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:
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:
The study has been extended into a phase III trial

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

4. Arm A: Folfox + RT 50 Gy
Cycle 1
Cycle 2
Cycle 3
d1-2
d3-5
d8-12
d15-16
d17-19
d22-26
d29-30
d31-33
CRT RT RT
CRT RT RT
CRT RT
Wk 1
Wk 2
Wk 3
Wk 3
Wk 5
d43-44
Cycle 4
Cycle 5
Cycle 6
d57-58
d71-72 CT CT CT
Wk 7
Wk 9
Wk 11
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

5. Arm B: 5FU-cisplatin + RT 50 Gy
Wk 1 CT
d50-53
Cycle 3
CRT
d29-32
d33
Cycle 2
d22-26 RT
d15-19
d1-4 d5
d8-12
Cycle 1
Wk 3
Wk 5
Wk 2
Wk 4
d71-74
Cycle 4
Wk 11
Wk 7
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:

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 Primary: progression-free survival 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)

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: Final accrual: 267 patients
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 Total Folfox 5FU/cisplatin Total randomized 134 133 267
Did not fulfill all eligibility criteria 9 6 15
Untreated patients 3*
5** 8
ITT population
134 (100%)
133 (100%)
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
Folfox
N=134
5FU/cisplatin
N=133 p
Median age (yrs)
[range] 61
[38-85]
[41-81] NS
Male gender
110 (82.1%)
107 (80.5%)
Baseline PS score 1 2
71 (53.4%)
62 (46.6%)
68 (51.1%)
3 (2.6%)
Weight loss grade 3
59 (44.0%)
43 (32.1%)
31 (23.1%)
1 (0.8%)
53 (39.8%)
43 (32.3%)
36 (27.1%)

13. Tumor 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%)
31 (23.3%)
7 (5.3%)
72 (54.1%)

14. Tumor 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%)

15. Safety: hematologic AEs
AE, % per patient
Folfox
N=131
5FU/cisplatin
N=128 p
Grade 3/4
Neutropenia
29.0
28.9 NS
Febrile Neutropenia
5.3
7.0
Infection with Neutropenia
1.5
2.3
Anemia
10.9
Thrombocytopenia
6.9
7.8
AE, adverse event

16. Safety: main nonhematologic AEs
AE, % per patient
Folfox N=131
5FU/cisplatin N=128
p-value all grades
All
Grade 3/4
Dysphagia
41.2 29
33.6
24.2 NS
Esophagitis
25.2
6.9
30.5
12.5
Fatigue
53.4
17.6
46.9
9.4
Vomiting
3.8
32.8
2.4
Mucositis
26.7
32.0
2.3
0.011
Diarrhea
15.3
1.5
14.8
0.7
Alopecia -
0.006
Peripheral neuropathy
18.3
0.8
0.0001
Creatinine
3.0
11.7
3.9
0.036

17. Treatment completion Folfox 5FU/cisplatin p-value No of treated pts
131
128
Median radiotherapy dose
50.0 Gy NS
Full radiotherapy dose
98.4 %
Full chemoradiotherapy
67.9 %
72.2 %
All cycles of chemotherapy
71 %
76.2 %
Treatment delayed
14.8 %
16.1 %

18. Responses and progressive disease
Folfox-RT
5FU-cisplatin-RT n %
Patients
134
133
Complete response 55
(41.0)
(41.3)
Events 94
(70.1) 93
(69.9)
First event of PD
Primary tumor
Lymph nodes
2nd 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 25 6 3 13 7
(23.7)
(17.2)
(26.9)
(6.4)
(3.2)
(14.0)
(7.5) *
*p= **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. Overall Survival Med OS Folfox+RT: 20.2 mo. [14.7 – 25.6]
Med OS FU/CDDP+RT: mo. [13.9 – 19.4]

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 days) given in an outpatient setting

22. Thank you ! 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.
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.

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