1. Surgery alone vs. chemoradiotherapy followed by surgery for localized esophageal cancer: analysis of a randomized controlled phase III trial FFCD 9901 C. Mariette, JF Seitz, E Maillard, F Mornex, PA Thomas, JL Raoul, V Boige, D Pezet, C Genet, L Bedenne French Federation of Digestive Oncology (FFCD) FRANCE

2. Background Resection = the best treatment for resectable EC Local recurrence, distant metastasis and poor survival remain an issue after surgery In locally advanced EC (T3N+), neoadjuvant CRT – Often investigated – More and more evidence for survival benefit However impact of neoadjuvant CRT in small tumors is unknown Mariette et al. Lancet Oncol 2005 Mariette et al. Lancet Oncol 2007

3. Aim of the study To assess whether preoperative CRT improves outcomes for patients with localized (stages I or II) resectable esophageal carcinomas This study complied with the French and European Health guidelines on research involving human subjects Registred on clinicaltrials.gov NCT00047112 Funding source: PHRC program from the French National Cancer Institute

4. Methods Randomized controlled phase III trial 195 patients randomized by minimization from 06/2000 to 06/2009 30 centers in France Stratification: center, histology, cTNM stage, tumoral location Eligibility criteria – resectable thoracic esophageal SCC or ADC – cTNM stage I or II = T1N0/N+, T2N0/N+, T3N0 M0 (CT scan + EUS) – < 75 years old – OMS status 0 or 1 – Weight loss < 15% – Written consent form

5. Study design Neoadjuvant CRT + surgery group (CRT+S group, n=97) 45Gy/25F/5 weeks with 2 courses of concomitant CT 5FU 800mg/m2/day D1-D4 + cisplatin 75mg/m2 D1 or D2 Surgery alone group (S group, n=98) Transthoracic approach with two-field lymphadenectomy R SURGERY 5FU-Cis x 2 RT 45 Gy 4 to 6 weeks

6. Endpoints Primary endpoint: Overall survival ( time from randomization to all causes of death) Secondary endpoints: – Disease free survival (events: first reccurrence, second cancer or all deaths) – 30-day postoperative mortality – Postoperative morbidity – R0 resection rate – Prognostic factors identification

7. Statistical analysis To demonstrate an increase of OS from 35% (S group) to 50% (CRT+S group) with α=5% and 1-β=80%  380 patients needed (195 deaths) Results of a planned interim analysis for primary endpoint after 106 deaths (O’brien-fleming) Intention to treat analysis Median follow-up (reverse kaplan-meier method): 68.7 [60.5-75.9] months

8. Patient characteristics CRT +S group N = 98 S group N = 97 Gender male87 (88.8%)80 (82.5%) female11 (11.2%)17 (17.5%) Mean age58.4 y57.3 y OMS status 076 (77.6%)71 (73.2%) 122 (22.4%)22 (22.7%) 201 (1%) unknown03 (3.1%)

9. Tumor characteristics CRT +S group N = 98 S group N = 97 Histology SCC67 (68.4%)70 (72.2%) ADC30 (30.6%)27 (27.8%) undifferenciated1 (1.0%)0 UICC clinical stage stage I17 (17.3%)18 (18.6%) stage IIA49 (50.0%)49 (50.5%) stage IIB32 (32.7%)30 (30.9%) Tumoral location Above carena8 (8.2%)10 (10.3%) Below carena90 (91.8%)87 (89.7%)

10. Neoadjuvant treatment toxicity Patients with at least one grade ¾ toxicity in the CRT + S group 10.2% during cycle 1 13.3% during cycle 2 → mainly leucopenia, neutropenia, thrombocytemia and mucositis

11. Serious adverse events (SAE) CRT+S group N = 98 S group N = 97 P At least one SAE47 (48.0%)26 (26.8%)0.002 No SAE51 (52.0%)71 (73.2%) Total nb of SAE62 (65.3%)33 (34.7%)0.003 Grade ¾ SAE30/47 (63.8%)14 /26 (53.8%)0.59

