Management of Barrett’s oEsophagus Joint Hospital Surgical Grand Round United Christian Hospital Dr C Leung

Definition A change in the normal squamous epithelium of the oesophagus to specialized intestinal metaplasia Normal eso squamous mucosa Intestinal metaplasia (goblet cells) Playford RJ. New British Society of Gastroenterology guidelines for the diagnosis and management of Barrett’s esophagus Gut 2006;55:442-3

Background Prevalence Premalignant condition 1.6-5.6% 10-15% in patients with reflux symptoms Premalignant condition 30-40 fold increased risk of oesophageal CA Difficult to truly know prevalence as many barretts individual are asymptomatic and never be evaluated

Etiology Combined acid and bile reflux > 50% of patients with GERD had abnormal levels of acid and bile in the oesophagus Barrett’s esophagus patients have the highest level Fein M. Br J Surg 2006; 93: 1475-82 Mucosal injury most common in mixed acid and bile exposure. Followed by acid alone and uncommon for bile alone (P<0.001)

Pathogenesis

Risk of Adenocarcinoma 0.25 to 0.4% per year Nondysplasic : 3.86/1000 person years Low-grade dysplaia: 7.66/1000 person years High-grade dysplasia Occult carcinoma: 30%-40% of patients 14.1/100 person years Sharma P. Clin Gastroenterol Hepatol 2006; 4: 566-72 Buttar NS. Gastroenterology 2001; 120: 1630-9

Endoscopic Evaluation Prague classification the maximal length (M) (including tongues) of Barrett esophagus length of the circumferential Barrett segment (C) For future endoscopic comparison Salmon color epithelium projected into tubular esophagus (projection can be tongues of tissue/ circumferential involvement of mucosa) Sharma P. Gastroenterology 2006; 131: 1392-9

Biopsies Seattle protocol 4 quadrant jumbo bx at 1cm intervals throughout whole length of Barrett’s Separate target bx of any irregularities (nodules/erythema/ erosions) Reid BJ. Am J Gastroenterol 2000; 95: 3089-95. -4 quadrant jumbo biopsies at 1 cm intervals throughout length of Barrett's esophagus (and inclusive of any neosquamous re-eepithelialized tissue growth and cardia) irregularities (tiny nodules, patches of friability/erythema, erosions, ulcers, strictures, or regions appears fixed and or poorly distensible) Currently, white light high definition endoscopy and chromoendoscopy help in localizing lesions

Treatment rationale Removal of diseased mucosa, not entire organ Prevent disease progression to adenoCA Tx rationale barrett mucosal disease before it progress to CA / crossing submucosa–removal of disease mucosa suffix

Treatment Options Cant reduce CA risk resection Anti-reflux treatment -PPI -Fundoplication +/- surveillance Endoscopic ablation Photodynamic therapy (PDT) Multipolar electrocoagulation Argon Plasma Coagulation Radiofrequency ablation (RFA) Cryoablation resection EMR/ ESD Esophagectomy Symptomatic control Cant reduce CA risk HGD / Tis , T1a adenoCA Role of endoscopic ablation in non-dysplastic/ low grade dysplasia is less clear Multifocal, extensive HGD/ persistent HGD despite ablation/ ? CA

Acid Suppression with Surveillance Acid suppression will not eliminate risk of adenocarcinoma/ consistent regression of Barrett’s Degree of dysplasia Surveillance OGD interval Non-dysplastic 3-5 year Low grade dysplasia 6-12 months High grad dysplasia Interval 3 months (if patient not receive invasive therapy) No reliable data on tx length -some keep patients on PPI indefinitely. Supra-therapeutic dose (for control of GERD) solely for chemoprevention is not warranted Optimal frequency of surveillance has not yet been determined, most recommend as above chart adenoCA discovered while screening for Barretts are early stage lesions and have a gd prognosis (5 year suvival >85%) ? Duration and dosage of PPI (indefinite) ?optimal frequency of surveillance

Anti-reflux Surgery Fundoplication eliminates acid and bile reflux in > 90% of patients with Barrett’s oesophagus Meta-analysis: 15.4% of patients undergone surgery will have regression of Barrett’s vs. 1.9% medically managed patients Swedish Cohort study showed that RR of adenocarcinoma in patients undergone surgery was 14.1 vs. 6.3 for medical treatment Reduce risk of adenoCA ? Mixed evidences so far Meta-analysis found no difference between fundoplication and medical treatment in prevention of adenocarcinoma Oelschlager BK. Ann Surg 2003; 238: 458-64. Chang EY. Ann Surg 2007; 246: 11-21. Lagergren J. Gastroenterology 2010; 138: 1297-301

PPI vs fundoplication Surgery can definitely treat reflux-related symptoms, but its role in protection against adenocarcinoma should be cautious Effectiveness in eliminating reflux symptoms Co- morbidities Patient’s choice/ compliance Medications S/E

Photodynamic Therapy Injecting a light-sensitizing drug into patient, then expose the portion of oesophagus to a specific wavelength Found NOT effective in eliminating Barrett’s ‘Buried glands’: a layer of normal-appearing squamous epithelium is present but under this layer, Barret’s metaplasia still present Stricture Phototoxicity Stricture esp in long segment Menon D. BMC Gastroenterol 2010; 10: 111.

