, MPH, FACG; et. Al.

Narrow band imaging Chromoendoscopy El Salvador Atlas of Gastrointestinal endoscopy . http://www.gastrointestinalatlas.com/english/barrett_s_esophagus.html

Screening: who to screen? No recommendation to screen the general population Patient selection is important Longstanding reflux symptoms (>5 years) Long-term PPI use Numerous risk factors or Family history

Risk factors: for Barrett’s and EAC Chronic GERD Men ( 4 to 8 x vs. women) Caucasian ( ~5x vs. African American) Age <50 Tobacco Obesity

Surveillance Guidelines Waxman, et. al, Rev. esp. enferm. ig. vol.106 no.2 Madrid feb. 2014 http://dx.doi.org/10.4321/S1130-01082014000200006 

Treatment For many years, esophagectomy was the standard treatment for Barrett’s patients with high grade dysplasia or early cancer. Esophagectomy is associated with a 40–50% risk of major complications and a mortality rate of 3–5% Photodynamic therapy (PDT) offered an alternative outpatient endoscopic procedure that eliminates dysplasia and superficial cancer and reduces the length of Barrett’s mucosa PDT utilizes the photochemical reaction between a photosensitizing drug (Porfimer sodium ), light and oxygen. Interaction of the three components results in production of free radicals that are highly cytotoxic, resulting in the ablation of illuminated tissue APC equally effective based on studies in early 2000

Treatment Options (continued) Radiofrequency ablation (RFA) Endoscopic mucosal resection (EMR) Endoscopic sub-mucosal dissection (ESD) Argon plasma coagulation (APC) Multipolar electrocoagulation (MPEC) Laser ablation (using neodymium-yttrium aluminum garnet (Nd-YAG), potassium titanium phosphate), Photodynamic therapy (PDT) Cryotherapy

Radiofrequency Ablation (RFA) In the year 2000, the founders of BÂRRX Medical, Inc. (scquired by Covidien and now Medtonic) developed an endoscopic device called the HALO360 System for treating Barrett's esophagus. In 2001, the U.S. Food and Drug Administration cleared the HALO360 System for use in the ablation of bleeding and non bleeding sites in the gastrointestinal tract including Barrett's. In January 2005, the Covidien Medical team conducted multi-center clinical trials to demonstrate the safety and efficacy of the system Trials have been completed for all types of Barrett's tissue: intestinal metaplasia, low-grade dysplasia, and high-grade dysplasia March 20, 2006 started a new landmark study comparing the effectiveness of the HALO Technology against a current standard of care for Barrett's (regular EGD surveillance and medical management of GERD) April 21, 2006, the HALO90System (focal ablation device), was cleared by the FDA 2007 DDW, the current data was presented demonstrating that 98.4% of participants were Barrett's-free after one to two treatment sessions at 30 months. http://www.medtronic.com/covidien/products/ablation-systems/barrx-circumferential-ablation-catheters

RFA (continued) http://www.medtronic.com/covidien/products/ablation-systems/barrx-circumferential-ablation-catheters

RFA: technique Landmark determination with EGD Cleaning of the esophageal wall to remove excessive mucus ( 1% acetylcysteine or water) Esophageal sizing: a sizing catheter is connected calibrated, introduced over a guidewire and inflated to 4.3 psi (0.30 atm) to measure the inner esophageal diameter at various distances Ablation catheter selection: Based on the esophageal inner diameter measurements. (all catheters are 165-cm long with a balloon in one of five outer diameters (18, 22, 25, 28, and 31 mm once inflated). The outer diameter of the ablation balloon should be smaller than the narrowest measured esophageal diameter.  Ablation: The ablation catheter is then inflated to 3 psi. Upon activation, radiofrequency energy is for ~1.5 seconds, after which the balloon automatically deflates. Moving distally, the balloon is repositioned, allowing a small amount of overlap with the previous ablation zone (5 to 10 mm). Standard ablation regimen consists of two applications of 12 J/cm2 , 1.5 sec each with a cleaning phase in between. http://www.medtronic.com/covidien/products/ablation-systems/barrx-circumferential-ablation-catheters

RFA: post treatment care After RFA, acid suppressive therapy is important to minimize patient discomfort and allow the esophagus to heal optimally. Patients should limit to a liquid diet for 24 hours, then gradually advance to a soft and then normal diet at their own discretion. Many patients require pain medicaiton. Tylenol is preferred first line over NSAIDs. Codiene or narcotics (vicodin/percocet) often used as well. Viscous lidocaine can be used as an adjunct. Patients with severe chest pain and/or fever following their procedures may need prolonged observation or admission. In rare cases, when there is a clear suspicion of severe complications, additional testing (eg, computed tomography) may be required.

RFA: potential complications Chest pain occurs in the majority of patients who are treated and generally lasts for a few days. In 1–2% of the patients, the pain has been more severe and longer lasting, and rarely, hospitalization for pain management is required. The most common delayed complication has been the development of esophageal strictures. The exact incidence is not known, but in published series it has been in the range of 1%. Perforations have occurred, but they are extremely rare and usually happened during insertion or removal of the ablation catheter. Sharma VK, Wang KK, Overholt BF, et al. Balloon-based, circumferential, endoscopic radiofrequency ablation of Barrett's esophagus: 1-year follow-up of 100 patients. Gastrointest Endosc 2007; 65:185-194.

RFA: outcomes Evidence from a number of well-designed studies, including RCT show that RFA is highly effective at removing Barrett's esophagus (BE) at both the endoscopic and histologic level with a favorable safety profile. Overall, studies report complete eradication of intestinal metaplasia rates of 54 to 100 percent and complete eradication of dysplasia rates of 80 to 100 percent. Long-term follow-up studies are still limited but the five-year follow-up data suggest that eradication is maintained in more than 90 percent of patients. Shaheen NJ, Sharma P, et al. Radiofrequency ablation in Barrett's esophagus with dysplasia. N Engl J Med 2009; 360:2277.

Role of PPIs Healing of esophagitis and control of reflux symptoms Prevention of stricture formation and pain reduction after ablation Reduces progression of Barrett’s mucosa and some studies have shown regression Unclear effect on EAC rates or mortality Peters , Ganesh S, Kuipers EJ, et al. (1999) Endoscopic regression of Barrett's oesophagus during omeprazole treatment: a randomised double blind study. Gut45:489–494.

Recap and Conclusions Esophageal cancer is an important and growing problem Barrett’s esophagus can lead to cancer, and progression may be preventable Variation exists in screening and surveillance strategies Good treatments are available, and carry minimal risk Knowledge of EAC risk factors is important for individualized care

Ongoing Controversies Who to screen and how often Ablation of non-dysplastic Barrett’s What about “buried glands” What about those with “silent reflux” Cost effectiveness? More research is needed…

Thank You