1. Individual patient data-based meta- analysis assessing the interest of pre- operative chemotherapy in resectable oesophageal carcinoma Abstract: 4512 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 3 rd : 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. Primary End-point: Overall Survival

7. HR = 0.87 [0.79;0.95], p= 0.003 4.3%20.4%16.1%5 years 5.1%37.5%32.4%2 years Absolute benefit Chemo pre-op Control Patients at risk Control1054321144743820 Chemo pre-op1047361153905231 Survival 0.0 0.2 0.4 0.6 0.8 1.0 Time (years) 0246810

8. Secondary End-point: DFS

9. HR = 0.82 [0.74;0.91], p=0.0001 4.4%11.8%7.4%5 years 7.0%30.1%23.1%2 years Absolute benefit Chemo pre-op Control Patients at risk Control92717887432210 Chemo pre-op922236111613820 Disease free survival 0.0 0.2 0.4 0.6 0.8 1.0 Time (years) 0-0.5246810

10. Secondary End-point: R0 Resection Rate Intention-to-treat Analysis Queen Mary48/7439/73-4.28.9 Italy37/4835/484.5 MRC EO-02233/400215/402-9.649.5 RTOG 8911144/233138/234-3.328.0 MD Anderson13/1716/190.71.4 Scandinavia 223/5616/50-2.46.2 Scandinavia 2R28/5320/58-5.16.9 Oeso-235/5840/640.77.3 Total561/939519/948-24.2112.7 Study Chemo preop No. Events / No. Entered Control O-EVariance Odds ratioOR (95% CI) Chemo preop effect with p = 0.02 Test for heterogeneity: p = 0.74 0.81 [0.67-0.97] Chemo preop better|Control better 0.00.51.01.52.0

11. Secondary End-point: Post-operative Mortality Rate Queen Mary1/745/73-2.01.4 Italy1/482/48-0.50.7 Songkla3/240/221.40.7 MRC EO-0236/40040/402-1.917.2 RTOG 89118/2335/2341.53.2 Oeso-29/587/641.43.5 Rotterdam4/853/840.51.7 Total62/92262/9270.428.5 Study Chemo preop No. Events / No. Entered Control O-EVariance Odds ratioOR (95% CI) No preop Chemo effect p = 0.94 NS Test for heterogeneity: p = 0.26 1.01 [0.7-1.46] Chemo preop better|Control better 0.00.51.01.52.0

12. Sub-group Analyses The overall survival and disease-free survival benefit of the addition of pre-operative chemotherapy was seen across:  Age (50 60)  Gender  Initial PS  Histological Type Adenocarcinoma282/385315/392-29.5148.4 Squamous cell450/564471/563-15.0226.7 Category Chemo preop No. Events / No. Entered Control O-EVarHazard ratioHR [95% CI] Test for interaction:p = 0.21 Chemo preop better|Control better 0.00.51.01.52.0

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 by French Cancer Ligue And the patients.