Le protocole de l`étude

Transcription

PAC ACCORD – ACCORD 17/07/07 – Prodige 5
PAC ACCORD
Actions concertées dans les Cancers COloRectaux et Digestifs
PRODIGE 5
PROTOCOLE ACCORD 17/0707
PHASE II-III STUDY COMPARING RADIOCHEMOTHERAPY WITH THE FOLFOX
REGIMEN VERSUS RADIOCHEMOTHERAPY WITH 5FU-CISPLATIN
(HERSKOVIC REGIMEN) IN FIRST LINE TREATMENT OF PATIENTS WITH
INOPERABLE OESOPHAGEAL CANCER
Working version n°11 containing amendement 1, 2, 3, 4, 5, 6, 7 and 8 accepted by CPP
10/09/2009
Pr Thierry CONROY
COORDINATOR
Centre Alexis Vautrin
Department of medical oncology
6, avenue de Bourgogne - 54511 Vandoeuvre les Nancy
Tel : 03.83.59.84.60
Fax : 03.83.59.85.50
e-mail : [email protected]
Pr. Laurent BEDENNE
ASSOCIATED
COORDINATOR
SPONSOR
Hôpital du Bocage
2 Bd Maréchal de Lattre de Tassigny - 21079 DIJON Cedex
Tél. : 03 80 29 37 50
Fax : 03 80 29 37 22
Email : [email protected]
Fédération Nationale des Centres de Lutte
Contre le Cancer (FNCLCC)
101, rue de Tolbiac - 75654 PARIS CEDEX 13 - FRANCE
Tel. +33.1.44.23.04.04
Fax: +33.1.44.23.55.69
V11 of 10/09/2009 containing amendement n°1-2-3-4-5- 6-7-8
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STUDY PROTOCOL AGREEMENT FORM
ACCORD 17/0707
Prodige 5
PHASE II-III STUDY COMPARING RADIOCHEMOTHERAPY WITH THE FOLFOX
REGIMEN VERSUS RADIOCHEMOTHERAPY WITH 5FU-CISPLATIN (HERSKOVIC
REGIMEN) IN FIRST LINE TREATMENT OF PATIENTS WITH INOPERABLE
OESOPHAGEAL CANCER
PROTOCOLE WRITING
COMITTEE
NAME AND FONCTION
Directeur du BECT (FNCLCC)
Dr. Jean GENEVE
Project Manager (FNCLCC)
Christine MONTOTO-GRILLOT
Investigateur Coordonnateur
Pr Thierry CONROY
Data Manager
Sébastien LOUVEAU
Biostatistician
Sophie GOURGOU - BOURGADE
T. Conroy, A. Adenis, D. Azria, L. Bedenne, V. Boige, O. Bouché, M.
Ducreux, P.L. Etienne, M. Giovannini, E. François, J. P Labat, F.
Lorchel, V. Magnin, J.P Metges, P. Michel, F. Mornex, D. Peiffert, J.P.
Pignon, T. Pignon, J.F. Seitz, F. Viret, M. Ychou, C. Montoto-Grillot.
ADDRESSES
DATE
(JJ-MM-AA)
SIGNATURE
FNCLCC/BECT
101 rue de Tolbiac
75654 Paris cedex 13
Tel : 01.44.23.55.52
Fax : 01.44.23.55.69
E-mail : [email protected]
FNCLCC/BECT
101 rue de Tolbiac
75654 Paris cedex 13
Tel : 01.44.23.55.67
Fax : 01.44.23.55.69
Centre Alexis Vautrin
6, avenue de Bourgogne
54511 Vandoeuvre les Nancy
Tél. : 03.83.59.84.60
Fax : 03.83.59.85.50
Euraxi Pharma
10 rue Gutenberg
BP 80325
37303 Joué-lès-Tours
Tél. : 02.47.74.30.47
Fax : 02.47.74.30.49
Centre Val-D’Aurelle
Parc Euromédecine
34298 Montpellier cedex 5
tel :04.67.61.37.75
fax : 04.67.61.37.18
e-mail : [email protected]
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PROTOCOL SYNOPSIS
TITLE
PHASE II-III STUDY COMPARING RADIOCHEMOTHERAPY WITH THE
FOLFOX REGIMEN VERSUS RADIOCHEMOTHERAPY WITH 5FUCISPLATIN (HERSKOVIC REGIMEN) IN FIRST LINE TREATMENT OF
PATIENTS WITH INOPERABLE OESOPHAGEAL CANCER
INVESTIGATORS
/
TRIAL LOCATION
STUDY OBJECTIVES
40 planned centers, France
Coordinated by Prof. T. Conroy
PHASE II STUDY :
Primary To assess the feasibility (completion of full treatment) in both arms.
Secondary To assess endoscopic complete response rate in both arms.
To assess the toxicity profile of each arm using NCI-CTC scale (version 3).
PHASE III STUDY :
Primary
To compare the progression-free survival (PFS) between 2 chemotherapy
schedules delivered during concomitant radiotherapy: Folfox regimen
versus Cisplatin/5-FU (Herskovic regimen).
The PFS will be defined by the following events:
- tumor progression
- metastasis diagnosis
- esophageal second cancer
- death from any cause
To compare overall survival, endoscopic complete response rate, incidence
Secondary of grade 3-4 toxicities NCI-CTC and time to treatment failure between both
regimens.
To evaluate the quality of life using EORTC QLQ-C30 (version 3) and a
validated diseasespecific module EORTC QLQ-OES18.
A multicenter randomized phase II trial followed by a phase III
STUDY DESIGN
STUDY POPULATION
Main
Criteria
Selection Inclusion Criteria:
Patients with:
− Histologically
proven
adenocarcinoma,
squamous
cell
or
adenosquamous carcinoma of the oesophagus ;
− Inoperable oesophageal carcinoma (disease status :any T, N0 or N1,
M0 or M1a) or surgical contre-indication conditions ;
− No prior treatment for oesophageal cancer (surgery, chemo- or
radiotherapy);
− Peripheral neuropathy ≤ NCI-CTC grade 1;
− Age ≥ 18 years;
− ECOG Performance Status (PS) ≤ 2;
− Sufficient (oral or with gastrostomy) calorific intake (> 1000
3/70
2
Kcal/m /day);
− Life expectancy ≥ 3 months ;
− Adequate bone marrow reserve, normal renal and liver functions:
• Neutrophil count ≥ 1500/mm³
• Platelet count ≥ 100 000/mm³
• Hemoglobin ≥ 10 g/dl (after transfusion, if necessary)
• Creatinine < 15mg/L
• Total bilirubin level<1.5 x ULN
• ALT/AST < 2.5 x ULN
• Prothrombin time ≥ 60%;
− Laboratory values obtained the week preceding study entry;
− Signed informed consent (prior to all study procedures);
− Start of treatment within 28 days of inclusion.
Exclusion Criteria:
− Metastatic disease except for third upper or cervical oesophagus tumor
with regional nodes, or third lower oesophagus tumor with celiac nodes
(M1a);
− Multiple carcinomas of the oesophagus;
− Small cell or undifferentiated carcinoma of the oesophagus;
− Patients with cardia tumor (Siewert II) or gastric tumor extensive to the
oesophagus (Siewert III) are ineligible.
− Complete dysphagia (grade 4 NCI-CTC), patient with exclusive
parenteral nutrition;
− Weight loss within 3 months > 20% normal body weight;
− Pregnant or breast-feeding woman;
− Fertile patient not using adequate contraception;
− Peripheral sensitive neuropathy with functional impairment;
− Auditory disorders;
− History of prior malignancies (other than cured non melanoma skin
cancer, cured cervical carcinoma in situ or stage I or II node negative
head and neck cancer cured > 3 years ago);
− Prior cervical, thoracic and abdominal radiotherapy with field overlapping
the proposed oesophageal radiotherapy field;
− Tracheo-oesophageal fistula or invasion of the tracheo-bronchial tree;
− Previous myocardial infarction (inferior or equal to 6 months). Patients
with a previous myocardial infarction superior to 6 months, could be
included only if:
• no transient ischemia is shown by thallium myocardial scintigraphy
and
• favourable advise for chemotherapy from a cardiologist is obtained;
− Other serious illness or medical conditions (such as symptomatic
coronary disease, left ventricular failure or uncontrolled infection);
− Arterial disease stage II to IV according to the DE LERICHE and
FONTAINE classification;
− Treatment with any other experimental drugs or participation in another
clinical trial within 30 days of study screening;
− Concurrent treatment with any other anti-cancer therapy;
− Concurrent treatment with phenytoine and Yellow fever vaccine;
− Geographical, social or psychological circumstances preventing regular
follow-up.
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Phase II : to have 80 evaluable patients (40 in each arm), 88 patients (44 in
each arm) will be included.
Phase III : 169 other evaluable patients ; total of 266 patients, (133 par arm
including the phase II patients).
EXPECTED NUMBER 25 centers for Phase II, 40 centers for phase III.
OF CENTRES
Oxaliplatin: Powder for parenteral use, 100mg vials, dilution in 20 mls of
STUDY DRUGS
water for injection or 5% glucose and reconstitution with 5%
Formulations
glucose solution to 250-500 ml.
Folinic acid : Commercially available formulation
5-FU :
Commercially available formulation
Cisplatin : Commercially available formulation
Administration route Intravenous.
Dose regimen
Radiation (two arms)
Rx > 6 MV, 2 to 4 beams, 50 Gy (at intersection of all fields), 2 Gy per
fraction, 5 fractions per week, all fields used every day, maximum dose to
spinal cord 40 Gy.
In the case of lymph nodes radiation, total dose 50 Gy.
Target volume: primary tumor (GTV : visible tumor ; PTV : expansion of 3
to 5cm of distal and proximal margins and lateral margins at mediastinal
interface). If tumor of the upper 1/3 of the oesophagus, proximal margin
must be adapted to the patient’s clinical situation.
TOTAL EXPECTED
NUMBER OF
SUBJECTS
Patients with cervical primary tumor with positive supra-clavicular or
cervical lymph nodes (defined as N1) are eligible.
Patients with radiographic evidence of enlarged (superior or equal to 1,5
cm) celiac lymph nodes seen on CT scan or echography are ineligible.
Patients with oesophageal tumor extensive to the cardia, classified Siewert
I (center of the tumor lying > 1 cm – 5 cm above Gastro-Oesophageal
Junction) are eligible.
Patients with cardia tumor (Siewert II) or gastric tumor extensive to the
oesophagus (Siewert III) are ineligible.
The choice of technic (number and orientation of the beams, level-heading)
will result from the analysis of the lungs DHV and CTV. Maximum dose to
spinal cord will be 40 Gy.
Gammagraph print or portal images will be done the first day of treatment
for all the beams and at each beams change. They will be compared to the
referential images. If these last don’t offer some anatomic locations,
orthogonal prints will be realized.
Chemotherapy
Arm A :
Total treatment of six 2-weekly cycles of FOLFOX, the first 3 cycles starting
on D1, D15 and D29 concomitant with 5 weeks’ radiotherapy.
Oxaliplatin: 85 mg/m² as 2 hours infusion, in 250 to 500 ml of 5% glucose
solution on day 1 of each cycle with a separate infusion of folinic acid.
Folinic acid: 200 mg/m² IV over 2 hours on day 1 of each cycle followed
by :
5-FU:
400 mg/m²/day IV bolus, on day 1 of each cycle then
5-FU:
1 600 mg/m² 46 h continuous IV infusion, over days 1 and 2 of
each cycle (approximately 800 mg/m² at day 1 and day 2)
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EVALUATION
CRITERIA
STATISTICAL
CONSIDERATIONS
DURATION OF
STUDY PERIOD (per
subject)
STUDY DATES
Arm B :
Two cycles of 5-FU / Cisplatin on week 1 and 5 of radiotherapy and two
cycles of chemotherapy with 5-FU / Cisplatin on week 8 and 11 (one cycle
each three weeks after the end of radiotherapy).
Cisplatin : 75 mg/ m² continuous infusion (1 mg/minute) on day 1 of each
cycle followed by :
5-FU :
1000 mg/ m² per day continuous infusion from day 1 to day 4 of
each cycle.
1° Phase II : In the two arms :
-Percentage of patients having completed the full treatment.
-Endoscopic complete response rate.
- Toxicity profile (NCI-CTC).
2° Phase III :
- Progression-free survival in each arm.
- Overall Survival, complete response rate, time to treatment failure in
each arm.
- Percentage of grade 3-4 toxicities in each arm.
General : Standard randomized phase II-III design
Sample size: 97 patients were included in the phase II study and 169
supplementary patients will be included in the phase III (total of 266
patients: 133 in each arm).
Arm A: 12 weeks or until disease progression, unacceptable toxicity,
patient refusal to continue treatment, or treatment delay > 2 weeks.
Arm B: 11 weeks or until disease progression, unacceptable toxicity,
patient refusal to continue treatment, or treatment delay > 2 weeks.
Planned start date phase II : October 2004
Effective start date phase II : October 2004
Planned recruitment closure phase II : March 2006
Effective recruitment closure phase II : December 2005
Planned start date phase III : February 2008
Planned recruitment closure phase III : February 2010
Planned end date phase III: September 2011
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TABLE OF CONTENTS
1.
INTRODUCTION AND RATIONALE
Background
Information on study drugs
1.2.1
Oxaliplatin
1.2.2
5-FU
1.2.3
Folinic acid
1.2.4
Cisplatin
1.3
Study Rationale
2.
STUDY OBJECTIVES
3.
STUDY DESIGN
3.1
Type of Study
3.2
Expected Number of Patients
3.3
Method of Treatment Allocation
3.4
Duration of the Study Period for One patient
4.
STUDY POPULATION
4.1
Inclusion Criteria
4.2
Exclusion Criteria
5.
STUDY PROCEDURES
5.1
Treatments
5.1.1
Treatment administration
5.1.2
Dose modifications
5.2
Schedule of Visits and Observations
5.2.1
Pre-registration work up
5.2.2
Evaluations during treatment
5.2.3
Post treatment follow-up
5.3
Randomization procedures
5.4
Study Measurements
5.4.1
Completion of full treatment
5.4.2
Tumor Response
5.4.3
Time-related Parameters
6.
SAFETY ASSESSMENTS
6.1
Concomitant Treatment Restrictions
6.2
Data Monitoring Committee
7.
DRUG SUPPLIES
7.1
Study Drugs
7.1.1
Oxaliplatin
7.1.2
5-FU : Information can be found in the package insert.
7.1.3
Folinic acid : Information can be found in the package insert.
7.2
Storage Conditions
7.3
Retrieval of treatments and/or destruction
8.
TRial discontinuation criteria
9.
Serious adverse event
10. COST AND EXCESS COSTS OF THE RESEARCH
11. QUALITY INSURANCE
12. OWNERSHIP AND CONFIDENTIALITY OF DATA
13. RULES FOR PUBLICATION
14. ETHICAL AND REGULATORY ASPECTS
15. COMMITTEE OF THE PROTECTION OF PERSONS
1.1
1.2
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10
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11
13
14
14
14
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17
17
17
17
18
18
18
19
19
19
19
23
27
27
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29
30
30
30
30
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33
33
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34
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40
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16. COMPETENT AUTHORITY
17. INFORMATION AND CONSENT OF PARTICIPANTS
18. SPONSOR'S RESPONSABILITIES
19. INVESTIGATOR'S RESPONSABILITIES
20. INTERRUPTION OF SUBJECT STUDY
20.1 Circumstance
20.2 Replacement of subjects
21. STATISTICAL CONSIDERATIONS
21.1 Parameters
21.1.1 Phase II
21.1.2 Phase III
21.2 Analysis Population
21.3 Statistical Methods
21.3 1. Demographics
21.3 2. Efficacy
21.3 3. Safety
21.3.4 Quality of life
21.3 5. Interim Analysis
21. 4. Sample Size Calculation
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41
41
42
42
42
43
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43
43
43
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44
44
45
45
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APPENDICES
Appendix 1 : ECOG Performance Status Scales/Scores
Appendix 2 : TNM classification of oesophageal carcinoma
Appendix 3 : US TNM echoendoscopic classification
Appendix 4 : De Leriche and Fontaine Classification
Appendix 5 : EORTC QLQ-C30 version 3
Appendix 6 : EORTC QLQ-OES18
Appendix 7 : Serious Adverse Event form
Appendix 8 : Notice d'information au patient et consentement éclairé
Appendix 9 : NCI-Common Toxicity Criteria version 3.0
Appendix 10 : Résumé des Caractéristiques du (des) produit(s) (RCP)
Appendix 11 : Siewert Classification 1998
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LIST OF ABBREVIATIONS AND
DEFINITION OF TERMS
AP
ASCO
AST
ALT
BP
CDDP
CEA
CI
CPP
CR
CRF
CT
CV
d/D
DHV
DLT
Dn
DNA
ECOG
FA
FFCD
FNCLCC
5-FU
FOLFOX
γGT
GI
GTV
Gy
H
Hb
ICRU
IV
OXA
LLN
MeV
MMR
MTD
N
N°/n°
NCI
NCI-CTC
PD
PNN
PMH
PR
PS
Alkaline Phosphatase
American Society of Clinical
Oncology
Aspartate Amino-Transferase
Alanine Amino-Transferase
Blood Pressure
Cisplatin
Carcino-Embryonic Antigen
Continuous Infusion
Comité pour la Protection des
Personnes
Complete Response
Case Report Form
Chemotherapy
Cardiovascular
day
Dose-Volume Histogram
Dose Limiting Toxicity
Day n after treatment
Deoxyribonucleic Acid
Eastern Cooperative Oncology
Group
Folinic Acid
Fédération Francophone de
Cancérologie Digestive
Fédération
Nationale
des
Centres de Lutte Contre le
Cancer
5-Fluorouracil
5-FU, FA and Oxaliplatin
chemotherapy regimen
γ-Glutamyl Transferase
Gastrointestinal
Growth Tumor Volume
Gray
Hour
Hemoglobin
Intersection
point
of
radiotherapy beams
Intravenous
Oxaliplatin
Lower Limit of Normal
Million electron Volts
Mismatch Repair
Maximum Tolerated Dose
Normal
number
National Cancer Institute
National
Cancer
Institute
Common Toxicity Criteria
Progressive Disease
Polynuclear Neutrophil count
Primary Medical History
Partial Response
Performance Status
pt(s)
PTV
RNA
RR
RTOG
SAE(s)
SD
Sd
UICC
ULN
vs
WBC
WHO
WNL
Patient(s)
Primary Tumor Volume
Ribonucleic Acid
Response Rate
Radiation Therapy Oncology
Group
Serious Adverse Event(s)
Stable Disease
Standard deviation
Union Internationale Contre
le Cancer
Upper Limit of Normal
Versus
White Blood Cells
World Health Organisation
Within Normal Limits
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1. INTRODUCTION AND RATIONALE
BACKGROUND
Oesophageal carcinoma is more common in France than in any other European country (1). There
are 4500 new cases every year, with a 94% mortality rate and a median survival of 9 months (2).
