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1 PHASE II-III RANDOMISED TRIAL OF DEFINITIVE CHEMORADIOTHERAPY WITH FOLFOX OR CISPLATIN AND FLUOROURACIL IN ESOPHAGEAL CANCER PRODIGE 5 - ACCORD 17 trial: final results T. Conroy, MP. Galais, JL. Raoul, O. Bouché, S. Gourgou, JY. Douillard, PL. Etienne, V. Boige, I. Martel-Lafay, P. Michel, C. Llacer-Moscardo, J. Bérille, L. Bedenne, A. Adenis; UNICANCER-GI/PRODIGE Group Centre Alexis Vautrin, Nancy; Centre François Baclesse, Caen; Centre Eugène Marquis, Rennes and Institut Paoli-Calmettes, Marseille; Centre Hospitalier R. Debré, Reims; Centre Val d’Aurelle, Montpellier; Institut de Cancérologie de l’Ouest, Nantes; Clinique Armoricaine, Saint Brieuc; Institut Gustave Roussy, Villejuif; Centre Léon Bérard, Lyon; Centre Hospitalier Universitaire, Rouen; UNICANCER R&D, Paris; Centre Hospitalier Universitaire, Dijon; Centre Oscar Lambret, Lille; FRANCE

2 Background Concurrent chemoradiation using 5FU-Cisplatin is the standard of care in unresectable localized esophageal cancer. With 5FU-cisplatin based chemoradiation (RTOG 85-01): 20% of patients experienced major toxicities Local failure rate was 45% Herskovic A et al., N Engl J Med 1992;326:1593-8. In a randomized phase II study in 97 patients comparing Folfox to 5FU-Cisplatin, definitive chemoradiotherapy with Folfox provided a high CR rate with a favorable toxicity profile Conroy T et al., Br J Cancer 2010;103:1349-55. The study has been extended into a phase III trial

3 Prodige 5 - ACCORD 17 trial design Stratification : adenocarcinoma vs squamous-cell vs adenosquamous pretreatment weight loss < 10% vs ≥ 10% performance status: 0 vs 1 vs 2 center Unresectable esophageal cancer RANDOMIZERANDOMIZE 50 Gy/5 weeks + Folfox, 3 cycles 50 Gy/5 weeks + 5FU/cisplatin, 2 cy. Folfox, 3 cycles 5FU/cisplatin, 2 cycles

4 Arm A: Folfox + RT 50 Gy Chemotherapy in Folfox arm: six bi-monthly cycles of FOLFOX, the first 3 cycles starting on D1, D15 and D29 concomitant with 5 weeks’ radiotherapy. Modified Folfox: On day 1, Oxaliplatin 85mg/m², leucovorin 200mg/m², 5-FU bolus 400mg/m²/d and from day 1 to 2, 5-FU continuous infusion 800 mg/m²/day. Tumor assessment on week 15 Cycle 3 CRTRT d3-5d8-12 RT CT d29-30 d31-33d22-26 RTCRTRT d17-19d15-16 Cycle 2 Wk 7Wk 9Wk 11 Wk 1Wk 3Wk 2 d43-44 Cycle 4 d57-58 Cycle 5 d71-72 Cycle 6 d1-2 Cycle 1 CRT RT Wk 3Wk 5

5 Chemotherapy in 5FU-Cisplatin arm: two cycles of 5-FU/Cisplatin on week 1 and 5 of radiotherapy and two cycles of chemotherapy with 5-FU/Cisplatin on weeks 8 and 11; 5FU-cisplatin regimen: On D1, Cisplatin 75 mg/m² with hydration and from day 1 to 4, 5-FU 1000 mg/m²/day. Tumor assessment on week 15 Herskovic A et al., N Engl J Med 1992;326:1593-8. Arm B: 5FU-cisplatin + RT 50 Gy Wk 1 CT d50-53 Cycle 3 CRT d29-32d33 Cycle 2 d22-26 RT d15-19 CRT d1-4d5d8-12 RT Cycle 1 RT Wk 3Wk 5Wk 2Wk 4 CT d71-74 Cycle 4 Wk 11 Wk 7

6 Main Inclusion Criteria Patients unfit for surgery or locally advanced esophageal carcinoma (disease status: any T, N0 or N1, M0 or M1a) Histologically proven adenocarcinoma, squamous-cell or adenosquamous carcinoma of the esophagus No prior treatment for esophageal cancer Age  18 years and ECOG performance status  2 Adequate bone marrow reserve, normal renal and liver functions Sufficient calorific intake > 1000 Kcal/m²/day Written informed consent

7 Exclusion Criteria Metastatic disease Multiple carcinomas of the esophagus Weight loss > 20% normal body weight Peripheral neuropathy > grade 1 Symptomatic arteritis, angor, or myocardial infarction < 6 months Invasion of the tracheo-bronchial tree or fistula