Argon Plasma Coagulation Systemic review: more effective than PDT, 3- month complete eradication 80% Less complications like stricture or bleeding Odynophagia 10% Li YM. Dig Dis Sci 2008; 53: 2837-46.

Radiofrequency Ablation One of the best studied method Applies bipolar electrical energy to mucosal surfaces, 10J for 1 second  mucosa is ablated to submucosal level Balloon based radiofrequency device for circumferential ablation RFA advantage : treat larger surface area than other thermal techniques, also true for focal disease (contact technique but not point technique)

Radiofrequency ablation Need standardized FU as complete ablation with single treatment in only 70% of patients FU OGD 3 months and 1 year, if not complete ablated  repeat RFA

Radiofrequency ablation Shaheen NJ (2009): Multicentre RCT Can eliminate Barrett’s oesophagus with high grade dysplasia and reduce risk of oesophageal carcinoma Wani S (2009): Meta-analysis Reduction in carcinoma progression in high-grade dysplasia Shaheen NJ (2011): Long term results 3 years follow-up: complete eradication persist in 96% patients with high-grade dysplaia Adenocarcinoma occurred in one per 181 patient-years of follow-up

Radiofrequency ablation Promising results S/E : esophageal stricture, GIB, chest pain Sustaintially lower than those in photodynamic therapy Long term data needed

Cryoablation Endoscopically directed spray of liquid nitrogen at -196oC Complete eradication of high grade dysplasia occurs in 68-97% of patients Not well studied as RFA ? Treat patient refractory to RFA Dumot JA. Gastrointest Endosc 2009; 70: 635-44. Shaheen NJ. Gastrointest Endosc 2010; 71: 680-5.

Endoscopic Mucosal Resection when a visible nodule is present or only a short segment of Barrett’s is seen substantial tissue for pathologist treat Tis or T1a adenocarcinoma Can combined with RFA Usually visible nodule has higher chance of ca Endoscopic resection followed by thermal ablation should be treatment of choice EUS to determine pass thro submucosa Thro submucosa,risk of LN met >20% EMR ~2 cm size specimen in each attempt while ESD can remove specimen en bloc regardless of size With submucosal invasion, 20% risk of LN met If confined to mucosa ,<1% LN met

Endoscopic therapy No single endotherapy achieve complete eradication without complications Recurrence For mucosal lesion Buried metaplasia

Esophagectomy ‘gold standard’ for high grade dysplasia and early adenocarinoma 20-40% of patients harbour early adenocarcinoma in HGD (old data) Mortality can be as low as 1% in high vol centre Significant morbidity For multifocal , too extensive HGD / intractable HGD /suspicious of carcinoma Traditionally esophagect gold standard for early ca and HGD Old data show 20-40% occult CA in HGD. Only 12 % in Jennifer Chennat at el 20101(gastrointest enodoscopy clin N AM 21 (2011)119-133 Vagal sparing esophagectomy , laparoscopically Ablation or resection not suitable for multifocal/ too extensive disease After esophagect, life long reflux/ regurg/ aspiration With potential early and long term cx and magnitude of procedure, usu discourage patient from doing esophagect Esophagect is a 1 shot procedure Surgery vs ablation for high grade/ early CA No RCT yet . All non randomized trails - all no significant difference in survival

Summary Barrett’s esophagus metaplasia LGD HGD Anti-reflux +surveillance OGD every3-5 year Anti-reflux+OGD every 6-12 months Repeat bx confirmed HGD Send to expert pathologist HGD –procedure shift from esophagectomy to endoscopic ablative /resection Flat HGD – ablation + PPI Nodular HGD EMR/ ESD +PPI Ablative therapy for metaplasia w/o dysplasia ? (non dysplastic barretts develop CA at only 0.5% per year, no study established that endoscopic ablation decreases risk) Also need surveillance OGD afterwards as we dunnno the chance of buried metaplasia and regrowth of barretts (review stuart et al surg oncol clin N AM 18 2009 509-521) similar for LGD- not much evidence on tx by ablative therapy, more outcome needed to support recommendation. Some have Spontaneous regression Intractable HGD/ suspicious of carcinoma – esophagectomy Some study on cost perspective- HGD most cost effective tx by RFA, EMR cost preferred than esophagectomy for early BE Endotherapy (ablative/EMR/ESD) If persist/ ? CA then esophagectomy

Take Home Messages Barrett’s esophagus is a pre-malignant condition Diagnosis relies on both endoscopic and histological findings Management should be based on risks stratification Emerging evidence on the use of endoscopic therapy Treatment should be individualized Risk stratification (no dysplasia/ LGD/ HGD) When to treat : currently no evidence for ablation in non dysplastic/ LGD - surveillance +PPI Surgery vs ablation equally effective – the best mx depends on patient characteristics , preference, local expertise. Multiple comorbities- endoscopic tx

Acid Suppression Without Surveillance Screening for Barrett’s oesophagus has not been shown to improve mortality from adenocarcinoma Economic model suggests that the adverse effects related to screening outweigh benefit of early detection of adenocarcinoma American Gastroenterological Association 2004 Chicago Workshop concluded that although surveillance can detect curable neoplasia but may not prolong survival Doesn’t change much of surveillance practice, even in US Garside R. Health Technol Assess 2006; 10: 1-142. Attwood SE. J Gastrointest Surg 2008; 12: 1646-54. Sharma P. Gastroenterology 2004; 127: 310-30.