.
Coordinators : J.P. SCULIER
Writing committee : J.P. SCULIER, J.J. LAFITTE, T. BERGHMANS, C. MASCAUX,
M. PAESMANS
P. MOMMEN
M. PAESMANS
Data manager :
Statistician :
Proposed : April 1999
Activated :

INDEX
1.
Group
2.
3.
Introduction
Study objectives
4. Study population
5.
Study design
6.
Investigations
7.
Treatment plan
8.
Trial quality control
9.
Drug procurement, preparation, storage and side effects
9.1
Etoposide
9.2
Cisplatin
9.3
Ifosfamide
9.4
Epirubicin
10.
Dose adaptation plan
11.
Criteria of evaluation
11.1
Measurability of the disease
11.2
Response criteria
11.3
Death
11.4
Toxicity
12. Off treatment regimen and off study definitions and procedures
12.1
Treatment regimen
12.2
Off treatment regimen
12.3
Off trial
13. Entry and randomisation procedures
14.
Data management and trial coordination
15.
Ethical considerations
16.
Statistical considerations
17.
Publication and authorship
18. References
Appendix I :
Appendix II :
Performance scale (Karnofsky)
Staging classification
Appendix III :
Appendix IV :
WHO's Criteria of toxicity.
The World Medical Association Declaration of Helsinki.
2

1. GROUP
Belgium
Bruxelles Institut Jules Bordet J. Klastersky,
J.P. Sculier,J. Body,.
M. Paesmans, P. Van
Houtte, E. Markiewicz,
P. Mommen, A.
Awada, D. Cullus, D.
Devriendt, T.
Berghmans, P.
Vermylen
Hôpital Brugmann
Hôpital Erasme
A. Drowart,
T. Prigogine
P. Rocmans,
S. Luce
Hôpital St Pierre
Boussu
Charleroi
Namur
Tournai
Hôpital de Warquignies
Hôpital civil de Charleroi
Clinique St Luc
Montignies-le- Tilleul C.H.U. A. Vesale
Hôpital de la Madeleine
Ath
IMC Mutualités Socialiste
Braine- l'Alleud
Mons
Hôpital de Braine l'Alleud
C.H. de Mons
Baudour
La Louvière
Clinique Louis Caty
C.H. de Tivoli
Verviers C.H. Peltzer-La Tourelle
R. Sergijsels,
V. Ninane,
T. Bosschaerts
M. Richez,
J. Thiriaux,
J. Lecomte,
O. Van Cutsem,
M. Mairesse
D. Brohée,
I. Louviaux
P. Ravez
A. Tagnon,
G. Nuttin
C. Finet
P. Wackenier,
P. Recloux,
C. Juquelier,
M. Thirion
V. Richard,
D. Diana
J. Michel,
J. Bruart,
A. Renaud,
A. Leleux
J.L. Corhay

Jumet
France
,
Douai
Hayange
Roubaix
Lille
Henin Beaumont
Dunkerque
Anzin
Montfermeil
Metz
Valenciennes
Boulogne s/Mer
Tourcoing
Hôpital Civil de Jumet
C.H. de Douai
Centre Pasteur
Hôpital d'Hayange
C.H. de Roubaix
Clinique de la Louvière
Hôpital A. Calmette
Polyclinique de H-B
Centre Oscar Lambert
Cabinet de Pneumologie
Centre Hospitalier de Dunkerque
Cabinet Médical Dampierre
C.H.I. de Montfermeil
Centre Hospitalier Régional de Metz-Thionville
Clinique Médico-Chirurgicale
Hôpital de Valenciennes
Hôpital Duchenne
Centre Hospitalier de Tourcoing
Cabinet de Pneumo-Allergologie
Cabinet de Pneumologie
A. Wattiez
M.C. Florin,
E. Maetz,
A.
Strecker
M. Guiselin
M.C. Berchier
F. Kroll,
F. Steenhouwer
F. Fortin,
J.M. Dernis,
J. M. Grosbois
J.J. Lafitte
R. Roboubi
B. Prévost
C. Deroubaix,
B. Mellin,
C. Rousselot
E. Lelieur,
V. Montagne,
E. Poret,
G.X. Trochu
B. Stach,
J.P. Roux
C. Zacharias
E. Barthelmé
G. Demarcq
M.L. Line,
P. Coleaux
J.L. Crépin
X. Ficheroulle
J.L. Duriez
Y. Watrigant
4

