T2N0 Esophageal Cancer: Does it Exist? Should we give Preop Therapy?

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1 T2N0 Esophageal Cancer: Does it Exist? Should we give Preop Therapy? Traves D. Crabtree Associate Professor of Surgery Washington University School of Medicine

2 I am a consultant for Ethicon Endo-Surgery

3 A 64 year old male presents with heme positive stools. Colonoscopy was negative but upper endoscopy revealed a 2.5 cm nonobstructing partially circumferential nodular mass just above the GE junction. Biopsy demonstrates a moderately differentiated adenocarcinoma. PET scan demonstrates uptake in the distal esophagus with no evidence of nodal or distant disease. EUS suggests T2N0 lesion. How would you proceed with treatment? 1. Primary esophagectomy 2. Induction chemoradiotherapy followed by esophagectomy

4 For a patient diagnosed with clinical T2N0 distal esophageal adenocarcinoma, what is the likelihood that the patient is pathologic T2N0? % % % % %

5 ct2n0 Esophageal Cancer Would consider Induction Therapy Clearly defined Survival advantage with induction Rx Equivocal survival w/ vs. w/out induction Rx Don t Believe in Induction Therapy Surgery +/- Adjuvant Rx Induction Rx No increased perioperative risk with Induction Rx Increased Perioperative Risk with Induction Rx Consider Induction Rx Assess Relative Cost of Trimodality Rx vs. Surgery First Rx Surgery +/- Adjuvant Rx

6 Clinically Staged T2N0 Esophageal Cancer: Distribution of Pathologic Stage Study N pt2n0 pt0-1n0 pt3n0 /TanyN1-3 Rice et al % 55% 32% Crabtree et al % 50% 44% Stiles et al % 23% 65% Zhang et al % 21% 50% Crabtree et al % 25.9% 46.7% Hofstetter et al % 44% 42% Hardacker et al % 42.8% 48.5% Speicher et al % 31.7% 41.6%

7 Distribution of Pathologic Stage in Patients Undergoing Primary Surgical Resection for ct2n0 Esophageal Cancer Crabtree et al. STS Database. Ann Thorac Surg 2013 Pathologic TN pattern Surgery (n=482) N (%) TisN0 7 (1.4) T0N0 1 (0.2) T1N0 117 (24.3) T2N0 132 (27.4%) 25.9% T0N1 1 (0.2) T1N1 35 (7.3) T1N2 3 (0.6) T2N1 56 (11.6) T2N2 3 (0.6) T2N3 2 (0.4) T3N0 40 (8.3) T3N1 68 (14.1) T3N2 9 (1.9) T3N3 5 (1.0) T4N0 1 (0.2) T4N1 1 (0.2) T4N2 1 (0.2) 46.7%

8 Distribution of Pathologic Stage in Clinically Understaged Patients Undergoing Primary Surgical Resection Crabtree et al. STS Database. Ann Thorac Surg 2013 Pathologic TN pattern Surgery (n=482) N (%) TisN0 7 (1.4) T0N0 1 (0.2) T1N0 117 (24.3) T2N0 132 (27.4) T0N1 1 (0.2) T1N1 35 (7.3) T1N2 3 (0.6) T2N1 56 (11.6) T2N2 3 (0.6) T2N3 2 (0.4) T3N0 40 (8.3) T3N1 68 (14.1) T3N2 9 (1.9) T3N3 5 (1.0) T4N0 1 (0.2) T4N1 1 (0.2) T4N2 1 (0.2) pt3-4n0 18.2% pt1-2n % pt3-4n %

9 Perspective from the NCDB Speicher et al. JTO mid- or distal esophageal cancers from (5.15%) clinical T2N0 2742/4799 (57%) ct2n0 ca underwent Nonoperative treatment 5 yr OS for definitive chemoradiation was 16.6% 5 yr OS for surgically treated patients was 39.2%

10 NCCN Guidelines Version Esophageal and Esophagogastric Junction Cancers Esophageal adenoca T1b, N+ T2-4a, N0- N+ Preoperative chemoradiation (preferred) Or Definitive chemoradiation Or Preoperative chemotherapy Or Esophagectomy (low-risk lesions, < 2cm, welldifferentiated lesions) T4b Definitive chemoradiation

11 Clinically Staged T2N0 Esophageal Cancer: Induction vs. Primary Surgery Study N Induction Therapy Primary Surgery Rice et al % 94.8% Crabtree et al % 94.4% Zhang et al % 20.3% Crabtree et al % 64.1% Hofstetter et al % 65% Hardacker et al % 51.5% Speicher et al % 55.9%

12 Incidence of Clinical T2N0 Diagnosis and Rate of Induction Therapy Given to Patients with ct2n0 Esophageal Cancer Crabtree et al. STS Thoracic Database. Ann Thorac Surg Induction Therapy for ct2n0 Incidence of ct2n

13 Clinically Staged T2N0 Esophageal Cancer: Perioperative Mortality w/ vs. w/out Induction Rx Study N 30-d postop mortality w/ Induction therapy 30-d postop mortality w/ Primary Surgery Zhang et al Crabtree et al % 3.7% Hofstetter et al 499 3% 3% Hardacker et al % 2.9% Speicher et al % 4.2%

