Abstract: 4512

1. Abstract: 4512 Individual patient data-based meta-analysis assessing the interest of pre-operative chemotherapy in resectable oesophageal carcinoma Thirion P.,Michiels S., Le Maître A., Tierney J. The Meta‑Analysis of Chemotherapy in Esophagus Cancer Collaborative Group

2. Rational & Background • Improvement of survival of patients with locally advanced resectable oesophageal cancer is warranted • Pre-operative strategies: • Pre-operative radiotherapy • IPD-Meta-analysis (Arnott et al., 1998) • Pre-operative chemotherapy • Literature-based Review (Cochrane, 2005) • Pre-operative Chemo-radiotherapy • Literature-based Review (Gebski et al., 2007)

3. Methods • Objectives • Primary end-point: • OS: Overall Survival • Secondary end-point: • DFS : Disease-Free Survival, using a 6-month landmark method • RO Complete Resection rate (UICC-AJCC definition) • Post-operative mortality rate • Statistical analyses • IPD updated / centrally collected, checked & re-analysed • Intention-to-treat analyses • Odds Ratio (OR), Hazard ratio (HR) & Logrank test - stratified by trial • Kaplan-Meier survival curves • Heterogeneity and interaction tests • Planned Sub-group analyses for OS and DFS: • Age, gender, initial Performance Status (PS) & histological type

4. Materials • 12 eligible trials identified - 2,290 patients • 9 available trials (10 comparisons) - 2,102 patients (92%) • Median follow up across trials: 5.3 years (range: 4.9 - 6.0)

5. Population Characteristics • Patient population characteristics • Age > 60 : 54% • Male: 79% • Initial PS 0-1: 71%(not available in 3 trials, 533 pts) • Squamous Cell Carcinoma: 54% • Tumour location: • Middle and lower 3rd: 67% • GE junction: 11% • Available outcome variables • OS: 9 trials - 2,102 patients • DFS: 7 trials - 1,849 patients • R0 Complete Resection rate: 7 trials - 1,887 patients • Post-operative mortality rate: 7 trials - 1,849 patients

6. No. Deaths / No. Entered Chemo preop Control Study O-E Variance Hazard Ratio HR [95% CI] Queen Mary 52/74 64/73 -13.3 27.8 Italy 35/48 37/48 -2.4 17.8 Songkla 20/24 16/22 5.7 8.5 MRC EO-02 280/400 316/402 -34.7 148.4 RTOG 8911 204/233 197/234 5.9 100.1 MD Anderson 11/17 16/19 -2.7 6.7 Scandinavia 2 53/56 50/50 -0.9 25.6 Scandinavia 2R 46/53 52/58 0.8 24.2 Oeso-2 44/58 52/64 -3.3 23.7 Rotterdam 61/85 72/84 -14.9 31.9 0.87 [0.79;0.95] Total 806/1048 872/1054 -59.8 414.6 0.25 1.00 4.00 Test for heterogeneity: p = 0.03 Chemo preop better | Control better Chemo preop effect: p = 0.003 Primary End-point: Overall Survival

7. Primary End-point: Overall Survival Control Chemo pre-op Absolute benefit 1.0 2 years 32.4% 37.5% 5.1% 0.8 5 years 16.1% 20.4% 4.3% 0.6 Survival HR = 0.87 [0.79;0.95] , p= 0.003 0.4 0.2 0.0 0 2 4 6 8 10 Time (years) Patients at risk Control 1054 321 144 74 38 20 Chemo pre-op 1047 361 153 90 52 31

8. No. Deaths / No. Entered Study O-E Variance Hazard Ratio HR [95% CI] Chemo preop Control Queen Mary 55/74 68/73 -14.7 29.3 Italy 36/48 41/48 -3.8 19.0 Songkla 20/24 16/22 3.3 8.8 MRC EO-02 296/400 331/402 -38.5 155.3 RTOG 8911 213/233 203/234 -3.1 103.3 Oeso-2 45/58 53/64 -4.1 24.4 Rotterdam 63/85 72/84 -13.3 32.5 0.82 [0.74;0.91] Total 728/922 784/927 -74.3 372.6 Test for heterogeneity: p = 0.11 0.0 1.0 2.0 3.0 Chemo preop better | Control better Chemo preop effect: p = 0.0001 Secondary End-point: DFS

