3/22/217 arrett s Esophagus: re We Making any Progress? Stuart Jon Spechler, M.D. hief, Division of Gastroenterology, V North Texas Healthcare System; o-director, Esophageal Diseases enter, Professor of Medicine, erta M. and ecil O. Patterson hair in Gastroenterology, UT Southwestern Medical enter Disclosures onsultant: Ironwood Pharmaceuticals 58 year-old man with 2 years of heartburn that has recently increased in frequency and intensity. Traditional oncept Reflux Esophagitis Is a austic, hemical Injury Esophageal Squamous cid urn H auses ell Death, Epithelium Reflux Granulocyte + Infiltration Pepsin H + H + asal ells Lamina Propria Severe, erosive reflux esophagitis How did GERD damage this esophagus? asal ell Death of Surface ells Induces Proliferative Response Rat Model for GERD: Esophago-Duodenostomy Esophagus Duodenum Transected Esophagus Sham-Operated ontrol Stomach Stomach Keratin Esophago- Duodenostomy Why should a caustic injury take weeks to develop? Resulted in severe, ulcerative reflux esophagitis in weeks Souza, Huo,..Spechler. Gastroenterology 29;137:1776. 1
3/22/217 Postoperative Day 3 Submucosal Lymphocyte Infiltration Inflammation did not start in the mucosa Lymphocyte Lymphocyte Mucosa intact Lymphocyte First inflammatory cells were lymphocytes, not granulocytes Souza, Huo,..Spechler. Gastroenterology 29;137:1776. Postoperative Week 3 asal ell and Papillary Surface ells Intact asal ell Papillary asal cell and papillary hyperplasia not due to death of surface cells Souza, Huo,..Spechler. Gastroenterology 29;137:1776. ultures of Esophageal Squamous ells Exposed to cid and ile Salts Secrete IL-8 (a Pro-Inflammatory ytokine) IL-8 Secretion (pg/ml) ells exposed to bile salts (4 M) at ph 4 for 1 minutes TID aseline * Day 1 Day 2 Day 3 Day 4 Day 5 * Souza, Huo,..Spechler. Gastroenterology 29;137:1776. * * Reflux Esophagitis: ytokine-mediated Injury Inflammatory cells mediate epithelial injury, not acid directly Reflux Reflux induces epithelial cells to secrete pro-inflammatory cytokines, H + which attract lymphocytes first, H + ile induce basal cell proliferation ytokine ytokine ytokine ytokine ytokine ytokine Does Reflux Esophagitis in Humans Develop as a ytokine-mediated Injury Rather than a austic hemical Injury? Patients typically have months to years of GERD symptoms before seeking medical attention. - Early histologic changes of reflux esophagitis not evaluated prospectively Severe reflux esophagitis healed by PPIs returns within 6-12 months of stopping PPIs. - Might induce acute reflux esophagitis by temporarily interrupting PPIs in patients with severe GERD? Study of cute Reflux Esophagitis in Humans 12 patients with severe (Los ngeles grade ) reflux esophagitis healed with PPI therapy 11 men, 1 woman Mean age 58 years (SD 13.1 years) Stopped PPIs for 2 weeks to induce acute reflux esophagitis Endoscopy at 1 and 2 weeks after stopping PPIs Dunbar, goston, Souza, Spechler. JM 216;315:214. 2
3/22/217 % Total Time ph <4 Esophageal cid Exposure Increases Dramatically When PPIs are Stopped n=1 Median 17.8%* Median 1.2% aseline on PPI 2 weeks off PPI Dunbar, goston, Souza, Spechler. JM 216;315:214. Development of Endoscopic Reflux Esophagitis fter Interruption of PPI Therapy Patient # aseline (on PPIs) Week 1 (off PPIs) Week 2 (off PPIs) Esophagitis Grade Esophagitis Grade Esophagitis Grade 1 2 3 4 5 6 7 8 9 1 11 12 Endoscopic Reflux Esophagitis Development Dunbar, goston, Souza, Spechler. JM 216; 315:214. aseline On PPIs arrett s aseline On PPIs 1 Week Off PPIs Dunbar, goston, Souza, Spechler. JM 216;315:214. 1 Week Off PPIs D3 Immunostaining (T Lymphocytes) Papillary Epithelium asal ell Lamina Propria 3