Only 26% of tumors are operable, but even these patients have a perioperative mortality of 8%
and three year survival of 25%. The incidence is 16 per 100 000 population. Survival of squamous
cell oesophageal carcinoma improved significantly between 1984-86 and 1987-88 in Finistère, the
benefit being attributed to increasing use of medical treatments either alone or in combination with
surgery (3).
These statistics clearly illustrate the fact that loco-regional treatment is not sufficient, and that
systemic therapies need to be developed.
Chemotherapy
Many agents have been used over the years in single agent therapy or combination, but few have
been tested in randomized trials (4). Response criteria have also been a discussion point, because
symptomatic improvement can be due to a small tumor regression and primary tumors prove very
difficult to measure at endoscopy, barium swallow and trans-oesophageal ultrasound. The most
reliable objective response criteria appear to be those obtained with a combination of
esophagoscopy, barium studies and CT-Scan. Treatment success in metastatic disease needs to
be measured using RECIST response criteria, symptom-free survival, progression-free survival
and overall survival (5-7).
Fewer agents have been tested in oesophageal adenocarcinoma than in squamous cell
carcinoma. Adenocarcinoma seems to respond less to chemotherapy, but this has never been
proven in a randomized clinical trial. 7 single agents seem to show activity in oesophageal cancer,
tested on small groups of patients (8-11) : mitomycin C (26% objective responses in historic trials),
cisplatin (CDDP) (19%), vindesine (20%), bleomycin (15%), 5-fluorouracil (5-FU) (17-82%),
vinorelbine (20%) and paclitaxel (28-34%)(4, 7, 12). The only randomized study comparing single
agent therapy showed response rates of 5% for adriamycin, 12% for methotrexate and 15% for 5FU.
Various modalities of combination therapy using 5-FU, CDDP, bleomycin, vindesine and etoposide
give response rates between 35% in metastatic disease and 50% in locally advanced disease.
However, the results of these studies are difficult to interpret due to variable inclusion criteria.
There are no large randomized trials that prove the superiority of one regimen over another.
Standard combination therapy remains CDDP combined with a 5 day 5-FU continuous infusion.
Patients with oesophageal cancer often present contraindications to this standard regimen:
peripheral arterial disease, angina, previous vascular events, impaired renal function or impaired
hearing. In a randomized phase II study in squamous cell oesophageal cancer, the EORTC found
that this regimen was superior to CDDP alone, both in terms of response (36 vs 18%) and
progression-free survival (9 vs 6 months), but there was no overall survival benefit mainly because
of a significant number of toxic deaths in the CDDP-5-FU arm (13). Etoposide, irinotecan and
paclitaxel appear to give similar results when combined with CDDP in phase II studies (14). Triplet
combinations increase toxicity without improving outcome (8, 9). The addition of folinic acid to 5FU/CDDP did not change outcome, but a 4-agent trial of 5-FU, FA, etoposide and CDDP gave
encouraging results in a pre-operative setting (10).
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Radiotherapy
Studies have shown that high-dose radiotherapy is capable of curing small oesophageal cancers
(16-17), disproving the discouraging results of earlier, under-dosed, trials (18-20). 5 year survival
has gone from 0-14% in early studies to 19-21% in the more recent trials. These results can be
explained by better pre-treatment staging (CT), improved targeting, higher-energy sources and
accelerated treatment reducing tumoral repopulation and sub-lethal lesion repair (16, 17, 21).
Chemoradiotherapy
In advanced oesophageal carcinoma, most exclusive chemoradiotherapy regimens tested in
phase II included 5-FU and either CDDP or mitomycin with 40-60 Gy. Despite the absence of
surgery, complete endoscopic responses ranged from 55-80% with a 29-40% two-year survival
and a median of 11-22 months (29-35). Another study confirmed these results (36), and a third
gave a non-significant 5-year survival difference of 16 vs 6% (27). A further study demonstrated a
significantly improved disease-free survival with chemoradiotherapy (46) over radiotherapy alone.
Eight studies comparing concomitant chemoradiotherapy to radiotherapy alone were published.
The most recent trials used a combination of cisplatin and 5-FU. In the RTOG study 85-01 first
published by Herskovic and coworkers (26,14), two courses of chemotherapy during 50 Gy
radiation therapy followed by additional two courses of the same chemotherapy versus 64 Gy
radiotherapy alone were investigated. No patient survived at three years in the radiotherapy group
but 26 % of the patients in the concomitant chemoradiotherapy group were surviving at 5-years. A
substantial reduction in local recurrences after chemoradiotherapy was demonstrated. However,
this was at the expense of a higher risk of grade 3-4 toxicities : 20 % of the patients suffered from
life-threatening toxicity and 40 % stopped chemotherapy before the completion of the treatment.
Median survival was only 14 months in the chemoradiation arm. The Patterns of Care Study (22)
confirmed these results and the superiority of chemoradiotherapy on radiotherapy alone, with 39%
2–year survival vs 20.6 % (p = 0.027) and lower 2-year local regional failure (30% vs 57.9 %; p =
0,0031).
Two subsequent trials confirmed that the Herskovic regimen is now the standard chemoradiation
regimen. The INT 0123 trial (23) compared high dose radiotherapy (64.8 Gy) versus standard
dose (50.4 Gy) with 5FU and cisplatin in 218 patients. Toxic death rates were 10% (high dose) and
2% (standard dose) respectively, with no significant difference in median survival. The FNCLCCFFCD 9305 trial (24) compared a split course radiotherapy to a standard fractionation radiotherapy
(50 Gy in 25 fractions and 5 weeks). With a median follow-up of more than 6 years, the 5–year
survival rate was significantly lower in the split course arm (10 vs 21% ; p = 0.047).
Currently, patients with inoperable disease at diagnosis, contraindications or objections to surgery
and metastatic disease with dysphagia are treated with combination chemoradiotherapy using 5FU/ cisplatin (2 cycles during and 2 cycles after radiotherapy) and 50 Gy. Chemoradiotherapy is
the treatment of choice for this group of patients (25), but it is by no means perfect. New
combinations of drugs are required to improve the recurrence and metastasis rates, and to allow
better dose-intensities. Synergistic combinations would be interesting in order to improve survival
of this poor prognosis disease.
INFORMATION ON STUDY DRUGS
Oxaliplatin
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Oxaliplatin (oxa), a new third-generation cisplatin analog in the 1,2-diaminocyclohexane (DACH)
family of platinum compounds, is active in several solid tumor types, including some
cisplatin/carboplatin refractory diseases and is licensied in many countries for the treatment in first
line of metastatic colorectal cancer (CRC).
Mechanism of action
Similarly to cisplatin, the main mechanism of action of oxaliplatin is mediated through the
formation of DNA-adducts (38), but in spite of many similarities between the two drugs, there are
important differences in their activity profiles(s). DACH platinum adducts are bulkier and more
hydrophobic than cisplatin adducts (39,40). The mismatch repair protein complex may be
prevented from binding to DACH-platinum DNA-adducts because of particular conformational DNA
distortions in the region of the adducts (41).
The induction of mismatch repair defects has been shown to correlate with acquired resistance to
cisplatin while the sensitivity to oxaliplatin was maintained. Data concerning the role of DNA
mismatch repair in platinum drug resistance indicate that oxaliplatin is likely to be more active in
cisplatin-resistant cancer (42). Several laboratories have shown that the mismatch repair
complexes recognize cisplatin diadducts, but not DACH-platinum diadducts in DNA (43,44).
Finally, oxaliplatin induces primary and secondary DNA lesions that lead to apoptosis in human
cancer cells.
Preclinical activity
Oxaliplatin has shown potent antiproliferative activity (as good or better than cisplatin) against
mouse and human cervical carcinoma, non-small cell lung cancer, leukemia, colon, ovarian,
breast, melanoma, bladder, glioma, and erythroleukemia cells lines (45,46).
Tolerance of oxaliplatin
The tolerability profile of oxaliplatin is as follows :
The limiting toxicity of oxaliplatin is neurological. It involves a sensory peripheral neuropathy
characterised by peripheral dysaesthesia and/or paraesthesia with or without cramps, often
triggered by the cold (85 to 95% of patients).
The duration of these symptoms, which usually regress between courses of treatment, increases
with the number of treatment cycles. The onset of pain and /or a functional disorder and their
duration are indications for dose adjustment, or even treatment discontinuation. This functional
disorder, including difficulties in executing delicate movements, is a possible consequence of
sensory impairment. The risk of occurrence of a functional disorder for a cumulative dose of
approximately 800 mg/m² (i.e. 10 cycles) is 15% or less. The neurological signs and symptoms
improve when treatment is discontinued in the majority of cases.
Acute neuro-sensory manifestations have been reported. They start within hours of administration
and often occurs on exposure to cold. They may present as transient paraesthesia, dysaesthesia
and hypoaesthesia or as an acute syndrome of pharyngolaryngeal dysaesthesia. This acute
syndrome of pharyngolaryngeal dysaesthesia (1-2% of patients) is characterized by subjective
sensations of dysphagia or dyspnea, without any laryngospasm or bronchospasm (no stridor or
wheezing); jaw spasm, abnormal tongue sensation, dysarthria and a feeling of chest pressure
have also been observed. Such symptoms are rapidly reversible with or even in the absence of
symptomatic treatment. Prolongation of the infusion time in subsequent cycle helps to reduce the
incidence of this syndrome.
Acute cold-induced dysesthesias : a frequent acute syndrome of dysesthesias of the hands, feet,
or throat. This syndrome may be manifested as laryngo-pharyngeal dysesthesia when swallowing
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cold food or drink. The intensity is generally mild to moderate and the symptoms are most often
observed during or within a day or two after the oxaliplatin infusion, lasting for a few minutes to a
few days, and are fully reversible.
Allergic Reactions :
Uncommon (single agent) or common (in combination with 5-FU +/- folinic acid) anaphylactic
reactions including bronchospasm, angioedema, hypotension and anaphylactic shock. Common
allergic reactions such as skin rash (particularly urticaria), conjunctivitis, rhinitis have been
observed. Typically, the reactions occured after several exposures to oxaliplatin. Frequent cases
of fever without infection (immune type) or with infection (associated or no to neutropenia) have
been reported.
Gastrointestinal disorders :
As a single agent, oxaliplatin may cause anorexia, nausea, vomiting, diarrhoea and abdominal
pain. In the majority of cases, these symptoms are not severe.
Prophylaxis and/or treatment with potent antiemetic agents are indicated.
In combination with 5-FU (with or without folinic acid), the frequency and severity of diarrhoea and
mucositis is significantly increased compared with that observed with 5-FU alone.
Stomatitis, mucositis, colitis including Clostridium difficile diarrhea has also been reported.
Metabolic disorders including dehydration, ileus, intestinal obstruction, hypokaliemia, metabolic
acidosis and renal impairment may be caused by severe diarrhea/emesis, particularly when
combining oxaliplatin with 5-fluorouracil.
Mild to moderate elevation of transaminases and alkaline phosphatases have been observed.
Haematological disorders :
Anaemia, neutropenia and thrombocytopenia have been reported.
The incidence of neutropenia and thrombocytopenia is greater when oxaliplatin is used in
combination with 5-FU and folinic acid than that observed using a combination of 5-FU and folinic
acid alone.
Other effects :
o Rare cases of acute interstitial lung disease and of pulmonary fibrosis have been
reported.
o Rare cases of immuno-allergic thrombocytopenia and hemolytic anaemia.
o Transient, reversible decreased vision within hours of receiving oxaliplatin, as well as
cases of optic neuritis has been rarely reported.
o Rare cases of deafness have been reported.
o Disturbance of renal function have been reported in approximately 3% of all patients
treated, with less than 1% of patients experiencing grade 3-4 abnormalities.
o Moderate alopecia has been reported in 2% of patients treated.
o Extravasation may result in local inflammation which may be severe and lead to
complication, especially when oxaliplatin is infused through a peripheral vein.
o Dysarthria has been rarely reported.
5-FU
5-FU, is a pyrimidine analog, used in cancer chemotherapy since 1963 in France. It has been
tested in a wide variety of bolus, short and long intravenous infusions for different indications in
many single-agent and combination chemotherapies.
The drug is metabolized to F d UMP (5 Fluoro-2'-deoxyuridinemonophosphate), which binds to
thymidylate synthase, preventing DNA synthesis. The activity of 5-FU depends on peak
13/70
concentrations and on duration of exposure (47). Continuous infusion of 5-FU is very well
tolerated. The limiting toxicity of 5-FU in continuous infusion is mucositis, hand-foot syndrome and
diarrhea rather than hematological (48). The continuous infusion schedule has demonstrated
efficacy in several tumor types (breast, head and neck, pancreas, gastric, rectal and colon
cancer). Overall response rate in the published series of single agent 5-FU in patients with
oesophageal cancer is between 18 and 82 % (4,7,10). 5-FU is included in most combination
therapies for oesophageal cancer and forms part of the standard chemoradiotherapy for locally
advanced disease.
Folinic acid
Folinic acid modulates the activity of 5-FU and thus improves outcome in both colorectal and
gastric cancer (49-53). It has been added to 5-FU in several small studies of oesophageal cancer
(54-58) with encouraging results, but large trials have yet to be performed. 5-FU and FA alone
gave 19% OR rate in a small phase II study of oesophageal adenocarcinoma (4) and 45%
combined with cisplatin and etoposide (69) with 31% two-year survival.
Cisplatin
Cis-dichlorodiammineplatine II (cisplatin) has been tested extensively against human tumor cell
lines in vitro and in clinical trials and has proven to be one of the most active antineoplastic agents
in clinical use, with a broad spectrum of antitumor activity, including esophageal cancer (Bleiberg
EJC 1997). Cisplatin has the activity of a bifunctional alkylating agent and binds directly to DNA,
inhibiting its synthesis by the formation of intrastrand cross-links.
Although the nephrotoxicity of cisplatin was originally felt to be dose-limiting, renal toxicity has
been preventable when adequate hydration is provided. Other toxicities include rare
hypersensitivity, acute and delayed nausea and vomiting (needing agressive prophylactic
antiemetics), hypomagnesemia, neurotoxicity and Raynaud’s phenomenon. Carboplatin, an less
toxic analog of cisplatin, was demonstrated as poorly efficient in esophageal cancer (59).
STUDY RATIONALE
Oxaliplatin is a diaminocyclohexane platinum complex that is active in several solid tumor types,
especially in some cisplatin/carboplatin refractory diseases, such as colorectal cancer, resistance
being generally due to a loss of mismatch repair (MMR) function. Loss of MMR function, observed
as genetic instability in microsatellite sequences, occurs in many types of sporadic cancers,
including oesophageal carcinoma (28,65,66). Data concerning the role of DNA mismatch repair in
platinum drug resistance indicate that oxaliplatin is likely to be more active in cisplatin-resistant
cancer (42,67). Loss of MMR also causes resistance to other drugs, but not to 5-FU in some
MMR-proficient and deficient cell lines (68).
Oxaliplatin is licensed in many countries for the treatment of first line of metastatic colorectal
cancer. A phase III European study of LV5FU2 +/- Oxaliplatin was conducted from August 1995 to
July 1997. Four hundred twenty patients were randomized (210 in each arm) and received 5-FU
400 mg/m2 bolus + 5-FU 600 mg/m2 continuous infusion and FA 200 mg/m2 on day 1 and day 2
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2
and Oxaliplatin 85 mg/m IV 2 hours on day 1, with cycles repeated every 2 weeks. The objective
response rate was 22% for FU/LV versus 50% with the addition of oxaliplatin (p= 0.0001), with a
median time to response in the oxaliplatin arm of 2.3 months. Time to progression was 6.2 vs 9.0
months (p= 0.0003) and overall survival 14.7 vs 16.2 months (p= 0.12) in the two arms
respectively (71).
Oxaliplatin demonstrates activity superior to that of cisplatin, having a broader spectrum of action
than the parent compound (69-74).
It has shown encouraging activity in tumors that respond to cisplatin or carboplatin: advanced
ovarian cancer (75-77) and non small cell lung cancer (78).
The combination of oxaliplatin and 5-FU is known to be active against several tumor types (79).
The synergy of the two agents has been confirmed by clinical trials (69-74,80). Extension of this
synergy to oesophageal cancer may be expected. Continuous 5-FU regimens appear to be more
effective than bolus ones (71) and the oxaliplatin dose of 85 mg/m2 every 2 weeks is well-tolerated
in combination with 5-FU with or without folinic acid. The 5-FU/oxaliplatin combination does not
present the same cardiovascular or renal risks as 5-FU/cisplatin, as it does not require
prehydration and has no renal toxicity.
In vitro studies of squamous carcinoma cell lines (CAL 27) using FOLFOX and radiotherapy are
currently underway.
The safety profile of oxaliplatin combined with 5-FU, is now well established.
