Final results of a randomized trial comparing preoperative 5-fluorouracil (F)/cisplatin (P) to surgery alone in adenocarcinoma of the stomach and lower esophagus (ASLE): FNLCC ACCORD 07-FFCD 9703 trial. V Boige, JP Pignon, B Saint-Aubert, P Lasser, T Conroy, O Bouché, P Segol, L Bedenne, P Rougier, M Ychou

Background 1995: no standard adjuvant or neoadjuvant treatment in resectable adenocarcinoma of the stomach and the lower esophagus (ASLE) 5FU in continuous infusion plus cisplatin (FP) = one of the most effective regimens in advanced ASLE Potential benefits of preoperative (preop) chemotherapy (CT) in resectable ASLE:  increases likelihood of curative surgery by tumor downstaging  eliminates micrometastases  assesses tumor chemosensitivity

Objectives To determine whether preop FP improves the outcome of resectable ASLE Primary endpoint: overall survival (OS) Secondary endpoints:  disease-free survival (DFS)  R0 resection rate  safety

Histologically-proven adenocarcinoma of the lower third of the esophagus or esogastric junction or stomach Suitable for curative resection Age: years WHO performance status (PS): 0 or 1 Stage II or greater Non-metastatic disease Adequate renal and hematological functions Informed consent Eligibility Criteria

Endoscopy Barium meal study Abdominal and thoracic CT scans Endoscopic ultrasonography : optional Staging

FP (*) x 2/3 every 28 days Resection Within 4 weeks weeks Resection 4 – 6 weeks FP x 3/4 or no treatment Follow-up Randomization CT + S S Study Design (*) FP = 5FU: 800 mg/m² CI x 5 days - CDDP: 100 mg/m² at d1 or d2, 1-hr infusion

Postoperative CT: protocol guidelines Curative surgery Tumor response* or stabilization after preop CT pT3 and/or pN+ tumor No grade 3-4 toxicity under preop CT * based on symptoms (dysphagia, weight loss), endoscopy, CT-scan and +/- endoscopic ultrasonography

 Central randomization stratified on center, PS and tumor site  Sample size: 250 patients (178 deaths) to detect an increase from 20% to 35% in 5-yr OS (two-sided logrank test,  = 5 %,  = 20%)  DFS calculated with a 6 months landmark time to take into account the difference in timing of surgery between the 2 groups  Intent-to-treat analysis  Kaplan-Meier survival curves and two-sided logank- rank test Statistical methods

Recruitment  Open to accrual: November 1995  Closed to accrual: December 2003  224 patients randomized  Eligibility criteria extended in March 1998 to include adenocarcinoma of the stomach

S CT + S n = 111n = 113 Median age (yrs) (range) (38-75) (36-75) Sex (%) Male91 (82) 96 (85) Female20 (18)17 (15) WHO PS (%) 083 (75) 84 (74) 128 (25) 29 (26) Patient characteristics

S CT + S n = 111n = 113 nb pts (%) Site Esophagus 10 (9) 15 (13) Esogastric junction74 (67) 70 (62) Stomach 27 (24) 28 (25) > 10% weight loss Yes16 (15) 21 (19) No88 (79) 87 (77) ND 7 (6) 5 (4) Patient characteristics

CT + S N = 113 Preop CT (2-3 cycles) N = 98 (89%) Surgery N = 109 (96%) Postop CT (1-4 cycles) N = 54 (51%) S N = 111 Surgery N = 110 (99%) Trial profile

Grade 3-4 Nb of pts (%) Neutropenia 22 (20) Nausea/Vomiting 10 (9) Thrombocytopenia 6 (5) Diarrhea 2 (1) Neurotoxicity 1 (1) Nephrotoxicity 1 (1) Mucositis 4 (4) Toxic death 1 (1) Total 40 (37) Preoperative CT: Toxicity

S CT + S n = 111 n = 113 No surgery 1 4* Surgery (%) 110 (99) 109 (96) Median time to surgery (days) Postoperative mortality (%) 5 (4) 5 (5) Postoperative morbidity (%) 21 (19) 28 (26) * toxic death (n = 1), disease progression (n = 3) Surgery

S CT + S n = 110 n = 109 nb pts (%) No resection 10 (9) 7(6) Transthoracic esophagectomy 47 (43) 46 (42) Transhiatal esophagectomy 9 (8) 10(9) Extended gastrectomy 7 (6) 9(8) Total gastrectomy21 (20) 23 (21) Distal gastrectomy14 (13) 15 (14) Other 1 (1)- Type of surgery

S CT + S n = 110 n = 109 nb pts (%) Extent of resection No resection 10 (9) 7 (6) R0 81 (74) 95 (87) p = 0.04 R1 6 (5) 4 (4) R2 12 (11) 2 (2) RX 1 (1) 1 (1) Surgical and pathological results

Pathological results S CT + Sp n = 85n = 98 Tumor stage (%) T0 0 (0) 3 (3) T1, T2 27 (32) 38 (39) T3, T4 58 (68) 57 (58)0.16 Nodal status (%) N-17 (20)32 (33) N+ 68 (80) 66 (67) Nb nodes removed median range (2 - 82) (1 - 49)

Postoperative CT Nb cyclesPts (%) (n = 109) 0 55 (50) 1 6(5) 2 8(7) 3 17(16) 423(21)

Follow-up and patterns of recurrence  Median follow-up: 5.7 years [ ] S CT + S Site of recurrence n = 111 n = 113 nb pts (%) Locoregional only 9 (8)14 (12) Systemic only 42 (38)34 (30) Both 20 (18)14 (12) Total 71 (64)62 (55)

Disease-free survival 5-year DFS: 21% (14-30%) vs 34% (26-44%) years At risk ___ S ___ CT + S Logrank p value = Hazard Ratio = 0.65 (95% CI )

___ S ___ CT + S years Overall survival At risk 5-year OS: 24% (16-33%) vs 38% (28-47%) Logrank p value = Hazard Ratio = 0.69 (95% CI )

Multivariate & subset analyses  Cox model including: age, gender, PS, tumor site, allocated treatment  Prognostic factors (multivariate analysis):  preop CT (p<0.013)  tumor site (stomach, p <0.01)  No variation of treatment effect according to tumor site (test of interaction, p = 0.26)

In resectable gastroesophageal adenocarcinoma, preoperative CT with 5FU/cisplatin: significantly increases curative resection rate significantly improves disease-free survival significantly improves overall survival Summary of results

Our results confirm those of the MAGIC trial* in a slightly different patient population with a non anthracyclin-based CT Conclusion * Cunningham D et al. N Engl J Med 2006;355:11-20

Participating centers (n=25) Amiens Clermont-Ferrand Montpellier Angers Clichy Nancy Bayonne Colmar Nantes Bicêtre Dijon Reims Bichat Eaubonne Rennes Boulogne Laennec Toulouse Bourg en Bresse Lille Vichy Bourgoin-Jallieu Marseille Villejuif Caen