Barrett s Esophagus: Ablate Everyone?

Nicholas J. Shaheen, MD, MPH, FACG Barrett s Esophagus: Ablate Everyone? Nicholas J. Shaheen, MD, MPH, FACG Center for Esophageal Diseases and Swallowing University of North Carolina Greetings from UNC, the University of National Champions! Men s Basketball: 24, 57, 82, 93, 05, 09 Women s Soccer: 82, 83, 84, 86, 87, 88, 89, 90, 91, 92, 93. 94, 96, 97, 99, 00, 03, 06, 08, 09, 12 Men s Soccer: 01, 11 Women s Basketball: 94 Men s Lacrosse: 81, 82, 86, 91, 16 Field Hockey: 89, 95, 96, 97, 07, 09 Women s Lacrosse: 13, 16 Page 1 of 19

The Conceptual Underpinnings for Endoscopic Therapy in Barrett s Esophagus Adenocarcinoma A Disease with a Rapidly Increasing Incidence S Kroep et al. Am J Gastroenterol 2014. Page 2 of 19

It is not going to change any time soon Kong CY et al, CEBP, 2014. It is clear that the status quo is failing. Page 3 of 19

The Case for Ablation in HGD The risk of progression of the lesion is high The risk of a metachronous cancer is substantial The competing strategy (surgery) is morbid Patients are often more comfortable with a proactive strategy Data suggest a decreased cancer risk RFA The AIM-D Trial RCT of 127 Subjects with LGD & HGD Intervention: RFA+PPI or Sham+PPI (2:1) Follow-up: 12 mos Assessment: Bx s q3 mos (HGD)/ 6 mos (LGD) 1 Outcomes: Ablation of all dysplasia: 81% of HGD 91% of LGD app 20% of controls Complete eradication of IM (77% of Rx, 2% Sham) SE s: Strictures in 6% of subjects 30 25 20 15 10 Shaheen NJ et al. N Engl J Med, 2009. 5 0 19% 2% Cancer Incidence (%) Sham +PPI RFA + PPI Page 4 of 19

3 year Durability Shaheen NJ et al, Gastroenterology 2011. AIM-D at 5 Years IM-free proportion 0.00 0.25 0.50 0.75 1.00 Kaplan-Meier analysis of the durability of CEIM 0 500 1000 1500 2000 Days since first CEIM at 12 months or after LGD HGD Shaheen et al. DDW 2015 Dysplasia-free proportion 0.00 0.25 0.50 0.75 1.00 Kaplan-Meier analysis of the durability of CED 0 500 1000 1500 2000 Days since first CED at 12 months or after LGD HGD Page 5 of 19

Complete Eradication, US RFA Registry Recurrence Rates by Baseline Histology, U.S. RFA Registry 0.00 0.25 0.50 0.75 1.00 0 1 2 3 Time after CEIM (years) Nondysplastic BE LGD IMC Indefinite dysplasia HGD Page 6 of 19

Nicholas J. Shaheen, MD, MPH, FACG If Someone Recurs, What Do They Come Back As? Pre- Treatment Histology IM Recurrence Histology Recurrence n (%) NDBE n (%) IND n (%) LGD n (%) HGD n (%) IMC n (%) EAC n (%) All Patients (N=1634) 334(20) 269 (81) 18 (5) 19 (6) 15 (4) 13 (4) 0 NDBE (N=668) 119 (18) 110 (92) 4 (3) 3 (3) 2 (2) Indefinite Dysplasia (N=114) 25 (22) 21 (84) 2 (8) 1 (4) 1 (4) LGD (N=323) 70 (22) 57 (81) 6 (9) 4 (6) 1 (1) 2 (3) HGD (N=416) 93 (22) 64 (69) 4 (4) 10 (11) 9 (10) 6 (6) IMC (N=92) 21 (23) 16 (76) 1 (5) 4 (19) EAC (N=21) 6 (29) 1 (17) 2 (33) 1 (17) 1 (17) 1 (17) Most Recurrences Are Handled Endoscopically Phoa KN et al. Gastroenterology 2013. Page 7 of 19

Complications with RFA Strictures: 233 Per Patient: 4.5% Per RFA: 1.5% 5,516 Patients 15,665 FAs Complications: 283 Per Patient: 5.4% Per RFA: 1.8% Bleeding: 28 Per Patient: 0.5% Per RFA: 0.2% Hospitalization: 47 Per Patient: 0.9% Per RFA: 0.3% Deaths: 0 Perforation: 2 Per Patient: 0.04% Per RFA: 0.01% Wolf A et al. DDW 2014. What are Cancer Rates after RFA? No. of Patient Years of No. Incident EAC Incidence Rate per 1000 Patients Follow-up EAC person-years Baseline n (%) [95% CI] Histology NDBE 2,473 (48) 5,691 3 0.5 [0.1, 1.4] IND 385 (8) 883 2 2.3 [0.4, 7.5] LGD 1049 (21) 2,563 14 5.5 [3.1, 8.9] HGD 972 (19) 2,591 81 31.3 [25.0, 38.7] Total, nonmalignant 4,879 (95) 11,729 100 8.5 [7.0, 10.3] No. Deaths from EAC EAC Mortality Rate per 1000 person-years [95% CI] 0 0 0 0 0 0 3 1.15 [0.29, 3.15] 3 0.26 [0.07, 0.70] IMC 178 (4) 459 1 2.18 [0.11, 10.7] IAC 60 (1) 155 0 0 Total 5,117 (100) 12,343 4 0.32 [0.10, 0.78] Wolf WA et al, Gastroenterology 2015. Page 8 of 19