3/22/217 onclusions of cute GERD Study Reflux esophagitis healed by PPIs returns within 2 weeks of stopping PPIs. cute reflux esophagitis is characterized by T-lymphocyte infiltration of esophageal mucosa. Neutrophils and eosinophils not prominent components Findings refute traditional concept that reflux esophagitis is a caustic chemical injury Findings support new concept that refluxed material does not kill esophageal squamous cells directly, but stimulates them to secrete cytokines that attract inflammatory cells that cause tissue damage Dunbar, goston, Souza, Spechler. JM 216;315:214. Stratified Squamous Epithelium Metaplastic olumnar Epithelium arrett s Esophagus The condition in which a metaplastic columnar epithelium that predisposes to cancer development replaces the stratified squamous epithelium that normally lines the distal esophagus ffects 5.6% of adult mericans G Medical Position Statement. Gastroenterology 211;14:184. U.S. Incidence of Esophageal denocarcinoma Has een Rising arrett s Metaplasia Esophageal denocarcinoma Incidence per 1,, 3 25 2 15 1 Incidence Time Trend 25.6 per million 26 7-Fold Increase In 3 Decades 5 3.6 per million 1973 1975 198 1985 199 1995 2 25 Pohl H. ancer Epidemiol iomarkers Prev 21;19:1468. Estimates of ancer Risk for Individual Patients with Non-Dysplastic arrett s Have een Falling 199s Estimate: 1% per year 1 in 1 patients per year Drewitz. m J Gastroenterol 1997;92:212. 2s Estimate:.5% per year 1 in 2 patients per year Shaheen. Gastroenterology 2;119:333. 217 Estimate:.1%-.3% per year ~1 in 4 patients per year G linical Guideline on Endoscopic Screening for arrett s Esophagus Not recommended for general population or for women Screening may be considered in men with chronic (>5 years) and/or frequent ( weekly) GERD symptoms (heartburn, acid regurgitation) and 2 risk factors ge 5 years White race entral obesity History of smoking Norman onfirmed history of arrett s esophagus or arrett esophageal adenocarcinoma in 1 o relative In women, screening may be considered in individual cases as determined by the presence of multiple risk factors m J Gastroenterol 216;111:3. 4
3/22/217 Recommendations for Endoscopic Surveillance of Non-Dysplastic arrett s Esophagus G, SGE, G Surveillance every 3 to 5 years Why Should Proton Pump Inhibitors (PPIs) Prevent ancer in arrett s Esophagus? cid reflux causes reflux esophagitis (chronic inflammation) PPIs heal reflux esophagitis cid causes DN double-strand breaks in arrett s epithelial cells (potentially carcinogenic) PPIs decrease esophageal exposure to this carcinogen cid promotes proliferation in arrett s metaplasia PPIs might prevent proliferation cid stimulates esophageal secretion of proinflammatory and pro-proliferative cytokines cid suppression may prevent cytokine secretion PPIs re Potentially ancer-protective. Why Might PPIs Promote ancer in arrett s Esophagus? PPIs re Potentially ancer-promoting. Pancreatic Enzymes H + Gastrin Gastrin acteria PPI Gastrin increases proliferation in arrett s metaplasia acteria deconjugate bile acids, convert nitrates to N-nitroso compounds Pancreatic enzymes not denatured by gastric acid can reflux into the esophagus Meta-nalysis Studies on Risk of Developing High-Grade Dysplasia (HGD) or denocarcinoma (E) in arrett s Patients on PPIs PPI use associated with Odds 71% Ratio reduction and 95% I in risk of advanced neoplasia Kastelein 213 Jung 211 Hillman 24 Nguyen 29 ltawil 211 Nguyen 21 de Jonge 26 Odds Lower Upper Ratio Limit Limit.47.19 1.17.23.3 1.74.5.1.37.42.18.98.3.1.91 1.5.61 3.67.9.5.17.29.12.71.1.1 1 1 1 Favors PPI Favors No PPI Singh