3. Background  Reports of long-term survivors (≥5 years) of locally advanced esophageal cancer (LAEC) have focused mainly on HRQL or GI symptoms  Only a handful of studies examined long term oncological outcomes and causes of death beyond 5 years  Are patients with LAEC “truly” cured of their disease? AATS 95 th ANNUAL MEETING, 2015

4. Objectives 1.To determine overall and CSS in patients with LAEC surviving at least 5 years 2.To determine the frequency and outcome of recurrent EC in 5 year survivors 3.To determine predictors of recurrence and mortality beyond the 5 year time point 4.To determine the incidence of second primary cancers 5.To determine competing causes of death AATS 95 th ANNUAL MEETING, 2015

5. Study Design Retrospective review of prospectively collected EC database of esophagectomy for clinical T2N0 or higher disease (1988 - 2009) 355 eligible patients with LAEC underwent esophagectomy Short-term <5-year survivors (n=210 patients) Long-term ≥5-year survivors (n=140 patients) AATS 95 th ANNUAL MEETING, 2015

6. Methods Definition of recurrence: Local if luminal or intramural Regional if in any nodes in dissected bed Distant visceral or nodes beyond dissected fields OS and CSS calculated from the landmark time of 5 th postoperative year using KM method Multivariable analysis performed for factors affecting recurrence and survival

7. Recurrence in entire cohort (198/355) AATS 95 th ANNUAL MEETING, 2015 Weill Cornell Medical College

8. AATS 95 th ANNUAL MEETING, 2015 Patient Demographics (Long-term survivors, n=140) Patients’ Characteristics No. of patients 140 (%) Age at esophagectomy median years (IQR)63 (55-70) Gender Male Female 107 (76.4) 33 (23.6) Charlson Comorbidity Index CCI = 0 CCI = Above 0 74 (52.9) 66 (47.1) Performance Status PS = 0 PS = 1,2 91 (65) 49 (35) Pulmonary Comorbidities Absence Presence 106 (75.7) 34 (24.3)

9. Clinical Staging AATS 95 th ANNUAL MEETING, 2015 cTNM stages Number (%) T1 N1 M0 T1 N2 M1 2 (1.4%) 1 (0.7%) T2 N0-1 M039 (27.9%) T3 N0-1 M0 T3 N1 M1 86 (61.4%) 8 (5.7%) T4a N0 M0 T4a N1 M1 3 (1.2%) 1 (0.7%)

10. Treatment details Patients’ CharacteristicsNo. of patients = 140 (%) Neoadjuvant therapy Surgery alone Adjuvant therapy 74 (52.9) 50 (35.7) 16 (11.4) En bloc resection 2-field 3-field 116 (82.9) 41 (29.3) 75 (53.6) Histological cell type Adenocarcinoma SCC 87 (62.1) 53 (37.9) Residual tumor status R0 R1, R2 138 (98.6) 2 (1.4) No. of LN median (IQR)30 (21 – 41) AATS 95 th ANNUAL MEETING, 2015

11. Pathological Staging AATS 95 th ANNUAL MEETING, 2015 pTNM stages Neoadjuvant therapy Surgery T0 N0 T0 N+ 12 3 ---- T1 N0 T1 N+ 7474 13 3 T2 N0 T2 N+ 6 11 7 T3/4 N0 T3/4 N+ 14 15 8 22 T any N any M+32

12. Incidence and patterns of recurrence in patients surviving 5 or more years AATS 95 th ANNUAL MEETING, 2015  Patients developing recurrent EC: n=32 Prior to 5 years: 24 After 5 years: 8  Incidence first recurrence after 5 years: 8/116 (7%)  Annualized incidence of recurrence until year 10: 1.4% per year (10 of 24 disease free at year 5) 10

13. Pattern of recurrent EC in LAEC surviving at least 5 years  Local only : 3 (2%)  Regional only : 11 (7.9%)  Distant : 16 (11.4%)  Regional/distant 2 (1.4%) After 5 years: 1 6