Activity of oxaliplatin in esogastric carcinomas
Gastric carcinoma and adenocarcinomas of the esophago-gastric jonction
Three trials assessed the activity of oxaliplatin combined to 5-FU and folinic acid. The first one,
(60) included 57 patients with gastric adenocarcinoma (including 18 cardia). Patients received
oxaliplatin 100 mg/ m2, folinic acid 400 mg/ m2, bolus 5-FU 400 mg/ m2 then 5-FU 3 g/ m2 as a
continuous infusion over 46 hours every 14 days. Forty-nine were assessable for response. Two
CR and 20 PR were observed, giving an overall RR of 44.9%. Median survival was 8.6 months.
Another trial from the Chicago University (61) confirmed these data. Thirty-six patients with
adenocarcinoma (n = 29), squamous cell carcinoma (n = 3) or poorly differentiated carcinoma (n =
3) of the esophagus or the cardia were included. They received a combination of oxaliplatin 85 mg/
m 2 day 1, folinic acid 500 mg/ m2 days 1 and 2, bolus 5-FU followed by 5-FU 600 mg/m2 22-hour
continuous infusion days 1 and 2 every 2 weeks. Response rate in this heterogeneous population
was 40% with a 8.6 month median survival.
Another trial was reported during the 2002 ASCO (62). Forty-one patients with gastric cancer
received a regimen consisting of Oxaliplatin 65 mg/ m2 days 1 and 8, 5-FU 2600 mg/ m2 plus
folinic acid 300 mg/ m2 days 1 and 8 every 3 weeks. Out of 29 evaluable patients, the PR rate was
55.2 % and the median survival was not yet reached.
The fourth trial was recently published (63). Twenty-six patients with advanced gastric cancer,
whose disease progressed while receiving, or after discontinuing, chemotherapy with a 5-FU and
platinum regimen, were enrolled. Treatment comprised oxaliplatin (85 mg/ m2 on day 1) as a 2-h
infusion followed by bolus 5-FU (400 mg/ m2 on day 1), and 48-h infusion of 5-FU 2.4-3.0 g/ m2
concurrently with folinic acid 150 mg/ m2. Cycles were repeated at 2-weeks intervals. Of the 23
evaluable patients, there were six PR (response rate 26%). The median time to progression was
4.3 months and the median overall survival was 7.3 months.
Another trial included patients with metastatic gastric cancer failing prior palliative first-line
chemotherapy. The regimen consisted in a combination of raltitrexed (3 mg/ m2) and oxaliplatin
(130 mg/ m2) every 3 weeks. One patient achieved a PR and 6 had stable disease, with a overall
median survival of 4.5 months (64).
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Oxaliplatin with radiation
Some trials assessed the safety and the efficacy of oxaliplatin combined with radiation therapy,
especially in rectal cancers. Two trials in patients with primary esophageal carcinoma are also
available.
One NCI-sponsored Phase I trial using oxaliplatin with protracted-infusion 5-FU plus radiotherapy
for patients with esophageal cancer was recently published (81). Patients received oxaliplatin on
days 1,15, and 29 with continuous 5-FU from days 8 to 42. Starting on day 8, patients received
radiotherapy 36 to 39.6 Gy in 1.8 Gy fractions, then 5.4 Gy to 9 Gy in a smaller volume. Eligible
patients could undergo surgery or begin a second cycle without radiotherapy. Six patients received
2
2
2
oxaliplatin at 85 mg/m and 5-FU at 180 mg/m /day. Then oxaliplatin was escalated to 100 mg/m
with dose-limiting toxicities (DLT) in 2 out 3 patients and dose escalation was discontinued.
However table 2 in the final report indicated 4 levels (2 dose levels for each drug) and no data is
reported on the other levels. Forty patients were enrolled and 38 were treated, including 32
adenocarcinoma, 4 squamous cell carcinoma and 2 with mixed histology. At the end of cycle 1, 36
patients underwent endoscopy and a 81% complete response rate was observed. Of the 13
patients taken to surgery, 5 (38%) had no cancer in the resected specimen. Neurotoxicity was
milder than expected and the combination appears less toxic than the Herskovic combination. The
effect of this treatment on pulmonary function was also published (82).
A Phase I study investigated the maximum tolerated dose (MTD) for an association of oxaliplatin
when administered with folinic acid 200 mg/m2 followed by 5FU bolus and 22 h continuous infusion
given on days 1 and 2, every 2 weeks with a 50 Gy radiation dose in patients with esophageal
cancers. Patients also received 3 courses of Modified Folfox 4 (with 85 mg/m2 oxaliplatin) every 2
weeks after the end of the radiotherapy period. Five levels have been investigated, as indicated
below.
Limiting Toxicity and response rate :
Level
Number of
evaluable
patients
Dose (mg/m2)
Oxaliplatin
5FU bolus
5FU Cl
50
300
400
50
400
600
Safety : 06
I
Efficacy : 05
II
06
Limiting toxicity
Number of
Type of toxicity
patients
G3 asthenia and
01
anorexia
G3 cutaneous reaction
01
(Epithelite)
Efficacy
2 CR, 1 PR,
2 PD, 1 NE*
01
G3 anorexia
4 PR, 1 SD,
1PD
01
1 CR, 4 PR,
1 SD, 1 NE*
III
06
75
400
600
01
G4 febrile neutropenia
after cycle 1
G3 asthenia and
anorexia
IV
07
85
400
600
01
G3 anorexia
3 RP, 1 SD,
2 PD, 1 NE*,
V
06
100
400
600
03
G4 asthenia
G3 diarrhea
G3 asthenia
2 RP, 3 PD,
1 NE*
* NE = not evaluable
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2
Dose-limiting Toxicities (DLT) occurred in 3 of 6 patients treated at level V, with a 100 mg/m dose.
So 3 extra patients have been included at the level IV to confirm the recommended dose of 85
2
mg/m oxaliplatin every 2 weeks. Encouraging efficacy data have been observed, with a 61 %
response rate in 28 evaluable patients.
Given these results, it is necessary to assess in a randomized phase II / III study the tolerance and
activity of chemoradiotherapy using Folfox 4 and Herskovic regimens in locally advanced
oesophageal carcinomas.
2. STUDY OBJECTIVES
Phase II :
Primary Objectives :
- To assess the feasibility (completion of full treatment) of combination chemotherapy containing
oxaliplatin, 5-fluorouracil and folinic acid (FOLFOX regimen) or 5-FU/Cisplatin with concomitant
radiotherapy in first line treatment of inoperable advanced oesophageal cancer.
- To assess endoscopic complete response rate in both arms.
Secondary Objective :
To assess the toxicity profile of each arm using NCI-CTC version 2.
Phase III :
Primary Objective :
To compare the progression-free survival between 2 chemotherapy schedules delivered during
concomitant radiotherapy : Folfox regimen versus Cisplatin/5-FU (Herskovic regimen).
Secondary Objectives :
- To compare overall survival, endoscopic complete response rate, incidence of grade 3-4
toxicities NCI-CTC and time to treatment failure between both regimens.
- To evaluate the quality of life using EORTC QLQ-C30 (version 3) and a validated diseasespecific module QLQ-OES18.
3. STUDY DESIGN
3.1 TYPE OF STUDY
Multicenter randomised phase II trial followed by a phase III.
3.2 EXPECTED NUMBER OF PATIENTS
97 patients were included in the phase II study and 169 supplementary patients will be in the
phase III (total of 266 evaluable patients :133 in each arm).
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3.3 METHOD OF TREATMENT ALLOCATION
Eligible patients will be randomized according to a randomization by minimization, between the two
arms of treatment with a stratification :
by histological type (adenocarcinoma or adenosquamous versus squamous cell
carcinoma),
by pretreatment weight loss in the prior 6 months (grade 1 : < 10% versus grade 2 : ≥
10%),
by ECOG performance status (0 - 1 - 2),
and by centre.
The patient number and the patient initial are to be entered on each page of the Case Report
Form.
3.4 DURATION OF THE STUDY PERIOD FOR ONE PATIENT
Arm A : treatment will be given for a total of six 2-weekly cycles of FOLFOX, the first 3 cycles
starting on D1, D15 and D29 concomitant with 5 weeks’ radiotherapy.
Arm B : two cycles of 5-FU / Cisplatin on weeks 1 and 5 of radiotherapy and two cycles of
chemotherapy with 5-FU / Cisplatin on weeks 8 and 11 (one cycle each three weeks after the end
of radiotherapy).
Subjects will be considered to be on-study for the duration of their treatment and in the 30 days
following treatment discontinuation. Treatment discontinuation is defined as the last day of study
treatment (chemotherapy or radiotherapy).
Subjects will continue on treatment until they have completed the study protocol, unless there is
disease progression, unacceptable toxicity, patient refusal, or treatment delay > 2 weeks.
All included patients will be followed up until recovery from residual toxicities/AEs, until progressive
disease is observed, and until death occurs.
4. STUDY POPULATION
4.1 INCLUSION CRITERIA
Patients with:
− Histologically proven adenocarcinoma, squamous cell or adenosquamous carcinoma of the
oesophagus ;
− Inoperable locally advanced oesophageal carcinoma (disease status : any T, N0 or N1,M0 or
M1a), or surgical contre-indication conditions ;
− No prior treatment for oesophageal cancer (surgery, chemo- or radiotherapy);
− Peripheral neuropathy ≤ NCI-CTC grade 1;
− Age ≥ 18 years;
− ECOG Performance Status (PS) ≤ 2;
− Sufficient(oral or with gastrostomy) calorific intake (> 1000 Kcal/m2/day);
− Life expectancy ≥ 3 months ;
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− Adequate bone marrow reserve, normal renal and liver functions:
Neutrophil count ≥ 1500/mm³
Platelet count ≥ 100 000/mm³
Hemoglobin ≥ 10 g/dl (after transfusion, if necessary)
Creatinine < 15mg/L
Prothrombin time ≥ 60%;
− Laboratory values obtained the week preceding study entry;
− Signed informed consent (prior to all study procedures);
− Start of treatment within 28 days of inclusion.
4.2 EXCLUSION CRITERIA
− Metastatic disease except for third upper or cervical oesophagus tumor with regional nodes, or
third lower oesophagus tumor with celiac nodes (M1a);
− Multiple carcinomas of the oesophagus;
− Small cell or undifferentiated carcinoma of the oesophagus;
− Patients with cardia tumor (Siewert II) or gastric tumor extensive to the oesophagus (Siewert III)
are ineligible.
− Complete dysphagia (grade 4 NCI-CTC) patient with exclusive parenteral nutrition;
− Weight loss within 3 months > 20% normal body weight;
− Pregnant or breast-feeding woman;
− Fertile patient not using adequate contraception;
− Auditory disorders;
− History of prior malignancies (other than cured non melanoma skin cancer, cured cervical
carcinoma in situ or stage I or II node negative head and neck cancer cured > 3 years ago);
− Prior cervical, thoracic and abdominal radiotherapy with field overlapping the proposed
oesophageal radiotherapy field;
− Tracheo-oesophageal fistula or invasion of the tracheo-bronchial tree;
− Previous myocardial infarction (inferior or equal to 6 months). Patients with a previous
myocardial infarction superior to 6 months, could be included only if:
no transient ischemia is shown by thallium myocardial scintigraphy and
favourable advise for chemotherapy from a cardiologist is obtained ;
− Other serious illness or medical conditions (such as symptomatic coronary disease, left
ventricular failure or uncontrolled infection);
− Arterial disease stage II to IV according to the DE LERICHE and FONTAINE classification;
− Treatment with any other experimental drugs or participation in another clinical trial within 30
days of study screening;
− Concurrent treatment with any other anti-cancer therapy;
− Concurrent treatment with phenytoine or yellow fever vaccine.
− Geographical, social or psychological circumstances preventing regular follow-up.
5. STUDY PROCEDURES
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5.1 TREATMENTS
Treatment administration
Radiation
Rx > 6 MV, 2 to 4 beams, 50 Gy (at intersection of all fields), 2 Gy per fraction, 5 fractions per
week, all fields used every day, maximum dose to spinal cord 40 Gy. In the case of lymph nodes
irradiation, total dose 50 Gy.
Target volume: primary tumor (GTV : visible tumor ; PTV : expansion of 3 to 5 cm of distal and
proximal margins and lateral margins at mediastinal interface).
If tumor of the upper 1/3 of the oesophagus, proximal margin must be adapted to the patient’s
clinical situation.
Patients with cervical primary tumor with positive supra-clavicular or cervical lymph nodes (defined
as N1) are eligible.
Patients with radiographic evidence of enlarged (superior or equal to 1,5 cm) celiac lymph nodes
seen on CT scan or echography are ineligible.
Patients with oesophageal tumor extensive to the cardia, classified Siewert I (center of the tumor
lying > 1 cm – 5 cm above Gastro-Oesophageal Junction) are eligible.
Patients with cardia tumor (Siewert II) or gastric tumor extensive to the oesophagus (Siewert III)
are ineligible.
The choice of technic (number and orientation of the beams, level-heading) will result from the
analysis of the lungs DHV and CTV. Maximum dose to spinal cord will be 40 Gy.
Gammagraph print or portal images will be done the first day of treatment for all the beams and at
each beams change. They will be compared to the referential images. If these last don’t offer
some anatomic locations, orthogonal prints will be realized.
Arm A : Total treatment of six 2-weekly cycles of FOLFOX, the first 3 cycles starting on D1, D15
and D29 concomitant with 5 weeks’radiotherapy.
Arm B : Two cycles of 5-FU/Cisplatin on week 1 and 5 of radiotherapy and two cycles of
chemotherapy with 5-FU / Cisplatin on week 8 and 11 (one cycle each three weeks after
the end of radiotherapy) [Herskovic regimen]
Gastrostomy or jejunostomy or nasogastric sound is recommended, if necessary before or
during the treatment.
Tumors of the upper 1/3 of the oesophagus: with the patient in dorsal decubitus position, arms
at their sides, 3 equally weighted beams should be used, systematically including the subclavian
lymph nodes, to a dose of 40 Gy at the ICRU point. The irradiated volume should then be reduced,
by decreasing the size of the 3 fields, to add a boost of 10 Gy (ICRU point) at the tumor target and
affected lymph nodes with a safety margin of 1 cm in all dimensions.
Tumors of the middle 1/3 of the oesophagus: if the upper limit of the lesion exceeds the carena,
the right and left retro-clavicular regions need to be included in the initial target volume.
Tumors of the lower 1/3 of the oesophagus: the irradiated field will include the celiac lymph
nodes.
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Dosimetry: Volumetric dosimetry will be performed on spinal cord and lung. Control
gammagraphs print or portal images should be performed for each field at start and at each
ballistic change (see section 5.4 for quality control measures).
If possible, the following constraint will be respected : lungs dose (volume of the two lungs – PTV)
receiving more than 20 Gy (V20) < 20 % of the total lung volume (V20 < 20 %).
Target volume: Target volume includes the tumor and any suspect lymph nodes, with a 5 cm
safety margin in the cranio-caudal axis above and below the tumor, and a 2 cm radial safety
margin. If tumor of the upper 1/3 of the oesophagus, proximal margin must be adapted to the
patient’s clinical situation.
If the upper limit of tumor or lymph nodes exceeds the carena, the right and left retro-clavicular
regions need to be included in the irradiated field. For lower 1/3 tumors, the irradiated field will
include the celiac lymph nodes. After 40 Gy the irradiated volume will be reduced to the initial
targets (tumor and nodes) with a 1 cm safety margin.
Chemotherapy :
Arm A (Modified Folfox regimen) :
Oxaliplatin : 85 mg/m² as 2 hour infusion, in 250 to 500 ml of 5% glucose solution on days 1, 15,
29, 43, 57 and 71 (every 2 weeks) with a separate infusion of folinic acid
Modified LV5FU scheme
Folinic acid: 200 mg/m² IV over 2 hours on day 1 and of each cycle followed by
5-FU:
400 mg/m²/day 10 min IV bolus, on day 1 of each cycle followed by
5-FU: 1600 mg/m² 46 h continuous IV infusion, over days 1 and 2 of each cycle (approximately
800 mg/m² at day 1 and day 2).
Modified FOLFOX regimen, every 2 weeks - 3 cycles during radiotherapy, 3 cycles after
radiotherapy.
RADIOTHERAPY:
↓Cycle 1
d1-2
d3-5
CRT RT
↓Cycle 2
d8-d12
RT
↓Cycle 3
d15-16
d17-19
CRT
RT
d22-d26
RT
d29-30
CRT
d31-33
RT*
↓Cycle 4
↓Cycle 5
↓Cycle 6
d43-44
d57-58
d71-72
CT
CT
CT
CT = chemotherapy
RT = radiotherapy
d36-40
Evaluation↓
↓
RT* = reduced field radiotherapy
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Arm B (Herskovic regimen) :
Two cycles of chemotherapy with 5-FU / Cisplatin on weeks 1(day 1) and 5 (day 29) of
radiotherapy and two cycles each three weeks after the end of radiotherapy on weeks 8 (day 50)
and 11 (day 71).
Hydration before Cisplatin administration :
During 03 hours : 1 liter of NaCL Isotonic + 22, 5 ml of KCL 10% + 9 ml of MgCL2 (adapted to
the blood ionogramme).
During 03 other hours : 1 liter of NaCL Isotonic + 22, 5 ml of KCL 10% + 9 ml of MgCL2.
Investigators could use this proposed scheme or another according to the local habits.
If diuresis is inferior to 2 liters, administer 100 ml of Mannitol 20%.
Cisplatin : 75 mg/m2 continuous infusion (1 mg/minute) in 250 ml of sodium chloride solution on
day 1of each cycle (or in case of hydration delay on day 2) followed by:
Hydration :
During 03 hours : 1 liter of NaCL Isotonic + 22, 5 ml of KCL 10% + 9 ml of MgCL2.
During 03 other hours : 1 liter of NaCL Isotonic + 22, 5 ml of KCL 10% + 9 ml of MgCL2.
5-FU : 1000 mg/m2 per day continuous infusion from day 1 to day 4 of each cycle.
