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

Rational for the EORTC Trial 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 …at the time of protocol preparation (1998)

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): !

Background EORTC 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?

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

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

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)

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

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%) !

Patient characteristics (N=144) CS (N=72) S (N=72) Age Median (years) 56 ( )58 ( ) Sex Male 50 (69.4%) WHO performancePS 0 48 (66.7%) 55 (76.4%) PS 1 24 (33.3%) 17 (23.6%) Clinical T stageT3 68 (94.4%)67 (93.1%) T4 4 (5.6%) 5 (6.9%) Histological subtypeintestinal 33 (45.8%) non-intestinal 39 (54.2%) Tumor localizationupper third + cardia II, III 37 (51.4%) 39 (54.2%) middle third 20 (27.8%) 18 (25.0%) lower third 15 (20.8%) ! !

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

Reason for discontinuing chemotherapy Major reason for protocol discontinuationCS (N=69) normal completion 45 (65.2%) PD 4 (5.8%) toxicity renal toxicity (max G2) 2 pts cardiac toxicity (G3) 1 pt nausea and vomiting (max G3) 4 pts neutropenia (max G2) 1 pt 8 (11.6%) refusal other worsening of symptoms (not PD): 2 pts non-compliance: 1 pt judgment of investigator: 3 pts infarction of the pons cerebri 1 pt (unrelated) 5 (7.2%) 7 (10.1%)

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). CS (N=70) S (N=68) D2 lymphadenectomy67 (95.7%)63 (92.6%) + transhiatal resection31 (44.3%)35 (51.5%) + hepatoduodenal lig. & rt. retroperitoneal excision20 (28.6%)22 (32.4%) Subtotal distal resection w/ systemic LN resection1 (1.4%)2 (2.9%) Multivisceral resection6 (8.6%)12 (17.6%) Type of reconstruction Roux-en-Y Pouch 48 (68.6%) 17 (24.3%) 50 (73.5%) 12 (17.6%)

Postoperative complications CS S Postoperative 3/70 1/68 deaths (4.3%) (1.5%) 2 sepsis1 sepsis 1 cardiac arrest + PE Postoperative 19/70 11/68 complications (27.1%) (16.2%)

Response to chemotherapy CR4/69(5.8%) PR21/69(30.4%) CR+PR25/69(36.2%) (95% CI: 25.0% %)

Pathology CS (N=72) S (N=72) R059 (81.9%)48 (66.7%) R19 (12.5%)15 (20.8%) R22 (2.8%)5 (6.9%) Not operated2 (2.8%)4 (5.6%) 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%) !

Pathology CS (N=70) S (N=68)P-value Median tumor thickness (mm) Median tumor length (mm) Median tumor width (mm) Extent of tumor* T0/1/2 T3/4 46 (65.7%) 24 (34.3%) 34 (50.0%) 31 (45.6%) Nodal status* N0 N (38.6%) 43 (61.4%) 13 (19.1%) 52 (76.5%) no lymphangiosis41 (58.6%)23 (33.8%) *2 unknown, 1 missing ! !

Survival !

Treatment Patients (N) Observed Events (O) Hazard Ratio (95% CI) P-Value (Log-Rank) % at 2 Year(s) (95% CI) CS (0.52,1.35) (60.66, 81.67) S (57.68, 79.24) CS (N=72) S (N=72)P-value Follow-up 4.7 years 4.1 years events: power of 25%!

Progression-free survival

Progression free survival Treatment Patients (N) Observed Events (O) Hazard Ratio (95% CI) P-Value (Log-Rank) % at 2 Year(s) (95% CI) CS (0.49,1.16) (46.16,69.07) S (35.93,58.88) CS (N=72) S (N=72) Progression documented 34 (47.2%) 43 (59.7%) Time to progression: HR=0.66 (95% CI: ), p=0.065 but two more deaths due to postoperative complications in the CS arm

Discussion based on the results - Accrual unexpectedly lowCompeting trials on the market High number of proximal tumorsEpidemiological evolution Unexpectedly high cT-category staging error Cardia is covered with fat, not serosa (“T2b”) Chemotherapy with only 63% complete courses Toxicity of PLF still too high Pathological findings as expectedNew effect on lymphangiosis Surgery arm with a median survival of at least 36 months (better than expected) Effect of D2-Lymphadenectomy? Result of “overestimation” of primary tumor category Result of center-oriented accrual (70% patients from two centers)

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

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