14. AATS 95 th ANNUAL MEETING, 2015 MVA Predictors of Recurrence (n=140) Independent VariablesHR95% CI‘p’ Values Performance status PS = 0 (n=91) PS = 1 or 2 or 3 (n=49) 1.00 0.570.24 – 1.330.192 Neoadjuvant therapy Neo-adjuvant (n=74) Surgery alone (n=66) 1.00 0.720.33 – 1.530.386 Pathological T class. T0, Tis, T1 (n=44) T2, T3, T4 (N=96) 1.370.53 – 3.530.510 Pathological N class. N0 (n=71) N1, N2, N3 (n=69) 3.001.28 – 7.060.012

15. Treatment of recurrence Treatment typePatients Surviving ≥5 after recurrence Chemotherapy only143 ChemoRT only94 Surgery +/- CT/RT94 6 patients remain disease free > 5 years after treatment of recurrent EC

16. Cancer Specific Survival (CSS) n=140 AATS 95 th ANNUAL MEETING, 2015 Weill Cornell Medical College Survival years 7 years 10 years 15 years N=14088%84%-- Patients at risk 914922 Median f/u = 101 months from surgery and 41 months from 5 year point

17. Overall Survival (OS) n=140 AATS 95 th ANNUAL MEETING, 2015 Weill Cornell Medical College Survival years 7 years 10 years 15 years N=14086%70%51% Patients at risk 914922

18. Causes of Death  Pulmonary diseases (Pneumonia = 5, Respiratory failure = 3, and Pulmonary embolism = 2) AATS 95 th ANNUAL MEETING, 2015 Causes of DeathNo. of patients (n = 47) Recurrence of Esophageal cancer 20 (42.6%) Pulmonary diseases10 (21.3%) Cardiac diseases7 (15%) Second primary cancer4 (8.5%) Stroke2 (4.3%) Renal failure1 (2.1%) Unknown cause3 (6.4%)

19. Second Primary Cancers (16.4%) AATS 95 th ANNUAL MEETING, 2015 Second Primary cancerNo. of patients (n = 23) Prostate cancer6 (4.3%) Lung cancer3 (2.1%) Gastric cancer2 (1.4%) Head and Neck cancers2 (1.4%) Breast cancer2 (1.4%) Ovarian carcinoma2 (1.4%) Skin cancers (melanoma and SCC) 2 (1.4%) Urinary bladder cancer2 (1.4%) Colon cancer1 (0.7%) Meningioma1 (0.7%)

20. Predictors of Mortality >5 Y. (n=140) Independent VariablesHR95% CI‘p’ Values Neoadjuvant therapy Neo-adjuvant (n=74) Surgery alone (n=66) 0.760.41 – 1.390.369 Extent of resection en bloc (n=116) non-en bloc (n=24) 4.171.69 – 10.300.002 Pathological N class. N0 (n=71) N1, N2, N3 (n=69) 1.040.50 – 2.180.914 Recurrence No recurrence (n=108) Recurrences (n=32) 4.652.42 – 8.93<0.001 AATS 95 th ANNUAL MEETING, 2015

21. Conclusions  The majority of patients with LAEC who do not recur by 5 years are, in fact, cured of their disease  A small subset of patients (<10%) remain at risk for recurrent EC  Nodal disease is the only independent variable for EC recurrence  Patients cured of EC are at risk for second primary cancers  Pulmonary disease leads to at least 20% of non – cancer deaths AATS 95 th ANNUAL MEETING, 2015 Weill Cornell Medical College

22. Recommendations  Careful follow up for patients with LAEC surviving 5 years should be continued due to the risk of late recurrence and second primary cancers  Therapy can be advocated for selected patients with recurrences  Because aspiration may be an important long term sequela of esophagectomy, patients need careful follow- up by physicians familiar with the management of esophageal diseases  AATS 95 th ANNUAL MEETING, 2015 Weill Cornell Medical College

23. Thank you

24. Conclusion Despite surviving at least 5-years after esophagectomy for LAEC, a small subset of patients at risk for  Recurrence of esophageal cancer  Second primary cancers  Pulmonary disease possibly related to esophagectomy Careful follow-up and surveillance are mandatory for LAEC patients even after 5-years follow-up AATS 95 th ANNUAL MEETING, 2015 Weill Cornell Medical College

25. Overall Survival for Neoadjuvant vs. Surgery alone (OS) n=140 AATS 95 th ANNUAL MEETING, 2015 Weill Cornell Medical College Survival years7 years10 years15 years Neoadjuvant(n=74)83%62%48% Surgery alone (n=66)88%74%58% Patients at risk7 years10 years15 years Neoadjuvant39155 Surgery alone483011