RADIOTHERAPY:
↓Cycle 1
d1-4
↓Cycle 2
d5
CRT RT
d8-d12
RT
d15-19
RT
d22-d26
d29-32
RT
CRT
↓Cycle 3
↓Cycle 4
d50-53
d71-74
CT
CT
CT = chemotherapy
RT = radiotherapy
d33
d34-49
RT*
Evaluation↓
↓
RT* = reduced field radiotherapy
Notice the number of vomiting and precise the diuresis curve each three hours.
Excessives loss of water and electrolytes will be compensated according to the ionogramme (with
calcemia and magnesemia) results, done the day of Cisplatin administration and the following day.
Vomiting will be prevented using antiemetics: corticosteroids, anti-5HT3.
FOLFOX should continue every 2 weeks after the end of radiotherapy for 3 cycles or until disease
progression, unacceptable toxicity, patient refusal to continue treatment, or treatment delay > 2
weeks.
5-FU/Cisplatin should continue for two cycles each three weeks after the end of radiotherapy or
until disease progression, unacceptable toxicity, patient refusal to continue treatment, or treatment
delay > 2 weeks.
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Dose modifications
A toxicity evaluation will be conducted weekly according to NCI criteria version 3.0 (Appendix 8).
Dose modifications will be made according to the worst toxicity observed during the previous cycle.
Arm A (Modified Folfox regimen)
Table. 1 : Summary of dose modifications for next cycles in case of toxicity
Type of toxicity
NCI-CTC Grade
Anemia (any grade)
Leucopenia
(any grade)
Neutropenia Grade 3 and 4
without or with fever
Thrombopenia Grade 3 and 4
Nausea and/or vomiting Grade
4 despite
pre-medication
Diarrhea Grade 3
Diarrhea Grade 4*
Stomatitis Grade 3
Stomatitis Grade 4*
Cardiac toxicity ≥ Grade 2
Skin toxicity Grade 3 or 4
Allergy Grade 3 or 4
Neurocerebellar
Neurosensory : specific
adaptation according to
symptomatology
Alopecia (any Grade)
Other toxicity
- Grade 1 and 2
- Grade 3
- Grade 4
Initial doses (mg/m²/cycle)
5-FU Bolus
5-FU C. Infusion
Oxaliplatin
400
1 600
85
Dose modification of study drugs (mg/m²/cycle)
None
None
None
None
None
None
No bolus
None
65
No bolus
None
65
Repeat cycle with adapted anti-emetic therapy.
If intolerable toxicity is observed, patient off study after agreement of
Sponsor and Investigator.
No bolus
No bolus
No bolus
No bolus
1 600
None
1 200
65
1 600
None
1 200
65
Stop treatment. Patient off study for toxicity
No bolus
1 200
None
None
None
As described table 2
None
None
None
None
No bolus
Stop
None
1 600
Stop
None
65
Stop
∗or repeated Grade 3 after 5-FU dose reduction
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Table. 2 Dose adjustments for oxaliplatin-related neurological toxicity
≤ 7 days
Toxicity
Duration of toxicity
Persistent between
>7 and <14 days
a
cycles
b
Paresthesias/dysesthesias that
do not interfere with function
(grade 1 NCI)
b
Paresthesia/ dysesthesias
interfering with function, but not
interfering with activities of daily
living
(grade 2 NCI)
b
Paresthesia/ dysesthesias with
pain or with functional
impairment interfering with
activities of daily living (grade 3
NCI)
Persistent
paresthesia/dysesthesias that
are disabling or life-threatning
ACUTE: (during or after the 2
hour infusion) laryngopharyngeal
dysesthesias
a
b
No change
No change
No change
No change
No change
65 mg/m²
NA
65 mg/m²
Stop
NA
NA
Stop
↑ duration of
next
infusion to 6
hours
↑ duration of next
infusion to 6 hours
↑ duration of next
infusion to 6 hours
Not resolved by the beginning of the next cycle
May be cold induced.
The neurotoxicity includes paresthesias and dysesthesias of the hands, feet, and peri-oral region.
Patients treated with oxaliplatin will be counseled to avoid cold drinks and exposure to cold water
or air, especially for 3-5 days following oxaliplatin administration.
Laryngopharyngeal dysesthesias :an unusual laryngopharyngeal dysesthesia: a loss of sensation
of breathing (acute respiratory distress) without any objective evidence of respiratory distress
(hypoxia, laryngospasm, or bronchospasm) also has been observed. This neurotoxicity may be
induced or exacerbated upon exposure to cold.
Should a patient develop laryngopharyngeal dysesthesia, the patient's oxygen saturation will be
evaluated via a pulse oximeter and, if normal, an anxiolytic agent or benzodiazepine will be given
and the patient should be observed in the clinic until the episode has resolved. Because this
syndrome may be associated with the rapidity of oxaliplatin infusion, subsequent doses of
oxaliplatin should be administered as 6-hour infusions (instead of the normal 2-hour infusion).
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Pulmonary fibrosis :
In the case of unexplained respiratory symptoms such as non-productive cough, dyspnea,
crackles or radiological pulmonary infiltrates, oxaliplatin should be discontinued until further
investigations exclude interstitial pulmonary fibrosis.
Allergic or anaphylactic reactions to oxaliplatin, FA or 5-FU:
skin rashes and infusion-related fever should not justify patient withdrawal. Paracetamol, antihistamines and corticosteroids can be administered both curatively and at subsequent infusions.
Patients with a history of allergic reaction to platinum compounds should be monitored for allergic
symptoms. In case of an anaphylactic-like reaction to oxaliplatin, the infusion should be
immediately discontinued and appropriate symptomatic treatment initiated. Oxaliplatin rechallenge
is contra-indicated.
Arm B (Herskovic regimen)
Table. 3 Dose adjustments for next cycles (weeks 5, 8, 11) in case of toxicity at D29, D50, D71 :
Initial doses
5-FU C. Infusion
Cisplatin
1000 mg/m²/d
75 mg/m²
Dose of study drugs
Type of toxicity
NCI-CTC
Anemia (any grade)
Leucopenia (any grade)
3
Neutrophils ≥ 1500/ mm
3
Platelets ≥ 100. 000/ mm
Creatininemia ≤ 1, 25 x ULN
3
Neutrophils ≥ 1500/ mm ,
3
Platelets ≥ 100. 000/ mm
Creatininemia > 1, 25 x ULN
3
1000/ mm ≤ Neutrophils < 1500 and / or
3
75. 000 ≤ Platelets < 100. 000/ mm
and / or persistent grade 1 or 2 digestive toxicity
(vomiting, stomatitis, oesophagitis, diarrhea)
3
Neutrophils < 1000/ mm and / or
3
Platelets < 75. 000/ mm and / or
persistent grade 3 or 4 digestive toxicity (nausea/
vomiting, stomatitis, diarrhea)
Cardiac toxicity ≥ Grade 2
Skin toxicity Grade 3 or 4
Allergy Grade 3 or 4
Alopecia (any Grade)
100%
100%
100%
100%
100%
100%
100%
0%
50%
50%
75%
Delay one week
(2 weeks if necessary)
100%
Delay one week
(2 weeks if necessary)
80%
80%
100%
100%
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Table. 4 Dose adjustments in case of toxicity during the intercycle :
Initial doses
5-FU C. Infusion
Cisplatin
1000 mg/m²/d
75 mg/m²
Dose of study drugs
Type of toxicity
NCI-CTC
Grade 4 neutropenia (Neutrophils < 500/ mm )
3
Febrile neutropenia (Neutrophils < 1000/ mm
with fever ≥ 38, 5°C)
Nausea and/or vomiting Grade 3
despite pre-medication
Nausea and/or vomiting Grade 4
despite pre-medication
Grade 3- 4 stomatitis
Grade 3- 4 Diarrhea
3
50%∗
50%∗
50%∗
50%∗
100%
50%
100%
0%
75%∗
75%∗
75%∗
75%∗
∗ in absence of residual toxicity at D 29 needing a 50% dose reduction.
Dose delays and radiotherapy interruption
Chemotherapy : in the Folfox arm should be administered if the patient has recovered from
hematological toxicity (neutrophils ≥ 1500/mm3 and platelet count ≥ 75. 000/mm3) and hand-foot
syndrome (≤ grade 1).
In the Herskovic arm, chemotherapy should be administered with 50% dose reduction of 5-FU and
Cisplatin if 1000/ mm3 ≤ PNN < 1500 and / or 75 000 ≤ Platelets < 100 000/ mm3 and / or
persistent grade 1 or 2 digestive toxicity (vomiting, stomatitis, oesophagitis, diarrhea).
In case of Neutrophils < 1000/ mm3 and / or Platelets < 75. 000/ mm3, the chemotherapy should be
delayed for one week, and if necessary 2 weeks, and administered for the next cycle with 25%
dose reduction of 5-FU. The cycle should be administered only if the patient has recovered from
toxicity (neutrophils ≥ 1500/mm3 and platelet count ≥ 75. 000/mm3)
Otherwise, the cycle will be postponed until recovery, whilst radiotherapy continues (for the
chemoradiotherapy period) ; but if the interruption was > 2 weeks the patient will be considered
off-study but should be monitored until recovery of all adverse events and for at least 30 days.
Further treatment will be at the clinician’s discretion.
Radiotherapy : may be interrupted until recovery (to ≤ grade 2) for the following toxicities :
− grade 3-4 nausea and vomiting that continues after adequate prophylactic and curative
treatment
− grade 3-4 cutaneous reaction or cutaneous reaction with infection
− grade 3-4 diarrhea
− grade 3-4 anorexia or weight loss during treatment.
− grade 4 mucositis/esophagitis
− grade 4 dysphagia in previously asymptomatic patients.
In case of mediastinal or thoracic infection with fever ≥ 38,5°C, radiotherapy will be interrupted
until complete recovery (apyrexia).
In case of severe aplasia, radiotherapy will be interrupted until recovery (neutrophils ≥ 1500/mm3
and platelets ≥ 50.000/mm3).
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Radiotherapy will be resumed on recovery, but if the interruption was > 2 weeks the patient will be
considered off-study but should be monitored until recovery of all adverse events and for at least
30 days. Further treatment will be at the clinician’s discretion.
SCHEDULE OF VISITS AND OBSERVATIONS
Pre-registration work up
INVESTIGATIONS
1.History and clinical - Written consent signed by the patient and
examination
investigator.
- Previous medical history includes:
* intercurrent and prior illness
* date of diagnosis of initial disease
* previous specific treatments
* concomitant treatments
* dysphagia (see NCI-CTC dysphagia)
- Physical examination:
* weight, height, PS (ECOG)
* head and neck examination
* complete neurological examination
* clinical tumor assessment
* clinical evaluation
2. Hematology
WBC, Neutrophils, Hb and platelets
3. Biochemistry
4. Quality of life
5. Other tests
6. Radiology,
endoscopy
AST, ALT, bilirubin, prothrombin and blood
ionogramme with creatinine
EORTC QLQ-C30 and QLQ-OES18
Where indicated, according to the clinical and
laboratory context
- Thoracic and abdominal CT-scan with vertical length
measure (height) of the tumour, preferably on a spiral
scan.
TIME
Within 2 weeks
prior to inclusion.
Within 1 week
prior to inclusion.
Within 1 week
prior to inclusion.
Within 2 weeks
prior to inclusion.
Within 1 week
prior to inclusion.
Prior to inclusion
and within 5 weeks
before start of
treatment.
Prior to inclusion
- Barium swallow / esophagogram (double contrast if
possible) optional
- Esophagoscopy and biopsy (photos if possible)
- Bronchoscopy if primary tumor < 30 cm from incisors
to exclude fistula or broncho-tracheal invasion
- Transoesophageal ultrasound optional
7. ECG
Within 1 week
prior to inclusion.
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Evaluations during treatment
: Folfox arm
1. Clinical
examination
2. Hematology
3. Biochemistry
4. Toxicity/symptoms
5. Quality of life
6. Radiology,
endoscopy
INVESTIGATIONS
- Intercurrent events
- Concomitant treatments*
- Performance status (ECOG),
weight
- Complete neurological examination
- Vital signs, temperature if indicated
- Clinical evaluation
Alkaline phosphatase, AST, ALT,
bilirubin and creatinine
Evaluation of toxicity related to
treatment, dysphagia (see NCI-CTC
dysphagia and dysphagia due to
radiation)
- Thoracic and abdominal CT-scan
- Barium swallow/esophagogram
optional
- Esophagoscopy (photos if
possible)
- Transoesophageal ultrasound
optional.
TIME
Every 2 weeks (first day of each
chemotherapy cycle), then one
month after treatment
discontinuation, then every 3
months thereafter.
Weekly**
chemotherapy cycle)°
chemotherapy cycle) then 4
weeks after end radiotherapy,
then every 3 months thereafter.
At week 5 (D29) of
radiotherapy, At D1 of sixth
Folfox administration ;
The day of the realization of
the first evaluation of the
response (CT Scan) then every
6 months after treatment
discontinuation during one year
and once a year during 3 years.
Week 15 then every 6 months
thereafter. ∗∗∗
*
Detailed description of the concomitant treatment (drug, daily dose, method of administration, start and end
date, reason for administration, etc)
**
Twice per week in the case of severe neutropenia or thrombocytopenia
∗∗∗ Biopsy is not mandatory to confirm a complete response, but could be done if the investigator decides it.
° More often in the case of hepatic or renal to xicity. Surgery may be proposed to the patient by the investigator in
case of occurrence of a partial response at the end of the treatment (particularly if the patient was considered
previously inoperable for carcinologic reasons).
Surgery should not be proposed in case of occurrence of a complete response.
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: Herskovic arm
1. Clinical
examination
2. Hematology
3. Biochemistry
4. Toxicity/symptoms
5. Quality of life
6. Radiology,
endoscopy
INVESTIGATIONS
- Intercurrent events
- Concomitant treatments*
- Performance status (ECOG),
weight
- Complete neurological examination
- Vital signs, temperature if indicated
- Clinical evaluation
Alkaline phosphatase, AST, ALT,
bilirubin
Blood ionogramme with creatinine
Evaluation of toxicity related to
treatment, dysphagia (see NCI-CTC
dysphagia and dysphagia due to
radiation)
- Thoracic and abdominal CT-scan
- Barium swallow/esophagogram
optional
- Esophagoscopy (biopsy & photos if
possible)
- Transoesophageal ultrasound
optional.
TIME
First day of each chemotherapy
administration (weeks 1,5, 8
and 11), then one month after
treatment discontinuation, then
every 3 months thereafter.
Weekly**
cycle). °
The day of each Cisplatin
administration and the following
day)°
administration) then one month
after treatment discontinuation,
then every 3 months thereafter.
At week 5 (D29) of
radiotherapy, At D1 of fourth 5FU/Cisplatin administration ;
The day of the realization of the
first evaluation of the response
(CT Scan) then every 6 months
after treatment discontinuation
during one year and once a
year during 3 years.
Week 15 then every 6 months
thereafter.∗∗∗
*
Detailed description of the concomitant treatment (drug, daily dose, method of administration, start and end
date, reason for administration, etc)
**
Twice per week in the case of severe neutropenia or thrombocytopenia
∗∗∗ Biopsy is not mandatory to confirm a complete response, but could be done if the investigator decides it.
°
More often in the case of hepatic or renal toxici ty
Post treatment follow-up
After the end of study treatment (whatever the reason for discontinuation), the patient will be
followed for 4 weeks following the last cycle during which all procedures listed above will be
followed.
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From the date of discontinuation for a period of 30 days, all SAEs will be reported. In the case of
toxicity persisting after the end of treatment, the patient will be followed until full recovery or
stabilisation.
A tumor evaluation should be performed during the week 15 and then every 6 months until
progression. If, on week 15 any doubt exist about endoscopic complete response evaluation
(ulceration or stenosis), a new endoscopy for control will be necessary within 2 months. Evaluation
of dysphagia should be performed at the same intervals according to NCI common toxicity criteria
(see appendix 8).
As precised in paragraph 5.2.2, EORTC QLQ-C30 and QLQ-OES18 must be collected every six
months after treatment discontinuation during one year and once a year during 3 years.
If feasible, post-treatment follow-up must be pursued until patient's death.
RANDOMIZATION PROCEDURES
After signing the consent form and validating the results of the baseline inclusion examination,
eligible patients will be randomised by the trial randomization centre.
The investigator must fax the completed and signed randomization form to the management
centre of the company EURAXI Pharma, Biometrics Department. In return, the data management
Centre will fax the confirmation of randomization by specifying the treatment arm and patient
number.
The contact details of the randomization centre are:
Management of Randomization and Data-Management
Sébastien LOUVEAU
EURAXI PHARMA
Department of Biometrics
from Monday to Friday between 9 am and 4 pm
Fax: 02.47.74.30.82 Phone: 02.47.74.30.47
Treatment must begin within 28 days after randomization.
STUDY MEASUREMENTS
Completion of full treatment
A patient included in the Folfox arm is considered as having completed the treatment if he has
received three cycles of radiochemotherapy and three cycles of chemotherapy alone.
A patient included in the Herskovic arm is considered as having completed the treatment if he has
received two cycles of radiochemotherapy and two cycles of chemotherapy alone.
Tumor Response
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Patient Evaluability
Folfox arm : patients must have received a minimum of 3 cycles of chemotherapy and 50 Gy
radiotherapy to be considered evaluable for response unless early disease progression occurs.
Herskovic arm : patients must have received a minimum of 2 cycles of chemotherapy (week 1
and 5) and 50 Gy radiotherapy to be considered evaluable for response unless early disease
progression occurs.
Patients on therapy for at least this period will have their response classified according to the
definitions set out below.
Tumor assessment for all lesions must have been performed at baseline, week 15 and every 6
months on follow-up visits for patients off study for other reason than PD. It is essential to examine
all target lesions at every evaluation.
