C. Schuhmacher , P.M. Schlag, F. Lordick, W. Hohenberger, J. Heise, C. Haag, S. Gretschel,

1. C. Schuhmacher, P.M. Schlag, F. Lordick, W. Hohenberger, J. Heise, C. Haag, S. Gretschel, M. Mauer, M.P. Lutz, J.R. Siewert Neoadjuvant chemotherapy versus surgery alone for locally advanced adenocarcinoma of the stomach and cardia Final results of the EORTC phase III randomized trial 40954

2. Rational for the EORTC Trial …at the time of protocol preparation (1998) Remarkable response rates in clinical trials of locally advanced and metastatic gastric cancer Phase II trials were always criticized for an incomplete pretreatment staging Postoperative chemotherapy (adjuvant trials) could not demonstrate significant benefit Adjuvant therapy had to be often delayed: postoperative deterioration of performance status and complications

3. Background Multimodal therapy in Gastric Cancer: Trials performed at a comparable point in time in The Netherlands, Great Britain, Switzerland, Italy, France, USA Staging Prospective phase II trial with endoscopic ultrasound and extended diagnostic laparoscopy: Exact cT-category and detection of peritoneal carcinosis or occult visceral metastases Regimen EORTC 40953: Combination of cisplatinum, folinic acid, and infusional 5-FU (good activity and well tolerated) J Clin Oncol. 2007;25(18):2580-5. !

4. Background EORTC 40954 • 2 cycles (d1 – d49) • Cisplatin (50 mg/m²) q 2 wks x 3 • 5FU (2000 mg/m²) q week x 6 • FA (500 mg/m²) q week x 6 • + surgery Does a purely neoadjuvant chemotherapy yield an overall survival benefit in the treatment of locally advanced gastric cancer?

5. Design Randomize CS S 1 cycle (d1 – d49) Cisplatin/5FU/FA <= 14 days Resection if possible Restaging within 3 days before cycle 2 <= 4 weeks If no PD/tox/WHO 2 Cycle 2 Resection <= 4 weeks Resection Follow-up

6. Endpoints • Primary: • Overall Survival • Secondary • R0 resection rate • Time to progression • Toxicity during preoperative chemo • Postoperative morbidity • Effect of chemo on lymph node metastasis

7. Main eligibility criteria Histologically proven adenocarcinoma of the stomach (∑ AEG Type II and III) cT3/4 NX M0 (only exception M1lymph) No histological confirmation of suspicious peritoneal lesions at diagnostic laparoscopy No prior chemotherapy and/or radiotherapy WHO PS 0-1; 18 ≤ age ≤ 70; adequate organ function • Randomization stratified by: • - institution • primary tumor cT3 vs. cT4 • localization of the tumor (upper vs. middle - lower 1/3) • gender • histological subtype (intestinal vs. non intestinal)

8. Statistical considerations Primary end-point: overall survival 282 events required to detect an improvement in median overall survival from 17 months to 24 months (HR=0.708) with a power of 80%, using a two-sided logrank test with a significance level of 4% - initially planned to perform a first analysis on patients who had an extended D2 resection - next to perform a second analysis on all randomized patients with a significance level of 2% N=360 patients (180:180) 4 years accrual 2 year additional follow-up

9. Recruitment Date of activation: July 15th, 1999 Date of closure: February 10th, 2004 Study was closed early at 144 pts (72:72) because of poor accrual. N=144/360 (40%) !

10. Patient characteristics (N=144) ! !

11. Treatment S (N=72) CS (N=72) Started chemotherapy n=69 (96%) 1 patient refusal but had surgery 2 patients with no records Underwent resection n=68 (94%) 2 patients with unresectable tumors, 1 patient with liver mets discovered intraoperatively, 1 patient without record Completed chemotherapy n=45 (63%) Discontinued n=24 (37%) ! Toxicity (n=8), Patient refusal (n=5), Other (n=7) PD (n=4) Underwent resection n=70 (96%)

12. Reason for discontinuing chemotherapy

13. Surgery Resection consisted of a subtotal or total gastrectomy with extension depending on the localization of the primary tumor with either a D1 lymphadenectomy (7 patients) or preferably a D2 lymphadenectomy (130 patients).

14. Postoperative complications CS S Postoperative 3/70 1/68 deaths(4.3%) (1.5%) 2 sepsis 1 sepsis 1 cardiac arrest + PE Postoperative 19/70 11/68 complications(27.1%) (16.2%)

15. Response to chemotherapy CR 4/69 (5.8%) PR 21/69 (30.4%) CR+PR 25/69 (36.2%) (95% CI: 25.0% - 48.7%)

16. Pathology ! • R0 resection rate was significantly higher in the CS arm (P=0.036) • (according to the pathology report) • By intraoperative assessment, R0 resection was achieved for 63 • patients in each arm (87.5%)

17. Pathology ! ! *2 unknown, 1 missing

18. Survival !

19. Survival 67 events: power of 25%!

20. Progression-free survival

21. Progression free survival Time to progression: HR=0.66 (95% CI:0.42-1.03), p=0.065 but two more deaths due to postoperative complications in the CS arm

22. Discussion based on the results -

23. Discussion with regard to literature • Neoadjuvant chemotherapy has an effect on gastric cancer • Who benefits the most? • nCtx appropriate for all patients or only a subgroup? • Will we be able to predict response in the future? • Are there predicitive molecular tools or imaging tools available? • Are there new and active regimen including biologicals? • What is the role of radiochemotherapy? • Neoadjuvant Chemotherapy has a relevant toxicity • Which is the least toxic but most effective regimen? • Influence of surgeon’s experience on survival • Japanese training and expertise as one of our important aims • International cooperation in gastric research • Support joint trials (MRC ST03, CRITICS, etc) • Cooperation for future trials

24. Acknowledgements Ulrich Fink Professor emeritus Medical Oncologist Visionary Physician Empathetic Personality Thanks to Patients and Participating Centers W. Bechstein, Frankfurt; P. Reichardt, Bad Saarow; CF. Eisenberger, Düsseldorf; A. Hoelscher, Koeln; H. Wilke, Essen; Munich Center : Katja Ott, Sonja Gillen, Maria Leibl and Rana Tabash; EORTC Headquarters M.A. Lentz, B. Meulemans, M.L. Couvreur, U. Bethe, J Welch, B. Hasan, M. Mauer, L. Collette