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

Unresectableesophagealcancer

RANDOMIZE

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

CTCTCT

d29-30 d31-33d22-26

RTCRT RT

d17-19d15-16

Cycle 2

Wk 7 Wk 9 Wk 11

Wk 1 Wk 3Wk 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

RTRT

d15-19

CRT

d1-4 d5 d8-12

RT

Cycle 1

RT RT

Wk 3 Wk 5Wk 2 Wk 4

CT

d71-74

Cycle 4

Wk 11Wk 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

CharacteristicsFolfoxN=134

5FU/cisplatinN=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

CharacteristicsFolfoxN=134

5FU/cisplatinN=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

CharacteristicsFolfoxN=134

5FU/cisplatinN=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

FolfoxN=131

5FU/cisplatinN=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=128p-value

all gradesAll 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

1.00P

rob

ab

ility

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

1.00P

rob

ab

ility

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 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.

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