For inclusion, endoscopy, oesophagogram and CT-Scan have to be performed (if possible spiral
CT-Scan should be preferred).
The reference method is the CT scan. Oesophageal tumor must be evaluated according to the
vertical length of the tumor (height on CT scan or Barium swallow), maximal dimension of the
oesophageal tumor in the transverse plane on CT-Scan and the maximal thickness of the
oesophageal wall on CT scan. If measurement of the tumor height is not feasible on CT scan,
tumor height should be measured on oesophagogram (or endoscopy if oesophagogram is not
available).
Endoscopic complete response is defined by IDMC members as follow:
- All endoscopic reports before and after treatment must be available
- Disappearance of the tumor lesion and no stenosis
- No ulceration (slough)
- No budding
- No appearance of any lesion on endoscopy (or echo-endoscopy)
- No local progression on CT-Scan
If, on week 15, any doubt exists about complete response evaluation (ulceration or stenosis), a new
endoscopy for control will be necessary within 2 months.
At inclusion, impassable tumors during the endoscopy will be classified as ycT3 or ycT4 if the CT
scan shows an extension to the adjacent organs.
At each tumor evaluation, dysphagia must be evaluated using NCI common toxicity criteria
(appendix 9).
Disease Measurability : RECIST Criteria
Complete response (CR) : disappearance of all target lesions associated with the disappearance
of all non target lesions and the normalization of tumor marker level. The persistence of one or
more non-target lesion and/or maintenance of tumor marker level above the normal limits will lead
to the evaluation of the response as partial. CR is confirmed if determined by 2 observations no
less than 4 weeks apart.
Partial response (PR) : at least a 30% decrease of in the sum of the longest diameter of the
target lesions, taking as reference the baseline sum longest diameter or a CR associated with
abnormal tumor marker level and/or persistence of non target lesions as described above.
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Progressive disease (PD) : at least 20% increase in the sum of the longest diameter of target
lesions, taking as reference the smallest sum longest diameter recorded since the treatment
started or the appearance of one or more new lesions.
Stable disease (SD) : neither sufficient shrinkage to qualify for partial response nor sufficient
increase to qualify for progressive disease, taking as reference the smallest sum longest diameter
since the treatment started.
Development of brain metastasis : The development of brain metastasis will be considered as a
sign of progression, even if the disease is responding outside the brain.
However, the investigator may decide to continue the study drug until progression outside the
brain concomitantly with the most appropriate treatment of the brain metastasis (e.g.
radiotherapy).
Time-related Parameters
Progression-free survival
Will start from the day of randomization until the documentation of tumor progression, metastasis
diagnosis, esophageal second cancer or death form any cause.
Time to treatment failure
Will start from the day of randomization until the documentation of progression, treatment
discontinuation for : toxicity, patient’s refusal, patient lost of view or death.
Overall Survival:
Survival is measured from the day of randomization to death, last contact or cutoff.
Quality of life
Quality of life will be evaluated using EORTC QLQ-C30 and a validated disease-specific module
EORTC QLQ-OES18 (see sections 5.2.1 and 5.2.2). The investigators must explain to the patients
the interest in answering the questionnaire and identifie precisely for each of them the dates of
collect of these questionnaires (see paragraphs 5.2.1 to 5.2.3).
An identified person must be in charge of the collect of the questionnaires in each centre
and a second person must be designed in case of absence of the first one.
The first questionnaires must be given and explained to the patient before the inclusion.
The patient must complete it before the randomization.
During the treatment, the questionnaires must be redacted by the patient in the centre (day 29 of
radiotherapy and the day of the administration of the sixth cycle of Folfox or fourth cycle of 5FU/Cisplatin).
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After the end of the treatment, the questionnaires must be completed by the patient in the centre
at the moment of the visit control each 6 months during the first year and once a year the next 3
years.
If a patient refuses to complet a questionnaire, the reason must be précised on the questionnaire
by the person in charge of the collect.
Clinical research associate of the sponsor will send the collected questionnaires to the datamanagement service (a copy being conserved in the patient’s file).
6. SAFETY ASSESSMENTS
All patients having received at least one dose of chemotherapy and one fraction of radiotherapy
will be considered as evaluable for safety.
Safety parameters will include: description of toxic deaths, premature withdrawals from treatment
for toxicity, description of Adverse Events, Serious Adverse Events (SAE), and evaluation of
toxicity, using NCI-CTC version 3.
6.1
CONCOMITANT TREATMENT RESTRICTIONS
No concomitant anti-cancer therapy, no high-dose long-term corticosteroids, no Calcium
Gluconate/ Magnesium Sulfate infusions, no hematopoietic growth factors and no oesophageal
dilatation are allowed during the trial. All concomitant medications must be thoroughly documented
in the source data. Refrigerated headwear should be avoided during/after oxaliplatin infusion.
Appropriate antiemetic treatment should be prescribed, both preventatively and curatively for each
chemotherapy administration.
6.2
DATA MONITORING COMMMITTEE :
An independent Data Monitoring Committee (DMC) will be set up to review trial enrolment, safety
and efficacy of the administered treatments and dosimetric documents. The DMC, including 2
medical oncologists, 2 radiotherapists and a statistician not participating to the trial will convene at
least every 6 months to review safety (toxicities, treatment exposure, SAEs including the rate of
deaths on study i.e. within 30 days of last chemotherapy administration) and other issues related
to the appropriate conduct of the trial.
Statistical listings, tables and analysis will be performed by an external statistician who will provide
the results to the committee.
The DMC will participate, at the end of the phase II, to the discussion about the continuation of the
trial as a phase III randomized study (see paragraph 9, ‘statistical considerations’).
7. DRUG SUPPLIES
STUDY DRUGS
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Oxaliplatin and 5-FU/FA will be administered in accordance with standard procedures for these
cytotoxic agents at the institution.
Products will be prepared according to Good Chemotherapy Practises and the procedures
described below.
Oxaliplatin, 5-FU and folinic acid will be provided by the Sponsor. The other products will be taken
from the usual pharmacy stock.
This product will be labelled in accordance with article R.5123 of the Code of Public Health and
the Recommendations of Appendix 1 of European Good Manufacturing Practises.
This product will be distributed to the different pharmacies of the healthcare centres according
to Good Distribution Practices (GDP).
Traceability of all products used within the scope of this clinical study, whether they are
provided by the sponsor or the hospital pharmacy, must be guaranteed throughout the
duration of the study.
7.1.1 Oxaliplatin
Active Ingredient
Chemical name :
International non proprietary name :
Empirical formula :
Relative molecular weight :
Physical properties :
Trans-/-diaminocyclohexane oxalatoplatinum cis[oxalato(trans-/-1,2-diaminocyclohexane) platinum(II)]
Oxaliplatin
C8H14N2O4Pt
397.3
White to off white cake or powder
Slightly soluble in water
Very slightly soluble in methanol
Insoluble in ethanol and acetone
The pH of an aqueous solution of 2 mg/ml is between
4.8 and 5.7
Finished Product
Presentation and composition
Oxaliplatin is presented in the form of a white to off-white cake or powder contained in clear glass
vials sealed with a rubber stopper and an aluminium seal with a flip-off cover.
Oxaliplatin
Lactose monohydrate
Nominal volume of vial
100 mg vials
100 mg
900 mg
50 ml
Reconstitution
The freeze-dried powder is reconstituted by adding 20 ml of water for injection or 5 % glucose
solution and then by diluting in an infusion solution of 250 to 500 ml of 5% glucose solution.
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Dispose of any reconstituted solution that shows evidence of precipitation. Always use the
recommended solvants. Never administer undiluted solution.
RECONSTITUTION OR FINAL DILUTION MUST NEVER BE PERFORMED WITH SODIUM CHLORIDE SOLUTION.
Incompatibilities
Do not combine with alkaline medications or media which cause oxaliplatin to degrade.
Do not administer simultaneously by the same line. Flush line after oxaliplatin administration.
Do not use preparation or administration needles or intravenous sets containing aluminium
components. There is a risk of degrading oxaliplatin.
Precautions
All cancer chemotherapeutic agents should be handled with utmost care during preparation and
administration. They should not be prepared by pregnant or breast-feeding women or by persons
allergic to that agent. To avoid any form of physical contact with the drug by the health care
provider, gown, gloves and masks should be worn when appropriate. As a parenteral agent,
oxaliplatin should be prepared in a vertical-flow biologic safety cabinet. All equipment used to
prepare and administer the drug should be destroyed according to standard hospital procedures
for disposal of cytotoxic waste. Refer to hospital guidelines for any additional precautions that may
apply.
7.1.2 5-FU : Information can be found in the package insert.
7.1.3 Folinic acid : Information can be found in the package insert.
7.2 STORAGE CONDITIONS
Oxaliplatin :
- Freeze-dried powder : May be stored for three years at 25°C ; excursions permitted to 15°C to
30°C, not exceeding 30°C.
- Reconstituted solution : In 5% dextrose solution or water for injection and in the original vial, the
solution should be diluted immediately.
- Solution for infusion : After dilution in 250 to 500 ml of 5% dextrose solution, the shelf-life is 24
hours at 2°C to 8°C.
8. TRIAL DISCONTINUATION CRITERIA
The trial may be suspended or stopped by the sponsor after discussion with the coordinator at the
request of the Competent Authority and/or Committee for the Protection of Persons (CPP) for the
following reasons:
- Unexpected incidence and/or severity of toxicity,
- Insufficient recruitment of patients,
- Poor quality of collected data.
9. SERIOUS ADVERSE EVENT
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GENERALE DEFENITION
Any event is considered to be a serious adverse event (SAE) when it:
•
•
•
•
•
•
Results in death,
Is life-threatening,
Requires patient hospitalization or prolongs existing hospitalization,
Causes a permanent disability or a serious temporary incapacity,
Causes a congenital malformation, foetal malformation or an abortion,
Is medically significant.
The terms disability and incapacity correspond to any temporary or permanent, clinically
significant physical or mental handicap with an impact on the patient’s physical activity
and/or quality of life.
A medically significant event is any clinical event or laboratory result which the investigator
considers to be serious and which does not correspond to the above-defined criteria of
seriousness. Such an event may represent a risk to the patient and require medical intervention in
order to prevent an outcome corresponding to one of the above criteria of seriousness (for
example: overdosage, a second cancer, pregnancy and new facts may be considered to be
medically significant).
The following adverse events are not considered to be serious adverse events (SAE):
• Hospitalisation < 24 hours,
• Elective hospitalisation scheduled before the start of the trial and/or planned in the protocol
(biopsy, chemotherapy).
DEFINITION OF AN EXPECTED SERIOUS ADVERSE EVENT (E-SAE)
An ESAE is an event already mentioned in the most recent version of the investigator's brochure
or in the Summary of Product Characteristics (SPC) for medicinal products that have already been
granted marketing authorisation (MA). This definition also applies to the trial medicinal product
when it is administered off-label for a same population.
DEFINITION OF AN UNEXPECTED SERIOUS ADVERSE EVENT (U-SAE)
An USAE is an event not mentioned or with a different nature, severity or outcome from that
described in the investigator's brochure or in the Summary of Product Characteristics (SPC) for
medicinal products that have already been granted marketing authorisation (MA).
CRITERIA OF SEVERITY
The criterion of severity should not be confused with the criterion of seriousness which is
used to define the need for expedited reporting.
The severity of events will be assessed according to version 3.0 of the CTC-AE classification (cf.
appendix 7). The severity of adverse events not listed in this classification should be assessed
using the following terms:
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Mild (grade 1): does not affect the patient’s usual daily activity
Moderate (grade 2): disturbs the patient’s usual daily activity
Severe (grade 3): prevents the patient’s usual daily activity
Very Severe (grade 4): Requires life-support/is life-threatening
Death (grade 5)
RECOMMENDED PROCEDURE IN THE EVENT OF AN SAE
The investigator must inform the Therapeutic and Clinical Studies Office drug safety monitor (PVBECT) of all expected (ESAE) and unexpected (USAE) Serious Adverse Events, whether or
not these are caused by the research, occurring during the study or in the 30 days following the
last dose of complete treatment (pre-operative + surgery + post-operative).
All delayed Serious Adverse Events (occurring after this 30 day period) which may
reasonably be considered to be related to the study treatment(s) or research must be
reported with no time limit.
SAE must be reported by sending a fax, within 48 working hours of their observation to BECT
PV.
Bureau d’Etudes Cliniques et Thérapeutiques (BECT)
Pharmacovigilance
Tél. : 01 44 23 04 16 – Fax : 01 44 23 55 70
Courriel : [email protected]
using the SAE report form (cf appendix 7).
The investigator should note for each event:
• As clear a description as possible according to medical terminology,
• Its severity,
• Time of onset and termination of the event,
• Measures taken and the need or not for corrective treatment,
• If the trial treatment was discontinued,
• Its outcome, in the event of a non-fatal event, the clinical course must be followed up
until cure or return to previous condition or stabilisation of any sequelae,
• The causal relation between this event and the trial treatment or a constraint related to
the research (period without treatment, additional examinations requested for the
research etc.),
• The causal relation with the trial medication(s), the disease treated or any other
concomitant disease or treatment. The investigator must also enclose with the serious
adverse event report, whenever possible:
• A copy of the hospital discharge report or prolongation of hospital stay report,
• A copy of the autopsy report,
• A copy of all the results of the additional tests performed, including the relevant
negative results together with normal laboratory values,
• Any other document that the investigator considers to be useful and relevant.
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All these documents must be anonymized.
Complementary information may be requested (by fax, telephone or during a visit) by the
monitor.
In the event of an unexpected SAE which may reasonably be related to one of the study
treatments, the investigator will be asked to provide pharmacovigilance with additional information.
Nevertheless, any expected event with a different severity, outcome or incidence will be
considered to be unexpected by pharmacovigilance.
FOLLOW-UP OF SAE
The investigator is responsible for providing appropriate medical follow-up to patients until
resolution or stabilisation of the effect or until the death of the patient. This may sometimes involve
continuation of follow-up after the patient has left the trial.
The investigator should send this complementary information to BECT PV using an SAE report
form (by ticking the box “Follow-up n° X” to specif y that this concerns follow-up and is not an initial
report) within 48 hours of obtaining it. The final follow-up form should also be sent after resolution
or stabilisation of the SAE.
The investigator should keep the documents about a suspected adverse effect in order to be able
to complete the previous information whenever necessary.
He must answer requests for additional information from BECT PV in order to document the initial
case report.
Toxic Deaths
A toxic death is defined as any death to which toxicity is thought to have made a contribution. It
should be treated as an SAE.
10. COST AND EXCESS COSTS OF THE RESEARCH
Any additional expenses stipulated in article R.112-1 of the Code of Public Health are subject to an
agreement negotiated between the FNCLCC and the representative of the hospital, taking into
account the financial means available to the FNCLCC for its public promotion activity.
The FNCLCC however, ensures the organisation of the trial and provides the following items:
protocol, case report file, investigator's dossier; and oxaliplatin, acid folinic and 5-FU in the
FOLFOX arm supply of the study medications.
The equipment, treatments, or services provided by other partners, must be specified in the
clinical trial agreement.
11. QUALITY ASSURANCE
In order to guarantee the authenticity and credibility of the data in accordance with GCP, the
sponsor must set up a quality assurance system comprising:
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- Trial management according to the Federation’s procedures,
- Quality control of investigator site data by the monitor, whose role is to check the agreement
and consistency of data in the CRF by comparison with the source document,
- Possible audit of investigator centres.
12. OWNERSHIP AND CONFIDENTIALITY OF DATA
The investigator undertakes, for himself and all the persons involved in following up the conduct of
the trial, to guarantee the confidentiality of all information provided by the French National
Federation of Cancer Centres (FNCLCC) until the publication of the trial results. This
confidentiality agreement does not apply to information that the investigator may have to give to
patients within the scope of their participation in the trial or to information that has already been
published.
The investigator undertakes not to publish, disclose or use, either directly or indirectly in any way,
the scientific or technical information related to the trial.
However, pursuant to article R 5121-13 of the Code of Public Health, the centre and the
investigator may give information about the trial to the following:
- Minister of Health,
- Public health inspectors,
- Public health inspecting pharmacists,
- The General Director and Inspectors from Afssaps.
No written or oral comment about the trial may be made without the agreement of the sponsor and
the coordinator; all the information made available or obtained during the conduct of the trial
belongs, as of right, to the French National Federation of Cancer Centres which may use it as it so
wishes.
13. RULES FOR PUBLICATION
Publishing PRODIGE trials in good-quality medical journals within a short period of time is one
essential objective to achieve therapeutical progress. Publications must be carried out under the
direct supervision of the PRODIGE Coordinating Committee (PCC) that decides for:
-
the time for publishing the trial's preliminary and definitive results.
-
the writing committee composition (at most 5 members).
All information resulting from the trial are deemed confidential, at least until the sponsor,
the trial's principal investigator and statistician have proceeded to an appropriate analysis
and control.
The Coordinating Committee (PCC) may delegate its functions to the trial's principal investigator.
In any cases, the PCC validates the choices and insures that the time-delays are respected. A text
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submitted by the writing committee is considered as accepted if the PCC has not answered within
1 month after its submission.
The Writing Committee comprises:
- The investigator (or both investigators when they are two) who has written the initial project.
He/she will be first author unless decided otherwise.
- The statistician(s) who have analyzed the data.
- The most important contributors.
- Possibly, one expert who has brought essential contribution to the data analysis (biologist,
anatomopathologist, …)
-
-
-
-
•
The first author commits to submit an article for publication within a short period of time
fixed by the PCC. The time delay should not exceed one year after the trial has ended. In
case the first author has difficulty complying with the writing, the PCC will designate a new
writer who will subsequently become first author. Recourse to a medical writer can be
appropriately used and writing workshops organized for the first author in collaboration with
the statistician.
Before any publication is submitted, a comprehensive list of inclusions and investigators
per center will be kept at the disposal of all the investigators participating in the trial.
•
The publication authors are listed in the following order, according to the amount of work
and the number of patients included:
The first author.
