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
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
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
R
A
N
D
O
M
I
Z
E
50 Gy/5 weeks
+ Folfox, 3 cycles
50 Gy/5 weeks +
5FU/cisplatin, 2 cy.
Folfox,
3 cycles
5FU/cisplatin,
2 cycles
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
CRT RT
d3-5 d8-12
RT
CT CT CT
d29-30 d31-33 d22-26
RT CRT RT
d17-19 d15-16
Cycle 2
Wk 7 Wk 9 Wk 11
Wk 1 Wk 3 Wk 2
d43-44
Cycle 4
d57-58
Cycle 5
d71-72
Cycle 6
d1-2
Cycle 1
CRT RT
Wk 3 Wk 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
d29-32 d33
Cycle 2
d22-26
RT RT
d15-19
CRT
d1-4 d5 d8-12
RT
Cycle 1
RT RT
Wk 3 Wk 5 Wk 2 Wk 4
CT
d71-74
Cycle 4
Wk 11 Wk 7
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
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
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
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)
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
Flow Chart
Folfox 5FU/cisplatin Total
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%) 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
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 score 0
1
2
71 (53.4%)
62 (46.6%)
0
68 (51.1%)
62 (46.6%)
3 (2.6%)
NS
Weight loss grade 0
1
2
3
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
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
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
Safety: hematologic AEs
AE, % per patient
Folfox
N=131
5FU/cisplatin
N=128 p
Grade 3/4 Grade 3/4
Neutropenia 29.0 28.9 NS
Febrile Neutropenia 5.3 7.0 NS
Infection with Neutropenia 1.5 2.3 NS
Anemia 5.3 10.9 NS
Thrombocytopenia 6.9 7.8 NS
AE, adverse event
Safety: main nonhematologic AEs
AE, % per patient
Folfox N=131 5FU/cisplatin N=128 p-value
all
grades All Grade 3/4 All Grade 3/4
Dysphagia 41.2 29 33.6 24.2 NS
Esophagitis 25.2 6.9 30.5 12.5 NS
Fatigue 53.4 17.6 46.9 9.4 NS
Vomiting 25.2 3.8 32.8 2.4 NS
Mucositis 26.7 6.9 32.0 2.3 0.011
Diarrhea 15.3 1.5 14.8 0.7 NS
Alopecia 1.5 - 9.4 - 0.006
Peripheral neuropathy 18.3 - 0.8 - 0.0001
Creatinine 3.0 0 11.7 3.9 0.036
Treatment completion
Folfox 5FU/cisplatin p-value
No of treated pts 131 128
Median radiotherapy
dose 50.0 Gy 50.0 Gy NS
Full radiotherapy
dose 98.4 % 98.4 % NS
Full
chemoradiotherapy 67.9 % 72.2 % NS
All cycles of
chemotherapy 71 % 76.2 % NS
Treatment delayed 14.8 % 16.1 % NS
Responses and progressive disease
Folfox-RT 5FU-cisplatin-RT
n % n %
Patients 134 133
Complete response 55 (41.0) 55 (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
1
16
8
(25.5)
(12.8)
(2.1)
(31.9)
(1.1)
(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
*
Progression-Free Survival
0.00
0.25
0.50
0.75
1.00
Pro
ba
bili
ty
134 90 50 29 17 8 4 3 2FOLFOX+RT133 89 44 29 18 11 5 1 05FU/CDDP+RT
Number at risk
0 6 12 18 24 30 36 42 48Months
5FU/CDDP+RT FOLFOX+RT
HR=0.93: 95%CI[0.70-1.24]
Med PFS Folfox+RT:
9.7 mo. [8.1 – 14.5]
Med PFS 5FU/CDDP+RT:
9.4 mo. [8.1 – 10.6]
0.00
0.25
0.50
0.75
1.00
Pro
ba
bili
ty
134 106 76 48 33 18 6 5 3FOLFOX+RT133 105 74 43 25 19 10 3 05FU/CDDP+RT
Number at risk
0 6 12 18 24 30 36 42 48Months
5FU/CDDP+RT FOLFOX+RT
HR=0.94: 95%CI[0.68-1.29]
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
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
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 project leaders 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.
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