S. Gut 214;63:1229. Recent, Large ase-ontrol Studies on Risk of Developing HGD or E in arrett s Patients on PPIs ll pts PPIs in Denmark increase with arrett s the risk 1995-29 of neoplasia? (n=9,883) Relative risk onfounding of developing high-grade by Indication? dysplasia or adenocarcinoma in long-term (>7 years) PPI users: PPI use is not associated with a significant 2.2 (95% I.7-6.7 ) low-adherence PPI users decrease in the incidence of esophageal 3.4 (95% I 1.1-1.5 ) high-adherence PPI users adenocarcinoma. Hvid-Jensen F. liment Pharmacol Ther 214;39:984. Population-based general practice registries (UK and NL), pts with arrett s 1996-213 (n=15,134) Odds ratio for developing high-grade dysplasia or adenocarcinoma in long-term (>2 years) PPI users: 1.5 (95% I.7-3.6 ) Masclee GM. MJ Open 215;5:e664. rguments Favoring ntireflux Surgery Over PPIs for ancer Prevention in arrett s Esophagus PPIs target acid exclusively, but acid is not the only harmful agent in refluxed gastric juice. Refluxed bile salts might contribute to carcinogenesis. ntireflux surgery can prevent reflux of all gastric material Some small, observational studies suggest that surgically-treated arrett s patients develop less dysplasia and cancer. 5
3/22/217 ntireflux Surgery Might Protect gainst ancer in arrett s Esophagus etter than Medical Therapy. Potential advantage is small Not clear that this small, potential advantage justifies the risks of antireflux surgery Norman arrett ge 13 G linical Guideline on Treatment of GERD in arrett s Esophagus Patients with arrett s esophagus should receive once-daily PPI therapy. Routine use of twice-daily dosing is not recommended unless necessitated because of poor control of symptoms or esophagitis. ntireflux surgery should not be pursued in patients with arrett s esophagus as an antineoplastic measure. However, this surgery should be considered in those with incomplete control of reflux symptoms on optimized medical therapy. m J Gastroenterol 216;111:3. Muscularis mucosae HGD T1 T2 Epithelium Lamina propria asement membrane HGD T1 T2 High Grade Dysplasia Intramucosal arcinoma Muscularis mucosae T1a T1b T1b: LN mets >1% Potentially curable with endoscopic therapy Potentially metastatic (1%-2% of cases) Drawing courtesy of Tom Rice Endoscopic therapy is appropriate for neoplasms confined to the mucosa. Drawing courtesy of Tom Rice ccurate T Staging rucial to Determine if urative Endoscopic Therapy Feasible High Grade Dysplasia, Intramucosal arcinoma Lymph node metastases in 1%-2% urative endoscopic therapy feasible Submucosal invasion Lymph node metastases in >1% Failure rate for endoscopic therapy unacceptable Endoscopic mucosal resection (EMR) the best procedure for T staging EMR is as much a staging procedure as it is a therapeutic procedure. If EMR shows submucosal invasion, then endoscopic therapy is not advised. 6
3/22/217 Radiofrequency blation (RF) Radiofrequency Energy Generator Radiofrequency blation of arrett s Esophagus losely spaced electrodes blated arrett s Metaplasia Randomized, Sham-ontrolled Trial of Radiofrequency blation for Dysplasia in arrett s Shaheen N et al. N Engl J Med 29;36:2277-88. Radiofrequency blation of Dysplasia Prevents Neoplastic Progression at One Year % with Progression 3.6% 16.3% Progression of Neoplasia Radiofrequency ablation Sham ablation 9.3% 1.2% Progression to ancer Shaheen. N Engl J Med 29;36:2277-88. Randomized Trial of RF vs. Surveillance for Low- Grade Dysplasia (LGD) in arrett s Esophagus 136 patients with LGD confirmed by expert pathologist Randomized to RF (68 pts.) or surveillance (68 pts.) Progression to high-grade dysplasia or