The members of the Writing Committee (see definition above).
A limited number of investigators (1 per center) listed in order of their participation, in principle
only one investigator per center, excepted special centers for which 2 investigators may be
selected by the Steering Committee. This rule may be modulated to allow some small- and/or
medium-size centers that have included a large number of patients to be included in the list of
authors. The PCC will validate this process to insure that nobody is penalized.
The maximum number of authors will be defined as the limit fixed by the medical journals.
Whatever the number of included patients is, there will be at least one author representing
one of the two partners: FFCD or FNCLCC.
In case of a second publication or a substudy, the list of authors may differ from the initial
article and reflects the medical expertise involved in the research work. For instance, in the
RCT trials, an article dedicated to radiotherapy may be signed by the co-investigator
radiotherapists of the center that have included patients. The last author of this derived
publication (having possibly equally contributed) is the first author of the initial article.
The Prodige partnership must be cited in the title or after the list of authors. In case of a
cooperative trial, the first association that is quoted is the one that has initiated the trial and
the others are mentioned, in the order of their participation, under the condition that they have
included at least 5 % of the patients.
Beside exception, in all the trials sponsored or managed by FFCD, a member of the INSERM
Unit U866, if he/she is not already first author, will be last author in order to insure that his/her
work is accounted for by the INSERM. In that case, the author before the last one will be
signaled as 'having equally contributed', whenever it is applicable with respect to the
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-
concerned medical journals.
As a general rule, the statistician will be listed with the authors beyond the third position.
He/she may be the first or second author of a specific publication (derived article or substudy).
All participants who are not listed with the authors are cited at the end of the article. The Data
Manager will be also cited and he/she may be included in the list of authors if it is deemed justified
by the PCC. The various partners are thanked. The authors and the sponsor will receive a
manuscript for internal review before it is submitted to a journal. They commit to respond within a
period of 15 working days (30 days during the summer period). Beyond this delay their opinion and
critics will not be taken into account.
• Oral communication based on the trial's results:
With both the PCC and Steering Committee agreements, an investigator may, in his/her name,
present all or part of the results orally. As a general rule, the list of authors is the same as for
written articles, but the order of appearance of the authors may sometimes differ between articles
and oral communications and vary according to congresses. In some cases (multidisciplinary
studies, or pathological, biological, echo-endoscopic studies carried out in parallel with a Prodige
trial) other authors may be selected in function of their contribution. The PRODIGE partnership,
and possibly other associations, must be cited.
14. ETHICAL AND REGULATORY ASPECTS
The clinical trial must be conducted in accordance with the following texts:
- Ethical principles of the current version of the Helsinki declaration,
- Good Clinical Practices of the International Conference of Harmonization (ICH–E6, 17/07/96),
- European Directive (2001/20/EC) on the conduct of clinical trials,
- The Huriet law (n° 88-1138) of December 20, 1988 concerning the Protection of Persons
participating in Biomedical Research and modified by the Public Health law (n° 2004-806) of
August 9, 2004,
- The Data processing and Liberties law n° 78-17 of January 6, 1978 modified by law n° 2004-801
of August 6, 2004 concerning the protection of persons with regard to the processing of personal
data,
- Bioethics law n° 2004-800 of August 6, 2004.
15. COMMITTEE FOR THE PROTECTION OF PERSONS
Before conducting biomedical research on human subjects, the sponsor must submit the project
for review to the competent Committee for the Protection of Persons of the site where the coordinating investigator practises his activity.
The application for an ethics opinion on the biomedical research project is sent to the committee
by the sponsor.
Applications for substantial amendments to the preliminary drafts are also sent by the sponsor to
the committee for an approbation.
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16. COMPETENT AUTHORITY
Before conducting or requesting the conduct of biomedical research the sponsor of this research
must send the competent authority an authorisation application.
The timeframe for examination of the authorisation application, except for cell therapy products
with a timeframe of 90 days and gene therapy products with a timeframe is 120 days, cannot
exceed 60 days from the date of receipt of the complete dossier. The competent authority must
inform the sponsor if it has justified objections to the implementation of the research within 30 days
from the date of receipt of the complete dossier, and inform the committee for the protection of
persons concerned.
17. INFORMATION AND CONSENT OF PARTICIPANTS
Before conducting biomedical research on human subjects, their informed consent must be
collected in writing after they have been informed, by the investigator during a visit and after a
sufficient period of reflection.
The information intended for participants in the trial must include all the items defined in the law of
public health of August 9, 2004 and must be written in a simple way, in a language
comprehensible to the patient (cf appendix 8). After reading the information sheet, the participant
must initial all the pages and the original must be placed in the investigator file and a copy given to
the participant in the research.
The consent form must be dated and signed personally by the participant in the research and the
investigator (the original form is archived by the investigator and a copy is given to the participant).
The information sheet and informed consent forms (appendix 8) must be grouped together on the
same document in order to ensure that all the information is given to the participant in the
research.
In the case of trials performed in order to conduct genomic or proteomic analyses, the information
form must specify the type of research that will be carried out and the patient must be able to
accept or refuse the keeping of his biological samples for the purpose of scientific research.
18. SPONSOR’S RESPONSIBILITIES
In accordance with the Huriet law, the sponsor is responsible for:
-
-
-
Taking out a civil liability insurance policy to cover any harm or injury caused by this research
on subjects taking part (art. L.1121-7),
Paying the competent Regional Health and Social Affairs Management (DRASS) the fixed
charge for consulting the Independent Ethics Committee (CCPPRB) (Order of 7/5/91 and
13/12/01),
Sending the French Agency for the Safety of Health Products (AFSSAPS), the initial
declaration of intent describing the essential data of the research accompanied by the IEC
opinion (art. L.1123-8),
Informing the Directors (art. L.1123-10, R.5124) and Pharmacists (art. L.5125-19, R.5124-1) of
the hospitals concerned,
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Making available all the necessary information to conduct the research to the investigators (art.
R.5122),
- Informing AFSSAPS about any Serious Adverse Event that may be related to the research and
about any premature discontinuation of the study as soon as they are known (art. L.1123-8).
The sponsor must also draft a declaration on the data processing of personal medical data, to the
Advisory board and French Data Protection Agency (CNIL), in accordance with the conditions of
application of the simplified procedure (Law n°94-5 48 dated 1/07/94 completing Law n°78-17
dated 6/01/78).
The sponsor must ensure the archiving of essential study documents under conditions ensuring
their safekeeping for the minimal duration specified by GCP, which is 15 years after the end of
research.
The sponsor of the clinical trial is the person or entity taking the initiative to conduct biomedical
research on human subjects, ensuring management and checking that it is adequately funded.
The sponsor must be established in the European Community or if not, have a legal representative
in a member state.
-
19. INVESTIGATOR’S RESPONSIBILITIES
The principal investigator of each hospital involved undertakes to conduct the clinical trial in
accordance with the protocol approved by the CPP and competent authority.
The investigator must make no amendment to the protocol without the written authorisation of the
sponsor and without the CCPPRB and the competent authority giving their authorisation for the
proposed amendments
The principal investigator is responsible for:
- Providing the sponsor with his/her curriculum vitae and those of the Co-investigators,
- Identifying the members of the team participating in the trial and defining their responsibilities,
- Starting patient recruitment after authorisation from the sponsor,
Each investigator is responsible for:
- Collecting the informed consent form which has been personally dated and signed by the
participant in the research before any trial-specific screening procedure,
- Regularly filling in the case report files (CRF) for each patient included in the trial and allowing
the Clinical Research Associate (CRA), appointed by the sponsor, direct access to the source
documents in order to validate the data in the CRF,
- Dating, correcting and signing corrections of the CRF for each patient included in the trial,
- Accepting regular visits by the monitor and where necessary by the auditors appointed by the
sponsor or inspectors from the regulatory authorities.
All the trial documents (protocol, consent forms, CRFs, investigator’s dossier, etc…), and all the
original documents (laboratory results, X-rays, study visit reports, clinical examination reports, etc)
must be considered to be confidential and kept in a safe place. The Principal Investigator must
keep the data as well as a patient identification list for a minimum period of 15 years after the end
of the study.
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20. INTERRUPTION OF SUBJECT STUDY PERIOD
CIRCUMSTANCES
Subjects will discontinue treatment in the event of :
• Completion of treatment (as described in section 5.4.1);
• Disease progression (or death due to progressive disease) : the date and evidence for
disease progression will be documented in the medical record;
• Adverse event, treatment limiting toxicity, inter-current medical problem;
• Voluntary withdrawal, investigator’s decision;
• Interruption of treatment > 2 weeks.
The reason and date of discontinuation are to be documented in the CRF. The investigator should
complete all end of treatment procedures when a patient withdraws from treatment.
REPLACEMENT OF SUBJECTS
Ineligible or or non-evaluable patients will not be replaced ; the sample size is increased of 10% (4
patients in more in each arm) to include 80 evaluable patients in phase II.
A new calculation of the phase III population will be done at the end of the phase II.
21. STATISTICAL CONSIDERATIONS :
At the end of the first part of the trial (randomised phase II) on 88 patients (44 in each arm), the
decision to continue the study will be taken by the coordinator, the sponsor and the statistician of
the study, with the help of the Data Monitoring Committee. Three conditions should be fulfilled to
decide to continue the trial :
- Good inclusion rates (88 patients in less than 18 months).
- Completion of full treatment over 60 % in the experimental arm.
- Endoscopic complete response rate of Folfox arm equal or superior to the endoscopic
response rate of 5FU/Cisplatin arm.
If it is decided to continue the study as a phase III randomised study, the main objective will be to
increase the progression-free survival. With a global alpha risk of 5 % and 90% power, a period of
the inclusion of 48 months (28 months phase II and 20 months for the continuation) and a
minimum follow-up of 12 months, the inclusion of 169 supplementary patients (total of 266
patients; 133 in each arm) will be necessary to demonstrate an improvement of 20 % in
progression-free survival at three years (from 30 % in the Herskovic arm to 50 % in the Folfox
arm, based on phase II results). The corresponding number of events is around 144.
However, a new calculation of the number of patients can be done after the interim analysis to
adjust the sample size (this calculation could confirm the sample size or increase it).
The analysis of results will be done on the “intent to treat” basis (all patients randomised will be
included in the final analysis) and per-protocol (eligible and evaluable patients).
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PARAMETERS :
PHASE II :
Primary Endpoints : percentage of patients having completed the full treatment in the two arms ;
percentage of endoscopic complete response in the two arms.
Secondary Endpoints : description of safety profile of each arm using NCI-CTC scale.
Characterisation of toxicity, SAEs, and treatment withdrawals.
PHASE III :
Primary Endpoint : comparison of the progression-free survival between the two arms.
Secondary Endpoints : comparison of overall survival, complete response rate, incidence of
grade 3-4 toxicities and time to treatment failure between both arms.
Evaluation of the quality of life using EORTC QLQ-C30 (version 3) and a validated diseasespecific module QLQ-OES 18.
ANALYSIS POPULATION
Safety: All subjects having received at least one dose of chemotherapy or one fraction of
radiotherapy will be considered evaluable for safety.
Response rate will be analysed in the per-protocol population all eligible, evaluable patients. i.e.,
patients having received at least : 3 cycles and 50 Gy in the Folfox arm, 2 cycles of chemotherapy
(week 1 and 5) and 50 Gy in the Herskovic arm, or having progressed before the first evaluation.
An intent-to treat analysis (on all randomized patients) will be performed for all the endpoints.
For the analysis performed on eligible, evaluable patients, patients categorized as early death,
toxic death and progressive disease will be considered as treatment failure. Response will be
evaluated in all patients.
STATISTICAL METHODS
DEMOGRAPHICS :
Descriptive statistics (mean, median, standard deviation and 95% confidence interval, range of
value) will be used for this study.
EFFICACY :
Response rate will be reported with the 95 % confidence interval.
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Rate of progression-free survival, time to treatment failure, overall survival and the corresponding
curves will be computed using the Kaplan-Meier method. The rates will be reported with their 95%
confidence interval.
Efficacy parameters will also be subjected to further appropriate analysis, considering correlation
with factors or probable prognostic value such as patient PS at entry, histology type
(adenocarcinoma / squamous cell carcinoma / adenosquamous), location of the tumor, weight loss
at inclusion (> ou ≤ 10%), length of the tumor (≤ ou > 5 cm).
2
Response parameters will undergo univariate analysis using the pearson X test and multivariate
analysis via logistic regression. Univariate analysis of time parameters will be carried out using the
log-rank test and the Cox test for multivariate analysis.
SAFETY :
Descriptive statistics will be employed to characterise the toxicity, toxic death, SAE and toxicityrelated treatment discontinuation profiles.Toxicity will be analyzed per cycle and per patient ; the
rate of grade 3-4 toxicities will be compared using chi2 test.
QUALITY OF LIFE :
The analysis will consist in the comparison of the different scores of “Global health status/Qol”
(primary objective) and dysphagia, asthenia, pain and physical functions (secondary objectives).
INTERIM ANALYSIS :
One interim analysis is planned during the phase III after the occurrence of 72 of the 144 planned
events. For this analysis, comparative analysis on efficacy (progression-free survival, response
rate, survival) and safety will be performed. The results will be presented to the Data Monitoring
Committee. The results of this analysis will be given to the principal investigator only if the Data
Monitoring Committee proposes to stop the trial.
The Data Monitoring Committee will propose to the sponsor and the coordinator to stop accrual of
new patients and to publish preliminary results earlier than anticipated only if after interim analysis
of the trial one of the following conditions is met:
- The results show clearly that experimental arm is either beneficial (increase of
progression-free survival, p<0.0031) or harmful (p>0,84, decrease of survival and/or major toxicity
according to IDMC appreciation’s).
- All the data from this or other ongoing trials are convincing enough to influence the
practice of most physicians.
SAMPLE SIZE CALCULATION :
Standard randomized phase II/ III design.88 patients will be included in the phase II study (44 in
each arm) and 266 in the phase III (133 in each arm).
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Rubin J,Gallagher JG, Schroeder G et al. Phase II trials of 5-fluorouracil and leucovorin in patients with
metastatic gastric or pancreatic carcinoma.Cancer 1996 Nov1;78(9):1888-91
50.
Louvet C, de Gramont A, Demuyinck B et al. High dose folinic acid, 5-FU bolus and continuous infusion in poor
prognosis patients with advanced measurable gastric cancer. Ann Oncol 1991 ;2 :229-230
51.
Johnson PWM, Thompson PJ, Seymour MT et al. A less toxic regimen of 5-FU and high dose folinic acid for
advanced gastrointestinal adenocarcinoma.Br JCancer 1991 ;64 :603-5
52.
Machover D, Goldschmid E, Chollet P et al. Treatment of advanced colorectal and gastric adenocarcinoma with
5-FU and high dose folinic acid. J Clin Oncol 1986 ;4 :685-95
53.
Machover D. A comprehensive review of 5-fluorouracil and leucovorin in patients with metastatic colorectal
carcinoma. Cancer 1997;80(7):1179-87
54.
Roca E, et al. Intensive chemoradiotherapy for organ preservation in patients with resectable and nonresectable ooesophageal cancer. Eur J Cancer 1996;32A(3):429-32
55.
Seitz JF, et al. 5-fluorouracil, high dose folinic acid and mitomycin C in the treatment of advanced digestive
cancers. Bull Cancer 1994;81(2):134-7
56.
Stahl M, et al. 5-Fluorouracil, folinic acid, etoposide and cisplatin chemotherapy for locally advanced or
metastatic carcinoma of the ooesophagus. Eur J Cancer 1994; 30A(3): 325-8
57.
Highley MS, et al. High-dose folinic acid with 5-fluorouracil bolus and continuous infusion in the treatment of
advanced gastric and ooesophageal adenocarcinoma. Br J Cancer 1993;67(2):407-8
58.
Trudeau M, et al. A phase I study of escalating interferon alpha-2a combined with 5-fluorouracil and leucovorin
in patients with gastrointestinal malignancies. Acta Oncol 1993; 32(5):537-9
59.
Lovett D, Kelsen D, Eisenberger M, Houston C. A Phase II trial of carboplatin and vinblastine in the treatment of
advanced squamous cell carcinoma of the esophagus. Cancer 1991; 67: 354-6.
60.
Sternberg C, Kelsen D, Dukemen M, Leichman L, Heelan R. Carboplatin: a new platinum analog in the
treatment of epidermoid carcinoma of the esophagus. Cancer Treat Rep. 1985; 69 (11): 1305-7.
61.
Louvet C, Andre T, Tigaud JM, Gamelin E, Douillard JY, Brunet R, Francois E, Jacob JH, Levoir D, Taamma A,
Rougier P, Cvitkovic E, De Gramont A. Phase II study of oxaliplatin, fluorouracil and folinic acid in locally advanced or
metastatic gastric cancer. J Clin Oncol; 20 (23) : 4543-8.
62.
Phase II study of oxaliplatin (OX), fluorouracil (FU) and leucovorin (LV) in metastatic carcinoma of the
esophagus/gastric cardia. Mauer AM et al Proc Am . Soc. Clin. Oncol 2002; 21, 139a, abstract 554.
63.
A phase II study of oxaliplatin and weekly 24-hour infusion of high dose 5-fluorouracil and leucovorin (HDFL) in
the first-line treatment of inoperable locally advanced or recurrent/metastatic gastric cancers. Chao Y et al Proc. Am.
Soc. Clin. Oncol 2002; 21, abstract 651.
64.
Kim DY, Kim JH, Lee SH, Kim TY, Heo DS, Bang YJ, Kim NK. Phase II study of oxaliplatin, fluorouracil and
leucovorin in previously platinum-treated patients with advanced gastric cancer. Ann Oncol. 2003; 14 (3): 383-7.
65.
Schmid KE, Kornek GV, Schull B, Raderer M, Lenauer A, Depisch D, Lang F, Scheithauer W. Second-line
treatment of advanced gastric cancer with oxaliplatin plus raltitrexed. Onkologie. 2003; 26 (3): 255-8.