8 Endpoints Secondary:  complete response rate  toxicity (NCI-CTC version 3.0 grading)  time to treatment failure  overall survival  quality of life (EORTC QLQ-C30 v 3.0 and QLQ-OES18) Primary: progression-free survival

9 Statistical considerations Hypothesis: Study designed to have 90% power to detect an increase of 20% in 3 year-PFS PFS defined as the first occurrence of tumor progression or metastasis, esophageal second cancer or death from any cause Sample size: 266 patients required to reach 144 events for final analysis, based on the use of the log-rank test with a two-sided significance level of 5% Intent to treat analysis (ITT)

10 Trial progress Recruitment: randomized phase II (97 patients): October 2004-December 2005 extension to phase III (170 patients): March 2008-August 2011 Final accrual: 267 patients Current analysis database lock: 28 February 2012 Number of events observed: 187 (70% of the sample size) Median follow-up: 25.3 months

11 Flow Chart Folfox5FU/cisplatin Total Total randomized134133 267 Did not fulfill all eligibility criteria 9 6 15 Untreated patients 3* 5** 8 ITT population 134 (100%) 133 (100%) 267 Safety population 131 (97.8%) 128 (96.2%) 259 * all with metastatic disease ** 3 patients with metastatic disease, 1 with high creatinine, 1 with myocardial ischemia

12 Patient characteristics Characteristics Folfox N=134 5FU/cisplatin N=133 p Median age (yrs) [range] 61 [38-85] 61 [41-81] NS Male gender 110 (82.1%)107 (80.5%) NS Baseline PS score012012 71 (53.4%) 62 (46.6%) 0 68 (51.1%) 62 (46.6%) 3 (2.6%) NS Weight loss grade01230123 59 (44.0%) 43 (32.1%) 31 (23.1%) 1 (0.8%) 53 (39.8%) 43 (32.3%) 36 (27.1%) 1 (0.8%) NS

13 Tumor characteristics Characteristics Folfox N=134 5FU/cisplatin N=133 p Tumor type Adenocarcinoma Squamous-cell carcinoma Adenosquamous 19 (14.2%) 114 (85.1%) 1 (0.7%) 18 (13.5%) 115 (86.5%) - NS TNM classification Stage I Stage II A Stage II B Stage III Stage IV A Stage IV B 0 (0%) 31 (21.1%) 10 (7.5%) 67 (50.0%) 8 (6.1%) 4 (3.1%) 1 (0.7%) 31 (23.3%) 7 (5.3%) 72 (54.1%) 8 (6.1%) 4 (3.1%) NS

14 Tumor characteristics Characteristics Folfox N=134 5FU/cisplatin N=133 p Median tumor length (mm) [range] 58 [11-150] 59 [7-120] NS Tumor location cervical upper thoracic middle thoracic lower thoracic 8 (6%) 35 (26.1%) 54 (40.2%) 37 (27.6%) 4 (3%) 40 (30%) 59 (44.4%) 30 (22.6%) NS

15 Safety: hematologic AEs AE, % per patient Folfox N=131 5FU/cisplatin N=128 p Grade 3/4 Neutropenia29.028.9NS Febrile Neutropenia 5.3 7.0NS Infection with Neutropenia 1.5 2.3NS Anemia 5.310.9NS Thrombocytopenia 6.9 7.8NS AE, adverse event

16 Safety: main nonhematologic AEs AE, % per patient Folfox N=131 5FU/cisplatin N=128 p-value all grades AllGrade 3/4AllGrade 3/4 Dysphagia41.22933.624.2NS Esophagitis25.26.930.512.5NS Fatigue53.417.646.99.4NS Vomiting25.23.832.82.4NS Mucositis26.76.932.02.30.011 Diarrhea15.31.514.80.7NS Alopecia 1.5- 9.4-0.006 Peripheral neuropathy18.3- 0.8-0.0001 Creatinine3.0011.73.90.036

17 Treatment completion Folfox5FU/cisplatinp-value No of treated pts131128 Median radiotherapy dose 50.0 Gy NS Full radiotherapy dose 98.4 % NS Full chemoradiotherapy 67.9 %72.2 %NS All cycles of chemotherapy 71 %76.2 %NS Treatment delayed14.8 %16.1 %NS

18 Responses and progressive disease Folfox-RT5FU-cisplatin-RT n%n% Patients134133 Complete response55(41.0)55(41.3) Events94(70.1)93(69.9) First event of PD Primary tumor Lymph nodes 2 nd esophageal T Metastases Toxic death Sudden death** Death: other causes Second cancer 24 12 2 30 1 16 8 (25.5) (12.8) (2.1) (31.9) (1.1) (17.0) (8.5) 23 16 1 25 6 3 13 7 (23.7) (17.2) (1.1) (26.9) (6.4) (3.2) (14.0) (7.5) *p= 0.06 **sudden death < 15 days from chemotherapy *