So Ablative Therapy Works But Does Everyone Need It? What is Rate of Progression of LGD? Hvid-Jensen F et al. N Engl J Med 2011. Page 9 of 19

How Benign is Low-Grade Dysplasia? 147 subjects with a diagnosis of LGD made in a community practice in the Netherlands Path reviewed by 2 expert pathologists Disagreements resolved by consensus 85% of cases were down-graded In the 15% who were not, the incidence rate of HGD or EAC was 13.4%/pt-yr (mean f/u: 51 months) Curvers WL et al. Am J Gastroenterol 2010. Is LGD an Indication for Endoscopic Intervention? SURF study RCT, n=140, surveillance EGD vs. ablation with RFA Primary outcome: occurrence of HGD/EAC Phoa KN et al. JAMA 2014 Page 10 of 19

Is Non-Dysplastic BE an Indication for Ablation? Is it effective? Most studies document high rates of reversion to squamous tissue Data from U.S. RFA Registry shows a markedly decreased rate of cancer in NDBE after RFA compared to historical controls (0.5/1000 p-y) Can we afford it? Cost-effectiveness is questionable Will treat 20 or more for one to benefit Effective intervention is still available if they progress to dysplasia Bottom line: Until better risk stratification is available, highly unlikely we will be recommending RFA for all NDBE An Algorithm for Endoscopic Management of Barrett s Neoplasia Page 11 of 19

Nodular Disease Should Be EMR ed! Ell C et al. GIE, 2007 Measure Twice, Cut Once Page 12 of 19

Algorithm, cont. For subjects with nodular disease, EMR histology decides further management No cancer, mucosal cancer, or maybe sm1 cancer -> ablative therapy Worse than sm1 -> consideration of multimodality Rx and esophagectomy Flat HGD -> ablation Given current data, RFA seems most appropriate Algorithm, cont. LGD Unifocal, elderly, and/or wishing conservative Rx -> surveillance endo s Multifocal, previously nodular, young, family hx of cancer, pathologically worried -> consider ablation Caveats about lack of data on decreasing cancer Non-dysplastic Ablation is an option, but role in average risk patients not clear Page 13 of 19

Unsettled Questions Should I Be Learning ESD? ESD is more technically challenging and time-consuming than EMR Asian endoscopists learn in the stomach and colon The only real data that ESD yields that EMR does not is lateral margin data Because depth of invasion is the only clinically actionable data from EMR, the lateral margin data are not essential Given the limited availability of training, the low utility of the incremental data, and the potential for greater complications, performing good EMR should be the focus for most Western endoscopists Page 14 of 19

Does Case Volume Matter and How Much Do I Need? 2.6 Predicted RFA Sessions to Achieve CEIM based upon Center Experience RFA Sessions 2.5 2.4 2.3 2.2 p=0.01 2.1 0 50 100 150 200 Patients Previously Treated at Center Predicted Value 95% CI Pasricha et al, Gastroenterology 2015. Recurrence after CEIM by Quintile of Enrollment Rate Pasricha et al, Gastroenterology 2015. Page 15 of 19

Rates of Recurrence after CEIM by Volume at USRFA Centers Pasricha et al, Gastroenterology 2015. Is Cryotherapy an Option? 98 subjects w/ HGD treated at 10 institutions 61 completed Rx, 27 ongoing 281 total procedures 4.0/pt No perfs, no buried glands, no bleeds or chest pain requiring hospitalization 97 86 58 One progression to CA Shaheen NJ et al. Gastrointest Endosc, 2010. Page 16 of 19

How About Stepwise Radical EMR? Multiple studies demonstrate high rates of complete eradication of BE with stepwise radical EMR However, stricture rates with this approach are high 100 75 50 25 EMR+RFA SRER 0 CR-IM Van Vilsteren FGI et al. Gut 2010. Stricture Rate When Is Endoscopic Rx Inadequate? Lesion too deep Anything SM1 or deeper deserves consideration of esophagectomy SM1 may be managed endoscopically if the patient is a poor surgical cancer Lesion too aggressive Poor differentiation Lymphovascular invasion Lesion not amenable to endoscopic Rx Won t raise, too large Page 17 of 19

What is the Likelihood of LN Involvement with IMC? Author, Yr Intramucosal Cancers Surgically Resected % Lymph Node Involvement Pech, 2011 38 0 (0/38) Sepesi, 2010 25 0 (0/25) Bollschweiler, 2006 16 0 (0/16) Stein, 2005 70 0 (0/70) Buskens, 2004 35 0 (0/35) Invasion depth and risk of LNM 0-3% 0 22% 36 54% m1 m2 m3 sm1 sm2 sm3? 500µm 1000µm ep lp mm sm Page 18 of 19

Conclusions In 2016, superficial neoplasia, incl. mucosal esophageal adenocarcinoma, is an endoscopic disease! Non-dysplastic BE is generally too low risk to warrant ablation CAVEATS Appropriately selected patient Amenable lesion Expertise and program in place Patient appraised of risks and benefits of this approach Endoscopist must know when cure becomes less likely Submucosal invasion is a contra-indication to endoscopic management in a good surgical candidate Results are overall durable, but recurrent intervention is not uncommon Close communication, with no recrimination, between surgeon, oncologist and endoscopist is essential Endoscopists must learn to think like oncologists Thanks! Page 19 of 19