66.
Dolan K, et al. Allelotype analysis of ooesophageal adenocarcinoma: loss of heterozygosity occurs at multiple
sites. Br J Cancer 1998;78(7):950-7
67.
Meltzer SJ. The molecular biology of oesophageal carcinoma. Recent Results Cancer Res 1996;142:1-8
68.
Fink D, Nebel S, Aebi S, et al. The Role of DNA Mismatch Repair in Platinum Drug Resistance. Cancer Res.
1996;56: 4881-6
69.
Boland CR, Thibodeau SN, Hamilton SR, et al. A National Cancer Institute workshop on microsatellite
instability for cancer detection and familial predisposition: development of international criteria for the determination of
microsatellite instability in colorectal cancer. Cancer Res 1998;58: 5248-57
70.
Giacchetti S, Zidani R, Perpoint B, et al. Phase III trial of 5-fluorouracil, folinic acid, with or without oxaliplatin in
previously untreated patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 1997;16: 805a
71.
De Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first line
treatment in advanced colorectal cancer.J Clin Oncol 2000, 16, pp 2938-2947
72.
André T, Bensmaïne MA, Louvet C, et al. Multicenter phase II study of bimonthly high-dose Leucovorin, 5Fluorouracil infusion and Oxaliplatin for metastatic colorectal cancer resistant to the same leucovoron regimen (Folfox 3/
4). Journal of Clinical Oncology, 1999.17.(11).3560-3568
73.
Becouarn Y, Ychou M, Ducreux M, et al. Phase II Trial of Oxaliplatin as First Line Chemotherapy in Metastatic
Colorectal Cancer Patients. J Clin Oncol 1998;16: 2739-44
74.
Gamelin E, Le Bouil A, Boisdron-Celle M, et al. Cumulative Pharmacokinetic Study of Oxaliplatin , Administered
Every Three Weeks, combined with 5-Fluorouracil in Colorectal Cancer Patients. Clin Cancer Res 1997;3: 891-9
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75.
Levi F, Zidani R, Misset JL, for the International Organisation for Cancer chemotherapy. Randomized
multiCentertrial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. Lancet
1997 ; 350 : 681-86
76.
Chollet P, Bensmaïne MA, Brienza S, et al. Single Agent Activity of Oxaliplatin in Heavily Pretreated Advanced
Epithelial Ovarian Cancer. Ann.Oncol. 1996;7: 1065-70
77.
Misset JL, Chollet P, Vennin P, et al. Multicentric phase II-III trial of oxaliplatin versus cisplatin both in
association with cyclophosphamide in the treatment of advanced ovarian cancer: toxicity and efficacy results. Proc Am
Soc Clin Oncol 1997;16: 1266a.
78.
V. Dieras, P. Bougnoux, T. Petit, et al. Multicentic phase II study of oxaliplatin as single agent in
cisplatin/carboplatin + or – taxane-pretreated ovarian cancer patients. Annals of oncology 13: 258-266, 2002.
79.
Monnet I, Brienza S, Hugret F, et al. Phase II study of Oxaliplatin in poor prognosis non small cell lung cancer
(NSCLC). Eur J Cancer 1998;34: 1124-7.
80.
Raymond E, Buquet-Fagot C, Djelloul S, et al. Antitumor activity of oxaliplatin in combination with 5-fluorouracil
and the thymidilate synthase inhibitor AG337 in human colon, breast and ovarian cancers. Anti-Cancer Drugs 1997;8:
876-85.
81.
The meta-analysis group in cancer. Efficacy of intravenous continuous infusion of fluorouracil compared with
bolus administration in advanced colorectal cancer. J Clin Oncol 1998;16: 301-308.
82.
Khushulani NI, Leichman CG, Proulx G, Nava H, Bodnar L, Klippenstein D, Litwin A, Smith J. Nava E, Pendyala
L, Smith P, Greco W, Berdzik J, Douglass H, Leichman L. Oxaliplatin in combination with protracted-infusion
Fluorouracil and radiation : report of a clinical trialfor patients with esophageal cancer. J. Clin. Oncol. 2002; 20: 2844-50.
83.
Gergel TJ, Leichman L, Nava HR, Blumenson LE, Loewen GM, Gibbs JE, Khushalani NI, Leichman CG,
Bodnar LM, Douglass HO, Smith JL, Kuettel MR, Proulx GM. Effect of concurrent radiation therapy and chemotherapy
on pulmonary function in patients with esophageal cancer: dose-volume histogram analysis. Cancer J. 2002; 8(6) 45160
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APPENDICES
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Appendix 1
ECOG Performance Status Scales/Scores
ECOG or Zubrod scale
Karnofsky score
0
Asymptomatic and fully active
1
Symptomatic ; fully
ambulatory ; restricted in
physically strenuous activity
80-90%
2
Symptomatic ; ambulatory ;
capable of self-care ; more
than 50% of waking hours are
spent out of bed
60-70%
3
Symptomatic ; limited selfcare, spend more than 50%
of time in bed, but not
bedridden
40-50%
4
Completely disabled ; no selfcare ; bedridden
20-30%
100%
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Appendix 2
TNM classification for oesophageal carcinoma (ICD-O C15)
T1
T2
T3
T4
N1
M1
Lamina propria, submucosa
Muscularis propria
Adventitia
Adjacent structures
Regional*
Distant metastasis:
Lower thoracic oesophagus
M1a Celiac nodes
M1b Other distant metastasis
Upper thoracic oesophagus
M1a Cervical nodes
M1b Other distant metastasis
Mid-thoracic oesophagus
M1b Distant metastasis including non-regional lymph
nodes
* regional lymph nodes:
cervical oesophagus - cervical nodes including supraclavicular nodes.
intrathoracic oesophagus - mediastinal and perigastric nodes, excluding celiac nodes.
Rules for classification
Physical examination, imaging and/or surgical exploration should be used to classify patients by N and M. Primary tumor
should also be assessed by endoscopy, including bronchoscopy.
Anatomical subsites
Cervical oesophagus
Between lower border of cricoid cartilage and thoracic inlet (suprasternal notch),
18 cm from incisors
Upper thoracic oesophagus
Between thoracic inlet and tracheal bifurcation, 24 cm from incisors
Mid-thoracic oesophagus
Proximal half of oesophagus between tracheal bifurcation and esophagogastric
junction, lower border 32 cm from incisors
Lower thoracic oesophagus
Distal half of oesophagus between tracheal bifurcation and esophagogastric
junction, lower border 40 cm from incisors
V10 of 12/05/2009 containing amendement n°1-2-3-4-5- 6-7
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APPENDIX 3 : US TNM ECHOENDOSCOPIC CLASSIFICATION
(TIO TL and al, Gastroenterology 1989 ; 96 : 1478-86)
T1 : Tumor invading mucosea and submucosea
T2 : Tumor invading muscularis but not exceeding it
T3 : Tumor invading adventitia (or serous)
T4 : Tumor invading adjacent structures
N0 : No lymph node invasion
N1 : invaded peritumoral lymph nodes : round, with the same echogenicity than tumor
N2 : invaded distant lymph nodes (5 cm above or below the tumor inferior or superior pole).
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APPENDIX 4 : De Leriche and Fontaine Classification for arteritis
Stage I : no clinical symptom
Stage II : clinical symptoms during the effort
Stage III : clinical symptoms during the rest
Stage IV : necrosis.
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Appendix 5 : EORTC QLQ-C30
(version 3 )
Nous nous intéressons à vous et à votre santé. Répondez vous-même à toutes les questions en entourant le
chiffre qui correspond le mieux à votre situation. Il n'y a pas de "bonne" ou de "mauvaise" réponse. Ces
informations sont strictement confidentielles.
Merci de préciser:
Date de naissance (jour/mois/année):
Vos initiales : |__|__|__|
|__‫|__׀__׀ __׀__| |__׀__׀__| |__׀‬
La date d`aujourd`hui (jour/mois/année): 31 |__‫|__׀__׀ __׀__| |__׀__׀__| |__׀‬
Pas du
tout
Un
peu
Assez
Beaucoup
1. Avez-vous des difficultés à faire certains
efforts physiques pénibles comme porter un sac à
provision chargé ou une valise ?
1
2
3
4
2. Avez-vous des difficultés à faire une longue
promenade ?
1
2
3
4
3. Avez-vous des difficultés à faire un petit tour
dehors ?
1
2
3
4
4. Etes-vous obligé(e) de rester au lit ou dans un
fauteuil pendant la journée ?
1
2
3
4
5. Avez-vous besoin d'aide pour manger, vous
habiller, faire votre toilette ou aller aux toilettes ?
1
2
3
4
Pas du
tout
Un
peu
Assez
Beaucoup
6. Avez-vous été gêné(e) pour faire votre travail
ou vos activités de tous les jours ?
1
2
3
4
7. Avez-vous été gêné(e) dans vos activités de
loisirs ?
1
2
3
4
8. Avez-vous eu le souffle court ?
1
2
3
4
9. Avez-vous ressenti de la douleur ?
1
2
3
4
10.Avez-vous eu besoin de repos ?
1
2
3
4
11.Avez-vous eu des difficultés pour dormir ?
1
2
3
4
12.Vous êtes-vous senti(e) faible ?
1
2
3
4
13.Avez-vous smanqué d'appétit ?
1
2
3
4
14.Avez-vous eu des nausées (mal au coeur) ?
1
2
3
4
15.Avez-vous vomi ?
1
2
3
4
Au cours de la semaine passée :
Passez à la page suivante S.V.P
55/70
Pas du
tout
1
Un
peu
2
17.Avez-vous eu de la diarrhée ?
1
18.Etiez-vous fatigué(e) ?
Assez
Beaucoup
3
4
2
3
4
1
2
3
4
19.Des douleurs ont-elles perturbé vos activités
quotidiennes ?
1
2
3
4
20. Avez-vous eu des difficultés à vous concentrer
sur certaines choses, par exemple, pour lire le
journal ou regarder la télévision ?
1
2
3
4
21.Vous êtes-vous senti(e) tendu(e) ?
1
2
3
4
22.Vous êtes-vous fait du souci ?
1
2
3
4
23.Vous êtes-vous senti(e) irritable ?
1
2
3
4
24.Vous êtes-vous senti(e) déprimé(e) ?
1
2
3
4
25. Avez-vous eu des difficultés pour vous
souvenir de certaines choses ?
1
2
3
4
26. Votre état physique ou votre traitement
médical vous ont-ils gêné(e) dans votre vie
familiale ?
1
2
3
4
médical vous ont-ils gêné(e) dans vos activités
sociales (par exemple, sortir avec des amis, aller
au cinéma...) ?
1
2
3
4
médical vous ont-ils causé des problèmes
financiers ?
1
2
3
4
16.Avez-vous été constipé(e) ?
Pour les questions suivantes, veuillez répondre en entourant le chiffre entre 1 et 7 qui
s'applique le mieux à votre situation :
29. Comment évalueriez-vous votre état de santé au cours de la semaine passée ?
1
Très mauvais
2
3
4
5
6
7
Excellent
30. Comment évalueriez-vous l'ensemble de votre qualité de vie au cours de la semaine passée ?
1
Très mauvais
2
3
4
5
6
7
Excellent
© Copyright 1995 EORTC Study Group on Quality of Life. Tous droits réservés Version 3.0.
56/70
Appendix 6 : EORTC QLQ-OES18
Les patients rapportent parfois les symptômes ou problèmes suivants.
Pourriez-vous indiquer, s’il vous plait, si, durant la semaine passée, vous avez été affecté(e) par l’un
de ces symptômes ou problèmes
Entourez, s’il vous plait, le chiffre qui correspond le mieux à votre situation.
Pas du
tout
Un
peu
Assez
Beaucoup
31. Pouviez-vous manger des aliments solides ?
1
2
3
4
32. Pouviez-vous manger des aliments mixés ou
mous ?
1
2
3
4
33. Pouviez-vous boire des liquides ?
1
2
3
4
34. Avez-vous eu du mal à avaler votre salive ?
1
2
3
4
35. Vous-êtes vous étranglé(e) en avalant ?
1
2
3
4
36. Avez-vous eu du mal à apprécier vos repas ?
1
2
3
4
37. Vous êtes-vous senti(e) rassasié(e) trop vite ?
1
2
3
4
38. Avez-vous eu du mal à manger ?
1
2
3
4
39. Avez-vous été gêné(e) de manger devant
d’autres personnes ?
1
2
3
4
40. Avez-vous eu la bouche sèche ?
1
2
3
4
41. Avez-vous eu des problèmes de goût ?
1
2
3
4
42. Avez-vous eu du mal à tousser ?
1
2
3
4
43. Avez-vous eu du mal à parler ?
1
2
3
4
44. Avez-vous eu des acidités ou des brûlures
d’estomac ?
1
2
3
4
45. Avez-vous été gêné(e) par des renvois d’acide
ou de bile dans la bouche ?
1
2
3
4
46. Avez-vous eu des douleurs en mangeant ?
1
2
3
4
47. Avez-vous eu mal dans la poitrine ?
1
2
3
4
48. Avez-vous eu des douleurs dans le ventre ?
1
2
3
4
© QLQ-C30-OES24 Copyright 1999 EORTC Study Group on Quality of Life. Tous droits réservés (phase III module)
57/70
Appendix 7 – Serious Adverse Event form
58/70
59/70
Appendix 8 : Notice d’information et de consentement éclairé
(1)
NOTE D'INFORMATION DESTINEE AUX PERSONNES PARTICIPANT AU
PROTOCOLE DE RECHERCHE BIOMEDICALE
(1)
Toutes les pages de cette note d'information doivent être paraphées par le participant à la recherche et l'investigateur.
ACCORD 17/0707 – Prodige 5
ETUDE DE PHASE II / III COMPARANT LA RADIOCHIMIOTHERAPIE AVEC LE SCHEMA FOLFOX A LA
RADIOCHIMIOTHERAPIE PAR 5FU/CISPLATINE (SCHEMA HERSKOVIC) EN TRAITEMENT DE
PREMIERE LIGNE DES PATIENTS PRESENTANT UNE TUMEUR DE L’OESOPHAGE INOPERABLE
Promoteur : Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC), 101 rue de Tolbiac, 75654 PARIS CEDEX
13
Investigateur Coordonnateur : Pr. Thierry CONROY, Département d’oncologie médicale, Centre Alexis Vautrin, 6 avenue de
Bourgogne, 54511 Vandoeuvre-lès-Nancy cedex
Document constitué en application de la loi du 20 décembre 1988 relative à la protection des personnes participant à la
recherche biomédicale (Loi Huriet) et ses amendements ainsi qu'à la Loi du 6 janvier 1978 relative à l'Informatique, aux
Fichiers et aux Libertés et ses amendements.
Ce document ne peut faire l’objet d’aucun traitement informatique.
****
NOTICE D'INFORMATION
Avant de participer à cette étude de recherche biomédicale, il est important que vous lisiez ce document
fournissant les informations relatives au déroulement de cette étude.
Vous pourrez donner votre consentement après un délai de réflexion.
En participant à cette étude, vous contribuez à un effort de recherche qui pourra aider d’autres personnes.
60/70
A. BUT DE L’ETUDE
Le traitement de votre tumeur de l’œsophage nécessitera des perfusions (chimiothérapie), des rayons
(radiothérapie), et les 2 associés.
Nous vous proposons de participer à un projet de recherche conduit par le Docteur ....................... en
collaboration avec la Fédération Nationale de Centres de Lutte Contre le Cancer (FNCLCC), portant sur un
médicament de chimiothérapie, l’oxaliplatine, en association avec le 5-fluorouracile (5-FU), l’acide folinique
(association connue sous le nom FOLFOX) et la radiothérapie. Le but de cette étude est de montrer que le
FOLFOX associé à la radiothérapie est mieux toléré et aussi efficace que le traitement de référence,
l’association 5-FU/Cisplatine avec la radiothérapie.
Deux cent soixante six (266) patients seront traités dans différents centres français.
Les sels de platine (dont le cisplatine) en perfusion ont une efficacité connue dans les tumeurs de
l’œsophage, en association avec le 5-FU et la radiothérapie.
L’oxaliplatine est un nouveau sel de platine, qui pourrait être efficace dans votre cas. Il est utilisé dans le
traitement d’autres tumeurs avec de bons résultats. Le 5-FU est un médicament actif dans votre maladie et
connu depuis de nombreuses années. L’acide folinique est une vitamine qui augmente l’action du 5-FU; il a
déjà été utilisé dans des cas comme le vôtre. La tolérance de ces 3 produits de chimiothérapie en
association a été étudiée chez des dizaines de milliers de patients et est donc bien connue.
La radiothérapie (rayons) est un traitement des tumeurs de l’œsophage dont l’efficacité est prouvée. Cette
efficacité est augmentée par une chimiothérapie administrée en même temps.
B. DEROULEMENT DE L’ETUDE
VOTRE TRAITEMENT :
Le choix du traitement (association de la radiothérapie au FOLFOX ou au 5-FU/cisplatine) sera établi par
un tirage au sort centralisé dans l’ensemble de la France.
• Si vous devez recevoir l’association Folfox + Radiothérapie :
Le traitement durera 12 semaines. Vous aurez une séance de rayons quelques minutes par jour, 5 jours
par semaine pendant 5 semaines. Toutes les 2 semaines, vous recevrez également de la chimiothérapie
sur 2 jours: le premier jour de chaque cycle de chimiothérapie vous recevrez l’oxaliplatine en perfusion
intraveineuse pendant 2 heures, et l’acide folinique, aussi en perfusion de 2 heures.
Ensuite, le 5-FU sera administré en perfusion très courte, suivi par une perfusion continue de 46 heures,
par voie intraveineuse à l’aide d’une petite pompe portable.
Vous continuerez de recevoir de la chimiothérapie deux jours toutes les 2 semaines à trois reprises, après
la fin des rayons. Néanmoins le traitement sera interrompu en cas de mauvaise tolérance ou de refus de
votre part de le poursuivre.