26. Disease Free Survival for Neoadjuvant vs. Surgery alone (DFS) n=140 AATS 95 th ANNUAL MEETING, 2015 Weill Cornell Medical College Survival years7 years10 years15 years Neoadjuvant(n=74)72%56%45% Surgery alone (n=66) 78%69%56% Patients at risk7 years10 years15years Neoadjuvant33123 Surgery alone432811

27. Cancer Specific Survival for Neoadjuvant vs. Surgery alone (CSS) n=140 AATS 95 th ANNUAL MEETING, 2015 Weill Cornell Medical College Survival years7 years10 years15 years Neoadjuvant(n=74)83%80%-- Surgery alone (n=66)92%87%-- Patients at risk7 years10 years15 years Neoadjuvant39154 Surgery alone482911

28. Overall Survival for pT0,pTis,pT1 vs. pT2-4 AATS 95 th ANNUAL MEETING, 2015 Weill Cornell Medical College Survival years7 years10 years15 years Path Tis,T0,T1 (n=44)97%77%69% Path T2,T3,T4 (n=96)80%65%49% Patients at risk7 years10 years15 years Path Tis,T0,T1 (n=44) 26103 Path T2,T3,T4 (n=96) 613513

29. Disease Free Survival for pT0,pTis,pT1 vs. pT2-4 AATS 95 th ANNUAL MEETING, 2015 Weill Cornell Medical College Survival years7 years10 years15 years Path Tis,T0,T1 (n=44)86%73%63% Path T2,T3,T4 (n=96)69%58%46% Patients at risk7 years10 years15 years Path Tis,T0,T1 (n=44) 2492 Path T2,T3,T4 (n=96) 523112

30. Cancer Specific Survival for pT0-1,pTis vs. pT2-4 AATS 95 th ANNUAL MEETING, 2015 Weill Cornell Medical College Survival years7 years10 years15 years Path Tis,T0,T1 (n=44)97%-- Path T2,T3,T4 (n=96)84%78%-- Patients at risk7 years10 years15 years Path Tis,T0,T1 (n=44) 26103 Path T2,T3,T4 (n=96) 613513

31. Overall Survival for pN0 vs. pN1-3 AATS 95 th ANNUAL MEETING, 2015 Weill Cornell Medical College Survival years7 years10 years15 years Path N0 (n=71) 94%79%60% Path N1-3 (n=69) 78%60%48% Patients at risk7 years10 years15 years Path N0 (n=71) 44239 Path N1-3 (n=69) 43227

32. Disease Free Survival for pN0 vs. pN1-3 AATS 95 th ANNUAL MEETING, 2015 Weill Cornell Medical College Survival years7 years10 years15 years Path N0 (n=71) 89%74%55% Path N1-3 (n=69) 60%51%45% Patients at risk7 years10 years15 years Path N0 (n=71) 43228 Path N1-3 (n=69) 33183

33. Cancer Specific Survival for pN0 vs. pN1-3 AATS 95 th ANNUAL MEETING, 2015 Weill Cornell Medical College Survival years7 years10 years15 years Path N0 (n=71) 94%-- Path N1-3 (n=69) 82%75%-- Patients at risk7 years10 years15 years Path N0 (n=71) 44239 Path N1-3 (n=69) 43227

34. Follow-up and Recurrence AATS 95 th ANNUAL MEETING, 2015  Median follow-up for 5-year survivors was 101 months (60-270 m.) For entire cohort (n=140):  198 developed recurrent EC in the entire cohort (n=355)  96 % occurred prior to the 5 th postoperative year.  107 in the first year (54%), 43 (22%) patients in year 2, 27 (14%) in year 3, 7 (4%) in year 4, 6 (3%) in year 5, and 8 (4%) after year 5. In 5-year survivors (n=140):  32 (23%) developed recurrence.  Local in 3 patients (2%), Regional in 11 (7.9%), Distant in 16 (11.4%) and both regional and distant in 2 (1.4%) patients.  11 patients survived at least 5 years after treatment of their recurrence.

35. Recurrence in entire cohort (n=355) AATS 95 th ANNUAL MEETING, 2015 Weill Cornell Medical College