cancer at 3 years Data 1.5% & RF Safety group Monitoring oard early termination: RF 26.5% superior surveillance to surveillance group for preventing neoplastic progression 25% Potential risk of for progression patient safety issues (95% I if trial 14.1-35.9%, continued P<.1) Progression to cancer at 3 years 1.5% RF group 8.8% surveillance group 7.4% risk of cancer (95% I -14.7%, P=.3) Phoa KN. JM 214;311:129. Endoscopic Eradication Therapy for Mucosal Neoplasia (Low-Grade or High-Grade Dysplasia, Intramucosal arcinoma) in arrett s Esophagus EMR of mucosal irregularities for staging and therapy - Endoscopists who plan to practice endoscopic ablative procedures should additionally offer EMR. : G Guideline. m J Gastroenterol 216;111:3. Radiofrequency ablation of remaining arrett s metaplasia to minimize metachronous neoplasia 7
3/22/217 Surveillance Endoscopy after Endoscopic Eradication Therapy for High-Grade Dysplasia Recurrence rates are substantial 197 patients with HGD/IM had complete eradication of dysplasia and IM Recurrent HGD/IM 1..75.5.25. Recurrence of Neoplasia after omplete Eradication of IM 25% 12 24 36 48 6 72 84 96 18 12 No controlled trials to guide surveillance intervals Follow-Up Months HGD IM Recurrence of Metaplasia after omplete Eradication of IM 1..75 5% HGD IM.5.25. 12 24 36 48 Follow-Up Months Small J et al. Gastrointest Endosc 215;81:1158. Recurrent IM fter RF, intestinal metaplasia recurs in ~1% per year. Guthikonda et al. m J Gastroenterol 217;112:87. Recurrent Intestinal Metaplasia after RF 2 198 patients had RF (96% for dysplasia) Number of Recurrences 29 of 32 recurrences 2 endoscopies after at complete GEJ or 1 cm eradication above of intestinal metaplasia (EIM) 15 4-quadrant biopsies at 1 cm intervals throughout ablated area and in gastric cardia denocarcinoma 1 Mean follow-up 3 years Intramucosal 32 patients (16%) had High-Grade recurrence 5 Low-Grade Non-Dysplastic ll visible 1 2 3 4 endoscopically Distance of Recurrence Proximal to GEJ (cm) Suggested biopsy protocol: 8 evenly-spaced biopsies around Z-line, 4-quadrant biopsies 1 and 2 cm above Z-line, biopsies above 2 cm only if visible abnormality otton. Gastrointest Endosc 215;81:1362. G linical Guideline on Management of arrett s Esophagus after Endoscopic Therapy Norman arrett ge 13 Following endoscopic therapy with complete elimination of intestinal metaplasia (EIM), endoscopic surveillance should be continued to detect recurrent metaplasia/dysplasia. Endoscopic surveillance following EIM For patients with HGD or IM: Q 3 months year 1, Q 6 months year 2, and annually thereafter. For patients with LGD: Q 6 months year 1, and annually thereafter. m J Gastroenterol 216;111:3. RF for Non-Dysplastic arrett s Esophagus? Generally requires several endoscopies for complete eradication omplication rate low, but not trivial Substantial rate of recurrence of metaplasia Efficacy in preventing cancer not established Does not eliminate need for surveillance hronic GERD symptoms and 1 risk factor(s) for adenocarcinoma (ge>5, male, white, hiatal hernia, obesity, intra-abdominal body fat, smoking) Knowledge is knowing a tomato is a fruit. No more screening No arrett s onsider screening endoscopy on screening arrett s esophagus No dysplasia Low-grade dysplasia High-grade dysplasia or intramucosal a Surveillance endoscopy every 3-5 yrs Spechler S, Souza R. N Engl J Med 214;371:836. Have diagnosis confirmed by expert pathologist Low-grade dysplasia Endoscopic eradication or surveillance endoscopy every 6-12 months High-grade dysplasia or intramucosal a Endoscopic eradication Wisdom is knowing not to put it in fruit salad. 8