19 Progression-Free Survival Med PFS Folfox+RT: 9.7 mo. [8.1 – 14.5] Med PFS 5FU/CDDP+RT: 9.4 mo. [8.1 – 10.6]

20 Med OS Folfox+RT: 20.2 mo. [14.7 – 25.6] Med OS FU/CDDP+RT: 17.5 mo. [13.9 – 19.4] Overall Survival

21 Conclusions Definitive chemoradiotherapy with Folfox does not improve PFS in unresectable localized esophageal cancer Full completion of treatment rates, CR rate and survival are similar for both regimens Folfox shows more gr. 1-2 peripheral neurotoxicity, results in fewer toxic and sudden deaths as well as less mucositis, alopecia and decreased renal toxicity Concomitant chemoradiotherapy with Folfox is a safer new option, especially in patients with contraindication to cisplatin Bottom line, Folfox is more convenient and leads to shorter chemotherapy (12 days vs 16-20 days) given in an outpatient setting

22 Thank you ! Trial supported by a Clinical Research Hospital Program grant (PHRC 2008) from the French Ministry of Health. Sanofi-aventis France for oxaliplatin supply. Grants from Sanofi-aventis France and from the French National League Against Cancer. To our patients and their families who trust us To our remarkably efficient leader projects, C. Montoto-Grillot and B. Juzyna To all investigators of the 27 active centers, including radiotherapists, pharmacists and research staff for excellent quality of the data To enthusiastic CRA (M. Torres-Macque, S. Lévêque, A. Barban, P. Do Nascimento), A-C. Le Gall, and safety department (J. Genève, MD, and collaborators) who also trust us... but check everything! To talented physicians and statisticians who helped to plan and execute this trial To IDMC members (B. Asselain, MD, JL. Van Laethem, MD, F. Cvitkovic, MD, A. de La Rochefordière, MD) for their sound advice.

23 Acknowledgements All investigators : Dr Marie-Pierre GALAIS Centre François Baclesse CAEN; Pr. Jean-Luc RAOUL Centre Eugène Marquis RENNES; Dr Olivier BOUCHE Centre Hospitalier R. Debré/Institut Jean Godinot REIMS; Dr Jean-Yves DOUILLARD Centre René Gauducheau NANTES - St HERBLAIN; Pr. Antoine ADENIS Centre Oscar Lambret LILLE; Dr Pierre-Luc ETIENNE Clinique Armoricaine de Radiologie SAINT BRIEUC; Pr. Thierry CONROY Centre Alexis Vautrin NANCY; Dr Valérie BOIGE Institut Gustave Roussy VILLEJUIF; Dr Isabelle MARTEL LAFAY Centre Léon Bérard LYON; Pr. Pierre MICHEL Hôpital C. Nicolle / Centre Henri Becquerel ROUEN; Pr. Marc YCHOU Centre Val d'Aurelle MONTPELLIER; Dr Eric FRANCOIS Centre Antoine Lacassagne NICE; Dr Gilles CREHANGE Centre GF Leclerc DIJON; Dr Meher BENABDELGHANI Centre Paul Strauss STRASBOURG; Dr Michel RIVES Institut Claudius Regaud TOULOUSE; Pr Jean-François BOSSET CHU Jean Minjoz BESANCON; Dr Bernard ROULLET CHU Milétrie POITIERS; Dr Angélique DUPARC Institut Bergonié BORDEAUX; Pr Jean-François SEITZ Hôpital La Timone MARSEILLE; Dr Véronique VENDRELY Hôpital Saint André BORDEAUX; Dr Brigitte VIE Centre Maurice Tubiana / Polyclinique du Parc CAEN; Dr Nicole TUBIANA-MATHIEU CHU Dupuytren LIMOGES; Pr. Laurent BEDENNE Hôpital du Bocage DIJON; Pr Martin HOUSSET Hôpital Européen Georges Pompidou PARIS; Dr Christian CHEVELLE Polyclinique du Parc TOULOUSE; Pr Philippe ROUGIER Hôpital Ambroise Paré BOULOGNE BILLANCOURT; Pr Emmanuel TOUBOUL Hôpital Tenon PARIS; Dr Laurent QUERO Hôpital St Louis PARIS; Dr Laurent MINEUR Clinique Ste Catherine AVIGNON; Dr Pascal ARTRU Clinique St Jean Lyon; Dr Xavier CAROLI-BOSC Hôpital de l’Archet NICE, all in France


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