Marcq en Baroeul
Lens
Arras
Bethune
Italy
Padoue
Spain
Valence
Greece
Athènes
Hungary
Czech Republic
Brno
Prague
Slovak Republic
Kosice
Cabinet Médical des Flandres
Centre Hospitalier du Dr Schaffner
Centre Hospitalier d’Arras
Centre Hospitalier Germon & Gauthier
De Bethune
Registro Tumori del Veneto
Hospital de Sagunto
Hellenic Cancer Intitute
Evangelismos General Hospital
National Koranyi Institute
Institut Masaryk d'Oncologie
Charles University Medical Faculty
Klinika Radiotherapie a Onkologie
E. Mensier
J. Amourette
J.F. Bervar,
F. Herengt,
Y. Lierman
C. Verkindre
L. Simonato
V. Giner Marco,
A. Galan Brotons
A. Efremidis,
G. Koumakis
C.G Alexopoulos,
M. Vaslamatzis
J. Moldvay
H. Coupkova
L. Petruzelka
J. Baumöhl
5

2. INTRODUCTION.
Chemotherapy has been a major advance in the treatment of small cell lung cancer (SCLC). It has not only resulted in high objective (75-95%) and complete (20-40 %) responses rates but also and mainly in significantly prolonged survival. However, only a minority of the patients can be considered as cured. Five-year overall survival is about 5 % and there are 10 times more long-term survivors in patients with limited disease (LD) than in those with extensive disease (ED).
Standard treatment today consists in a combination of chemotherapy and radiotherapy for limited disease and in polychemotherapy for extensive disease, that represents lesions that can not be encompass in a single radotherapy field. There is however no consensus about the type of chemotherapy regimen to be used. Americans mainly recommend “cisplatin and etoposide” like regimens and Europeans “cyclophosphamide-adriamycin-etoposide” like combinations. The
European Lung Cancer Working Party is currently using the first regimen in its trial for limited disease and has shown in randomised trials that epirubicin is associated with better cardiac tolerance than adriamycin when combined to ifosfamide and etoposide (1).
As there is no good randomised trial comparing the so-called standard regimen, our Group performed a meta-analysis of the literature on the topic with a methodological quality assessment of the studies. We selected published randomised trials (from 1980 to 1998) comparing first-line regimens. Trials methodology was assessed by the Chalmers and ELCWP scores. For each trial, we estimated the hazard ratio (HR) of the survival distributions on the basis of reported statistics or, if not available, by extracting, from the survival graphical representations, the data required to construct the difference between expected and observed numbers of events as calculated in the logrank statistic.
We identified 36 eligible trials classified into 4 groups: I : 1 trial testing a CDDP-based regimen against another arm without CDDP or VP16; II : 17 a VP16-based regimen (without CDDP) against a regimen without VP16; III : 9 a regimen including CDDP/VP16 to a regimen without these drugs;
IV : 9 trials a regimen based on both drugs to a VP16 only regimen. Their global reported results are summarised in table I.
Table 1. Type of trials and results summary.
Group Randomised comparison N of eligible trials P < 0.05 for survival
1 CDDP vs no CDDP 1 0
2
3
VP16 vs no VP16
CDDP + VP16 vs none of 2
17
9
5
5
4 CDDP + VP16 vs VP16 9 2
Overall, Chalmers and ELCWP scores correlated well (r
S
=0.76, p<0.001) with respective median scores of 50.3% and 63.7 %. The number of eligible patients did not have a significant impact on the scores as well as the trials group, the trials positivity (a positive trial defined as showing itself a survival benefit for one of the tested drugs) overall or in categories, the year of publication A combined hazard ratio was obtained by the Peto method (a value < 1 meaning a benefit for CDDP and/or VP16). Table 2 summarised the meta-analysis.
6