• Si vous devez recevoir l’association 5-FU/cisplatine + Radiothérapie :
Le traitement durera 11 semaines. Vous aurez une séance de rayons quelques minutes par jour, 5 jours
par semaine pendant 5 semaines. Vous recevrez également quatre cycles de chimiothérapie sur 4 jours: le
premier jour de chaque cycle de chimiothérapie vous recevrez du cisplatine en perfusion intraveineuse puis
une perfusion continue de 5-FU d’environ 96 heures du premier au quatrième jour de chaque cycle.
Le deuxième cycle vous sera administré à la cinquième semaine, le troisième cycle à la huitième semaine
et le quatrième et dernier cycle à la onzième semaine.
Les doses de chaque médicament seront adaptées en fonction de votre tolérance au traitement.
Votre médecin vous préviendra de toute modification.
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SUIVI DU TRAITEMENT ET QUALITE DE VIE :
Les médecins responsables de votre chimiothérapie ou de vos rayons vous examineront régulièrement
avant l’administration de chaque cycle de chimiothérapie. A l’occasion de chacune de ces consultations, ils
prescriront les examens habituels nécessaires à la surveillance de votre état de santé et de votre
traitement. D’autre part, des prises de sang seront réalisées chaque semaine tandis que les radiographies,
scanners et endoscopies, eux, seront réalisés avant et 15 semaines après le début de votre traitement pour
évaluer l’efficacité du traitement. Par la suite, votre médecin suivra l’évolution de votre état de santé tous
les 3 mois.
Deux questionnaires de qualité de vie vous seront remis; nous vous demandons de bien vouloir répondre
soigneusement aux questions qui vous sont posées et de remettre régulièrement ces deux questionnaires
à l’équipe en charge de votre radio-chimiothérapie.
• Si vous êtes traité(e) par l’association Folfox-Radiothérapie : nous vous prions de les remplir avant le
début de votre traitement puis au premier jour de la cinquième semaine de traitement, au premier jour du
sixième cycle, lors de la première évaluation de l’efficacité de votre traitement puis tous les 6 mois pendant
une année et une fois par an pendant trois ans.
• Si vous êtes traité(e) par l’association 5-FU/cisplatine-Radiothérapie : nous vous serions reconnaissant
de les remplir avant le début de votre traitement puis au premier jour de la cinquième semaine de
traitement, au premier jour du quatrième cycle, lors de la première évaluation de l’efficacité de votre
traitement puis tous les 6 mois pendant une année et une fois par an pendant trois ans.
L’analyse de ces questionnaires est indispensable en vue de l’évaluation de votre qualité de vie en rapport
avec votre traitement et votre état de santé; aussi, nous vous demandons de ne pas oublier de les remplir.
C. EFFETS INDESIRABLES POTENTIELS DU TRAITEMENT
Comme vous le savez, toute chimiothérapie ou radiothérapie peut entraîner des effets indésirables, appelés
« effets secondaires ».
L’oxaliplatine est déjà commercialisé en France pour d’autres tumeurs. Des effets secondaires ont pu être
constatés chez certains patients. Tous ces effets secondaires sont le plus souvent réversibles.
•
Les effets indésirables les plus courants sont des nausées, vomissements ou diarrhée (qui peuvent
provoquer dans les cas sévères une altération de la fonction rénale et des complications intestinales
sévères), des aphtes, une perte de l’appétit ainsi qu’une modification de la sensibilité des extrémités
qui peut être provoquée ou aggravée par le froid. Si vous constatez une sensation anormale de
fourmillements, des douleurs au niveau des mains, des pieds ou une gêne pour réaliser certains
mouvements, avertissez immédiatement votre médecin. De même, des sensations de crampes ou des
troubles de la sensibilité de la région buccale ou de la gorge doivent être signalés à votre médecin.
•
D’autres effets indésirables peuvent être dus à une diminution des cellules sanguines. Il peut s’agir
d’une anémie (diminution des globules rouges), de saignements anormaux ou d’ecchymoses (baisse
des plaquettes), d’infections parfois sévères (diminution des globules blancs).
•
Une surveillance de la numération de la formule sanguine est donc nécessaire pendant le traitement
par l’oxaliplatine.
•
Très fréquemment, une fièvre peut survenir lors du traitement; la signaler à votre médecin.
•
On retrouve fréquemment des réactions allergiques lors de l’injection : éruption cutanée, conjonctivite,
rhinite, sensation de malaise, baisse de la tension artérielle, difficultés pour respirer.
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•
•
Rarement : on constate une diminution de la vue (qui doit être signalée immédiatement à votre
médecin), une diminution de l’audition, des troubles de la parole, une insuffisance rénale, l’apparition
de symptômes respiratoires ou une perte des cheveux.
Un contact du produit de perfusion au niveau de la peau peut provoquer des rougeurs légères.
Le 5-FU peut entraîner les effets suivants:
• Des aphtes (petites ulcérations) dans la bouche qui sont prévenus par des bains de bouche
systématiques;
• Des diarrhées;
• Une rougeur avec douleur des mains et des pieds et plus rarement la peau qui pèle;
• Des larmoiements, voire des conjonctivites;
• Des troubles de l’équilibre;
• Des douleurs au niveau de la poitrine;
• Une réaction allergique.
Lors d’un traitement par l'oxaliplatine et le 5-FU, des élévations des paramètres hépatiques lors des
examens sanguins de contrôle sont communément reportées. Ces élévations sont généralement de faible
sévérité et n'entraînent aucun symptôme que vous pouvez ressentir. Dans quelques cas, des symptômes
cliniques peuvent être associés avec ces élévations des paramètres hépatiques et consister en une
jaunisse, ascite (accumulation de liquide dans l'abdomen), une augmentation de volume du foie et/ou de la
rate.
Ces anomalies du foie et les symptômes cliniques peuvent être liés à votre maladie ou, dans de rares cas,
refléter un effet direct du traitement sur le tissu hépatique, qui pourrait inclure des modifications des
vaisseaux sanguins dans le foie (maladie veino-occlusive). Pendant la durée de l'étude, la fonction
hépatique sera contrôlée de façon régulière par des examens sanguins et, lorsque nécessaire (si un
dysfonctionnement hépatique ou des symptômes cliniques non reliés à votre maladie) surviennent, des
investigations complémentaires vous seront proposées.
L’acide folinique peut accentuer les effets secondaires du 5-FU.
La combinaison 5-FU-oxaliplatine et acide folinique (Folfox) peut entraîner la survenue des effets suivants:
• Des diarrhées, souvent modérées et bien contrôlées par un traitement anti-diarrhéique oral;
• Des aphtes dans la bouche, plus souvent qu’avec le 5-FU ou l’oxaliplatine seuls;
• Une diminution un peu plus importante du nombre des globules blancs pour laquelle les précautions à
prendre ont été détaillées plus haut;
• Une chute modérée des cheveux est rapportée chez moins de 2% des patients : lorsqu’elle survient, elle
est le plus souvent réversible.
L’addition des rayons à une chimiothérapie (Folfox ou 5-FU/cisplatine) peut entraîner la survenue des effets
suivants :
• Des rougeurs de la peau;
• Une perte d’appétit;
• Des nausées et vomissements;
• Des difficultés pour avaler;
• Une fatigue générale;
• Eventuellement d’autres effets secondaires que nous ne pouvons pas prévoir entièrement car
l’association de la radiothérapie avec l’oxaliplatine est un nouveau traitement.
Tous ces effets secondaires, dont nous tenons à vous donner le descriptif détaillé, sont le plus souvent
modérés et ne nécessitent pas l’arrêt du traitement. Ils ne justifient pas l’interruption systématique du
traitement. Il faut les signaler à votre médecin qui vous proposera l’attitude la plus adaptée à votre situation.
Les effets secondaires n’influencent en aucun cas l’efficacité du traitement.
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Le cisplatine peut entraîner les effets suivants :
• Une élévation du taux d’urée ou de la créatininémie, mais votre médecin vous administrera des
perfusions préventives à base de perfusions de sérum salé;
• Des bourdonnements d’oreilles et une baisse de l’audition;
• Une baisse du nombre de globules blancs et/ou de plaquettes ou de globules rouges;
• Des nausées et vomissements mais un traitement préventif sera systématiquement prescrit par votre
médecin, juste avant l’administration du traitement;
• Une élévation du taux d’acide urique;
• Des fourmillements dans les pieds et les mains, le plus souvent après des traitements prolongés (4 à 7
mois);
• Des réactions allergiques peuvent survenir dans les minutes qui suivent l’administration du cisplatine;
• Plus rarement, ont été observés des troubles cardiaques et une perte d’appétit.
Il est obligatoire d’utiliser une contraception pendant l’étude et les six mois suivants.
D. PROTECTION DES PATIENTS
Le médecin qui vous propose cette étude vous laissera le temps de réfléchir. Vous êtes libre de participer
ou non à cette étude. Vous pouvez vous réserver le droit à tout moment d’interrompre votre participation
sans que cela ne porte préjudice aux soins qui vous seront prodigués et sans avoir à en donner les raisons.
Ce protocole de recherche a été soumis au Comité Consultatif de Protection des Personnes se prêtant à la
Recherche Biomédicale de Lorraine qui a émis un avis favorable à sa réalisation le 27 Mai 2004.
Pour participer à cette étude, vous devez être bénéficiaire d’un régime de sécurité sociale en tant qu’assuré
ou ayant-droit. Vous ne serez inclus dans l’étude que si vous signez et paraphez ce consentement qui vous
est remis. Vous ne pourrez participer en même temps a une autre recherche biomédicale. Vous pouvez
ensuite vous retirer à tout moment de l’essai sans justification, sans conséquence sur la suite de votre
traitement ni sur la qualité des soins qui vous seront fournis et sans conséquence sur la relation avec votre
médecin ; vous pourrez être suivi par la même équipe médicale.
Le promoteur de cet essai qui en assure la gestion et la responsabilité est la Fédération Nationale des
Centres de Lutte Contre le Cancer (FNCLCC) située au 101, rue de Tolbiac, 75654 Paris Cedex 13 –
France. Elle en assure également la prise en charge globale.
La FNCLCC a pris toutes les dispositions prévues par la loi sur les Recherches Biomédicales
(anciennement Loi Huriet- décret d’application 2006-477 du 26 avril 2006 modifiant le titre II du livre 1 du
Code de la Santé Publique) relative à la protection des personnes se prêtant à des recherches
biomédicales.
La FNCLCC devant assumer l’indemnisation des éventuelles conséquences dommageables de la
recherche biomédicale pour la personne qui s’y prête, a souscrit une assurance de recherches
biomédicales, conformément à la législation en vigueur (n° de contrat 906812007009 Protocole
ACCORD 17 / 0707), auprès de la Société Gerling France (111-113 rue de Longchamp, 75016 Paris – Tél.
01 44 05 56 00)
Lorsque la responsabilité du promoteur n’est pas engagée, les participants peuvent être indemnisés auprès
de l’ONIAM, (Office National d’Indemnisation des Accidents Médicaux, 36, Avenue du Général de Gaulle,
93175 BAGNOLET Cedex , N° Vert : 0800 779 887).
Votre dossier médical restera confidentiel et ne pourra être consulté que sous la responsabilité du médecin
s’occupant de votre traitement ainsi que par les autorités de santé et par des personnes dûment
mandatées par le promoteur de l’essai et soumises au secret professionnel.
Dans le cadre de la recherche biomédicale à laquelle il vous est proposé de participer, un traitement
automatisé et anonymisé de vos données personnelles va être mis en œuvre pour permettre d’analyser les
64/70
résultats de la recherche au regard de l’objectif de cette dernière qui vous a été présenté. A cette fin, les
données médicales vous concernant et les données relatives seront transmises au Promoteur de la
recherche ou aux personnes ou sociétés agissant pour son compte, en France ou à l’étranger. Ces
données seront identifiées par un numéro de code et/ou vos initiales. Ces données pourront également,
dans des conditions assurant leur confidentialité, être transmises aux autorités de santé françaises ou
étrangères.
Conformément aux dispositions de loi relative à l’informatique et aux libertés (loi n° 78-17 du 6 janv ier 1978
modifiée par la loi n° 2004-801 du 6 août 2004) vou s disposez d’un droit d’accès, de rectification et
d’opposition relatif au traitement de vos données personnelles. Ces droits s’exercent auprès du médecin en
charge de la recherche qui seul connaît votre identité. Vous pouvez également accéder directement ou par
l’intermédiaire d’un médecin de votre choix à l’ensemble de vos données médicales en application des
dispositions de l’article L 1111-7 du Code de la Santé Publique.
Les informations concernant votre identité seront tenues confidentielles par votre médecin.
De plus, vous serez informé, à votre demande auprès du médecin qui vous a pris en charge, des résultats
globaux de l’essai par l’investigateur.
Enfin, il est également important de vous signaler que vous pouvez avoir accès à des informations sur
l’essai en consultant le site Internet de la Fédération (http://www.fnclcc.fr/)
E. A QUI DEVEZ-VOUS VOUS ADRESSER EN CAS DE QUESTIONS OU DE PROBLEMES ?
En cas de problèmes, d’événements indésirables en cours d’essai ou de questions, vous pouvez-vous
adresser aux personnes suivantes :
Vos contacts dans l’étude (titre, nom, prénom, adresse et téléphone) :
……………………………………………………………………………………………………………………………
……………………………………………………………………………………………………………………………
Coordonnées du médecin référent du patient
……………………………………………………………………………………………………………………………
……………………………………………………………………………………………………………………………
Votre médecin traitant sera tenu informé de votre suivi dans cet essai par votre médecin investigateur
65/70
FORMULAIRE DU RECUEIL DE CONSENTEMENT
ACCORD 17/0707 – Prodige 5
ETUDE DE PHASE II / III COMPARANT LA RADIOCHIMIOTHERAPIE AVEC LE SCHEMA FOLFOX A
LA RADIOCHIMIOTHERAPIE PAR 5FU/CISPLATINE (SCHEMA HERSKOVIC) EN TRAITEMENT DE
PREMIERE LIGNE DES PATIENTS PRESENTANT UNE TUMEUR DE L’OESOPHAGE INOPERABLE
Je soussigné(e) :
Nom :………………………………………….Prénom :………………………………………………….
Adresse :……………………………………………………………………………………………………
CONSENS EXPRESSEMENT A PARTICIPER A CETTE RECHERCHE DANS LES
CONDITIONS QUI M’ONT ETE PRECISEES DANS LA FICHE D’INFORMATION.
J'ai été bien informé(e) des objectifs de cette étude et de ses conditions de réalisation, ainsi que des
risques qu’elle pourrait comporter. J’ai eu réponse à toutes mes questions concernant l’étude. Je sais que
mon médecin doit me communiquer, à tout moment pendant et après ma participation à l'étude, toute
nouvelle information concernant l'étude ou tout dommage éventuel qui y serait lié.
J’ai donné librement mon consentement pour participer à cette étude et je sais que j'ai le droit de me retirer
à tout moment de cette étude, sans préjudice d'aucune sorte.
J'accepte que, pour le besoin de l’étude, le promoteur et/ou les Autorités Sanitaires puissent accéder
directement aux documents médicaux originaux pour vérifier les procédures cliniques et/ou les données
sans violation de la confidentialité.
J’accepte que les données médicales enregistrées à l’occasion de cette recherche, puissent faire l’objet
d’un traitement informatisé par le promoteur ou pour son compte. J’ai bien noté que le droit d’accès prévu
par la loi « Informatique et Liberté » (article 40 et suivants) s’exerce à tout moment auprès du médecin de
l’étude. Je pourrais exercer mon droit de rectification auprès de ce même médecin.
J’ai reçu une copie du présent document et j’ai été informé(e) qu’une copie sera également conservée par
le médecin qui me propose de participer à cette étude, dans des conditions garantissant la confidentialité,
et j’y consens.
Mon consentement ne décharge pas de leurs responsabilités les organisateurs de la recherche. Je
conserve tous mes droits garantis par la loi.
Je déclare avoir répondu à toutes les questions qui m'ont été posées à propos de mes antécédents
médicaux et je m'engage à suivre toutes les consignes et instructions qui me seront données par l'équipe
médicale et qui sont détaillées dans la notice d'information.
•
______________________________________________
Nom du patient ou de son représentant légal
I__I__I I__I__I I200__I
Date
•
______________________________________________ I__I__I I__I__I I200__I
Nom du médecin investigateur ou du médecin qui le Date
représente (co-investigateur)
______________________________
Signature
______________________________
Signature
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Appendix 9 – NCI-Common Toxicity Criteria version 3.0
Se référer à l’échelle d’évaluation de la toxicité CTCAE qui est jointe séparément et que l’on peut
télécharger sur le site du NCI
http://ctep.cancer.gov/
Common Terminology Criteria for Adverse Events v3.0 (CTCAE)
(Publish Date December 12, 2003)
CTCAE v3.0, a new version of the CTEP, NCI CTC v2.0, includes Adverse Events applicable to all
oncology clinical trials regardless of chronicity or modality.
67/70
Appendix10 – Résumé des Caractéristiques du (des) Produit (s)
Les RCP des produits (à préciser) sont joints séparément.
Se référer aux dernières versions en vigueur sur le site des agences réglementaires Afssaps,
EMEA ou sur le site du VIDAL :
http://agmed.sante.gouv.fr/
http://www.emea.eu.int/
http://www.vidalpro.net/
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Appendix 11 – Siewert Classification 1998 : tumour center lying
Type I
:
> 1 cm – 5 cm above GEJ
Usually Barrett’s adenocarcinomas
Type II
:
1 cm above to 2 cm below GEJ
= true carcinoma of the cardia
Type III
:
tumour center 2 to 5 cm below GEJ
= subcardia, proximal gastric center
From Siewert JR, Stein HJ, Br J Surg 1998; 85 : 1457-9
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Le protocole de l`étude

Transcription

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