12. Causes for no surgery Patients who finally underwent surgery – 84/98 = 86% in the CRT + S group – 91/97 = 94% in the S group CRT +S group N = 14 S group N = 6 Total N=20 Tumoral progression437 (35%) Treatment toxicity/ poor OMS status 404 (20%) Cirrhosis112 (10%) Patient’s refusal202 (10%) Others325 (25%)

13. Postoperative course CRT + S group N=84 S group N=91 P 30-day postop mortality 6 (7.1%)1 (1.1%)0.054 Postoperative morbidity 37 (44.1%)45 (49.5%)0.18 Mean nb of resected nodes 17.723.9<0.001 R0 resection81 (96.4%)84 (92.3%)0.33 pCR24 (28.6%)-- Mean LOS (d)24.822.10.87

14. Overall survival CRT + S groupS groupPHR Median survival (months) 31.8 [25.2-72.5]44.5 [29.8-59.1] 0.680.92 [0.63-1.35] 3-year survival48.6%55.2% With 55% of events and alpha =0.005, the probability of showing a difference between the 2 groups was judged very low, so the trial was stopped for futility ( according to O’brien-fleming stopping rule boundaries ) 0.00 0.25 0.50 0.75 1.00 Overall Survival 01224364860728496108 Time (months) 9781554032211583Surgery 98705037322620104RT/CT + Surgery Number at risk

15. Disease free survival CRT + S groupS groupPHR Median DF survival (months) 24.6 [14.9-46.9]26.0 [22.9-43.1]0.981.01 [0.71-1.43] 3-year survival41.2%43.9% 0.00 0.25 0.50 0.75 1.00 Disease free Survival 9770483325161072Surgery 98664332282319104RT/CT + Surgery Number at risk 01224364860728496108 Time (months)

16. To summarize When comparing CRT+S vs S alone in small EC – High surgical quality (R0, LN, mortality) – Efficacy of the standard CRT regimen (pCR 28.6%) – More SAE but not severe SAE in the CRT+S group – No significant difference regarding postoperative mortality (p=0.054) but clinically relevant (7-fold increase) – No survival benefit – No chance for showing any difference in favour of CRT+S, reason why the trial was stopped even if a relatively small number of patients included

17. Conclusion In esophageal cancers Neoadjuvant CRT followed by surgery does not improve survival for stage I or II tumors With a trend toward higher postoperative mortality

18. Discussion Were patients overtreated? → Benefit-risk balance is against neoadjuvant CRT Is surgery alone the standard treatment for stage I or II? → Probably no for N+ patients due to poor survival To discuss – Others CT or CRT regimen? – Intensity Modulated Radiation Therapy ? – Tailored approach with neoadjuvant chemo for T1/T2 N+ patients? – Better administation of preoperative treatment regarding patient’s global health status?

19. Thanks to Investigators – Lille (Prs C Mariette- JP Triboulet) – Marseille (Pr JF Seitz, Pr PA Thomas) – Lyon (Pr F Mornex, Pr J Baulieu) – Rennes (Prs JL Raoul, B Meunier) – Villejuif (Dr V Boige) – Clermont-ferrand (Pr D Pezet) – Limoges (Dr C Genet) – Dijon (Pr L Bedenne) – Besançon ( Pr JF Bosset) – Angers (Pr E Gamelin) – Avignon Clinique (Dr L Mineur) – Boulogne sur mer (Dr J Charneau) – La Roche sur Yon (Dr R Faroux) – Nantes (Pr B Buecher) – Vandoeuvre les Nancy (Pr T Conroy) – Montpellier (Pr M Ychou) – Bourg en bresse (Dr D Pillon) – Bourgoin-Jallieu (Dr N Stremsdoerfer) – Brest (Pr P Lozac’h) – Colmar (Dr B Denis) – Meaux (Dr C Locher) Investigators – Mulhouse (Dr B Vedrenne) – Paris G Pompidou (Dr B Landi) – Saint Malo (Dr P Thevenet) – Strasbourg (Dr JC Ollier) – Briis sous forges (Dr MC Clavero-Fabri) – Vannes (Dr V Klein) – Paris (IMM) (Pr B Gayet) Biostatisticians E. Maillard, F. Bonnetain Research project manager and data manager ( M. Moreau, F. Ricard, C. Fuchey) Study nurses and the FFCD team Patients