14 Post-operative Complications in ct2n0 patients Undergoing Esophagectomy with or without Induction Therapy Crabtree et al. STS Thoracic Database. Ann Thorac Surg 2013 Complication Induction Therapy (n=270) Primary Surgery (n=482) Total (n=752) N (%) N (%) N (%) Complications (at least one) 125 ( 46.3) 217 (45) 342 (45.5) 0.76 Air leak > 5 days 3 (1.1) 3 (0.6) 6 (0.8) 0.67 Pneumonia 19 (7.0) 51 (10.6) 70 (9.3) 0.12 Vent support > 48 hours 11 (4.1) 15 (3.1) 26 (3.5) 0.53 Atrial arrhythmia requiring treatment 56 (20.7) 86 (17.8) 142 (18.9) 0.33 Anastomotic complication requiring medical treatment only 17 (6.3) 33 (6.8) 50 (6.6) 0.88 Anastomotic complication requiring surgical treatment 8 (3.0) 35 (7.3) 43 (5.7) Chylothorax requiring drainage/medical treatment only 11 (4.1) 6 (1.2) 17 (2.3) Chylothorax requiring surgical treatment 4 (1.5) 11 (2.3) 15 (2.0) 0.59 P

15 Esophageal Cancer Study Group Hofstetter et al. A multi-institutional study on staging deficiencies, treatment patterns, and outcomes in ct2n0 esophageal cancer (in press). Presented at the AATS. Toronto, 2014

Mark Smithers (University of Queensland, Brisbane Australia) Nabil Rizk (Memorial Sloan Kettering NY,NY) Antoon Lerut, Philippe Nafteux (University Hospital Leuven, Belgium) Katie Nason, James

16 Mark Smithers (University of Queensland, Brisbane Australia) Nabil Rizk (Memorial Sloan Kettering NY,NY) Antoon Lerut, Philippe Nafteux (University Hospital Leuven, Belgium) Katie Nason, James Luketich (University of Pittsburgh Medical Center) Mark Orringer, Andrew Chang (University of Michigan, Michigan) Wayne Hofstetter, Stephen Swisher, Arlene Correa (MD Anderson Cancer Center, Houston TX) Nassar Altorki (The New York Hospital, Weill Cornell Medical Center NY,NY) JJ van Lanschot (Erasmus Medical Center, Rotterdam, the Netherlands) Traves Crabtree (Washington University, St Louis MO) Donald Low (Virginia Mason Medical Center, Seattle WA) Gail Darling (University of Toronto, Canada) Lorenzo Ferri (McGill University, Montreal Quebec) Steven DeMeester, Thomas DeMeester, Stephanie Worrell (University of Southern California, Los Angeles) Daniel Vallboehmer (University of Duesseldorf, Germany) Jarmo Salo (University of Helsinki, Finland) Alex Little (University of Arizona) Tom Rice, Eugene Blackstone (Cleveland Clinic Foundation) Henning Gaissert (Harvard Medical School) Shanda Blackmon (Mayo Clinic, Rochester MN) Steve Yang (Johns Hopkins, Maryland) Tom D Amico (Duke University Medical Center, NC) Thomas Varghese (University of Washington, Seattle, WA) Daniel Miller (WellStar Healthcare, GA) Paul M Schneider (University Hospital Zurich) Jeff Peters, Tom Watson (University of Rochester, NY) Mark Krasna (Jersey Shore University Medical Center, Neptune NJ) Programs that provided data Study design and editing, no data

17 Overall Survival: All Therapies Hofstetter et al. Esophageal Cancer Study Group.

18 Induction therapy vs. Initial Surgery for clinical stage T2N0 esophageal cancer. Speicher et al. JTO 2014

19 Speicher et al. Induction therapy does not improve survival for clinical stage T2N0 esophageal cancer. J Thorac Oncol. Aug Speicher et al. Induction chemoradiation therapy prior to esophagectomy is associated with superior long-term survival for esophageal cancer. Dis Esophagus. Sept Induction therapy should be considered in all medically appropriate patients with resectable ct2-3n0 and ct1-3n+ esophageal cancer

20 NCDB Clinical T2N0 Esophageal Cancer Samson et al. In progress

21 NCDB Clinical T2N0 Esophageal Cancer Samson et al. In progress P=0.1

22 NCDB Clinical T2N0 Esophageal Cancer Samson et al. In progress P<0.0001

23 Factors Associated with pathologic upstaging of ct1-2n0 Esophageal Ca Crabtree et al. Ann Thorac Surg 2011 Marked/intense SUV on PET (OR 5.76, , p-0.021) Poor tumor differentiation (p=0.055)

24 Predictors of pn+ disease Surgery Alone Esophageal Cancer Study Group HR CI p LVI* Tumor Size *nearly 70% chance of pn+ when LVI Variables also included; age, sex, histology, tumor location *329/499 complete data

25 NCDB: Factors Associated with Upstaging of ct2n0 Esophageal Ca Samson et al. In progress Lymphovascular Invasion Tumor differentiation (poorly differentiated tumors)

26 Factors Associated with Pathologic Upstaging of ct2n0 Esophageal Cancer Poor tumor differentiation (preop biopsy) Lymphovascular invasion (preop biopsy) Tumor length PET SUV (need to standardize) Gender? Histology??

27 Now What? Clinical staging inaccurately predicts pt2n0 disease in most patients across all studies Large database reviews demonstrate no difference in survival in ct2n0 patients treated with or without induction therapy Better clinical staging (i.e. EMR) and/or better predictive modeling is needed to guide selection of therapy in ct2n0 disease

28 T2N0 Esophageal Cancer: Does it Exist? Should we give Preop Therapy? THANK YOU!

Accuracy of endoscopic ultrasound staging for T2N0 esophageal cancer: a national cancer database analysis

Review Article Accuracy of endoscopic ultrasound staging for T2N0 esophageal cancer: a national cancer database analysis Ravi Shridhar 1, Jamie Huston 2, Kenneth L. Meredith 2 1 Department of Radiation