9. Secondary End-point: DFS 1.0 Control Chemo pre-op Absolute benefit 2 years 23.1% 30.1% 7.0% 0.8 5 years 7.4% 11.8% 4.4% 0.6 Disease free survival 0.4 HR = 0.82 [0.74;0.91] , p=0.0001 0.2 0.0 0-0.5 2 4 6 8 10 Time (years) Patients at risk Control 927 178 87 43 22 10 Chemo pre-op 922 236 111 61 38 20

10. Secondary End-point: R0 Resection Rate Intention-to-treat Analysis No. Events / No. Entered Study O-E Variance Odds ratio OR (95% CI) Chemo preop Control Queen Mary 48/74 39/73 -4.2 8.9 Italy 37/48 35/48 -1.0 4.5 MRC EO-02 233/400 215/402 -9.6 49.5 RTOG 8911 144/233 138/234 -3.3 28.0 MD Anderson 13/17 16/19 0.7 1.4 Scandinavia 2 23/56 16/50 -2.4 6.2 Scandinavia 2R 28/53 20/58 -5.1 6.9 Oeso-2 35/58 40/64 0.7 7.3 0.81 [0.67-0.97] Total 561/939 519/948 -24.2 112.7 p = 0.74 Test for heterogeneity: 0.0 0.5 1.0 1.5 2.0 Chemo preop better | Control better Chemo preop effect with p = 0.02

11. Secondary End-point: Post-operative Mortality Rate No. Events / No. Entered Odds ratio OR (95% CI) Study O-E Variance Chemo preop Control Queen Mary 1/74 5/73 -2.0 1.4 Italy 1/48 2/48 -0.5 0.7 Songkla 3/24 0/22 1.4 0.7 MRC EO-02 36/400 40/402 -1.9 17.2 RTOG 8911 8/233 5/234 1.5 3.2 Oeso-2 9/58 7/64 1.4 3.5 Rotterdam 4/85 3/84 0.5 1.7 1.01 [0.7-1.46] Total 62/922 62/927 0.4 28.5 0.0 0.5 1.0 1.5 2.0 p = 0.26 Test for heterogeneity: Chemo preop better | Control better No preop Chemo effect p = 0.94 NS

12. No. Events / No. Entered Category O-E Var Hazard ratio HR [95% CI] Chemo preop Control Adenocarcinoma 282/385 315/392 -29.5 148.4 Squamous cell 450/564 471/563 -15.0 226.7 0.0 0.5 1.0 1.5 2.0 Test for interaction: p = 0.21 Chemo preop better | Control better Sub-group Analyses • The overall survival and disease-free survival benefit of the addition of pre-operative chemotherapy was seen across: • Age (50<, 50-60, >60) • Gender • Initial PS • Histological Type

13. Conclusions • For patients with resectable oesophageal cancer, pre-operative chemotherapy: • Improves significantly Overall Survival and Disease Free Survival, regardless of age, gender, PS & histological type. • Increases R0 resection rate, without increasing post-operative mortality rate

14. Acknowledgments • Writing/Steering Committee: Thirion P., Piedbois Y., Tierney J., Stenning S.,  Pignon J.P., Buyse M., Piedbois P.,  Bosset J.F. • Secretariat: Thirion P., Michiels S., Pignon J.P., Piedbois P., Le Maître A. • Collaborators (Investigators & Statisticians): Ancona E., Apinop C., Bancewicz J. , Clark P., De Vathaire F., Giuli R., Hansen H.S., Kelsen D., Kok T.C., Kullathorn T., Law S., Maipang T., Nygaard K., Parmar M., Roth J., Ruol A., Steinberg S., Tierney J, Tilanus H.W., Van der Gaast A., Winter K., Wong J. • Supported byFrench Cancer Ligue • And the patients.