Table 2. Meta-analysis of the literature.
Group 1
TRIAL
Kanitz (1992) (2)
Group 2
TRIAL
Daniels (1984) (3)
Livingston (1984) (4)
Lowenbraun (1984) (5)
Hirch (1987) (6)
Messeih (1987) (7)
Jackson (1988) (8)
Everson (1989) (9)
Hong (1989) (10) LD
ED
Mc Illmurrray (1989) (11)
Ettinger (1990) (12)
Jett (1990) (13)
Nikkanen (1990) (14)
Jones (1991) (15)
Nou (1992) (16)
Postmus (1992) (17)
Erkisi (1993) (18)
Abratt (1995) (19)
OVERALL
HR
0.70
0.64
0.85
1.13
0.90
0.68
0.63
0.46
1.39
0.77
0.81
0.71
HR
0.56
1.00
0.94
0.85
0.75
0.57
1.21
0.82
1.00
0.57
0.80
0.69
0.54
0.60
0.73
CI 95%
0.41 - 1.21
CI 95%
0.39 - 0.79
0.39 - 0.79
0.71 - 1.26
0.60 - 1.20
0.51 - 1.10
0.39 - 0.84
0.35 - 1.18
0.62 - 1.16
0.82 - 1.56
0.49 - 1.66
0.33 - 1.42
0.41 - 0.98
0.28 - 0.74
0.79 - 2.45
0.65 - 0.91
0.61 -1.06
0.45 - 1.14
0.68 - 2.16
0.46 - 1.46
0.54 - 1.85
0.28 - 1.14
0.46 – 1.37
0.41 - 1.17
1.19 – 1.50
0.32 – 1.13
0.67 – 0.78
P<0.001
7

Group 3
Evans (1987) (20)
Haveman (1987) (21)
Einhorn (1988) (22)
Fukuoka (1991)(23)
Wampler (1991) (24)
Monnet (1992) (25)
Roth (1992) (26)
TRIAL HR
0.74
0.68
0.60
0.96
0.71
0.76
1.64
0.25
0.65
0.45
0.91
0.57
CI 95%
0.54 – 1.00
0.52 – 1.00
0.41 – 0.89
0.72 – 1.30
0.52 – 0.96
0.55 – 1.03
0.79 – 3.41
0.08 – 0.80
0.11 – 3.80
0.27 – 0.75
0.64 – 1.31
0.51 – 0.64
P<0.001
Farris (1993) (27)
Veronesi (1994) (28)
OVERALL
Group 4
Wolf (1987) (29)
Goodman (1990) (30)
Sculier (1990) (31)
Smith (1991) (32)
Sculier (1993) (33)
Joss (1994) (34)
Kosmidis (1994) (35)
Joss (1995) (36)
Souhami (1997) (37)
TRIAL HR
0.64
0.94
0.95
0.95
0.87
0.71
0.94
0.95
0.45
0.59
CI 95%
0.42 – 0.97
0.76 – 1.16
0.72 – 1.27
0.53 – 1.71
0.66 – 1.15
0.47 – 1.07
0.62 – 1.44
0.63 – 1.44
0.26 – 0.77
0.39 – 0.89
OVERALL 0.74 0.66 – 0.83
P<0.001
Combined hazard ratios with 95% confidence intervals were : 0.70 (0.41-1.21) for group I, 0.73
(0.67-0.78) for group II, 0.57 (0.51-0.64) for group III, 0.74 (0.66-0.83) for group IV, justifying with high significance levels, the use of both drugs. Overall survival benefits could also be shown for CDDP (HR=0.61, CI : 0.57-0.66) as well as for VP16 (HR=0.65, CI : 0.61-0.69). Robustness of these results has to be confirmed by randomised trials. The purpose of the present trial is thus an attempt to confirm the superiority of the cisplatin- etoposide combination over an etoposidecontaining regimen without cisplatin as often used in Europe. We have chosen the IVE regimen with epirubicin and etoposide as shown in our prior trials (1, 38).
3. STUDY OBJECTIVES.
3.1. Primary endpoint. to determine if a cisplatin-etoposide regimen improves survival in comparison to a regimen containing etoposide and without platinum derivative.
8

3.2. Secondary endpoints.
to compare the response rates obtained with both regimens
to determine the toxicities of both treatment approaches.
4. STUDY POPULATION.
4.1. Criteria of eligibility include:
Histological or cytological diagnosis of small-cell lung cancer
Extensive disease (i.e. a disease with distant metastases or that cannot be included in a single irradiation field incorporating primary tumour, mediastinum and supraclavicular lymph node(s))
Availability for participating in the detailed follow-up of the protocol
Presence of an evaluable or measurable lesion
Informed consent
4.2. Criteria of ineligibility include :
Prior treatment with chemotherapy, radiotherapy or surgery
Performance status < 60 on the Karnofsky scale
A history of prior malignant tumour, except non-melanoma skin cancer or in situ carcinoma of the cervix or a cured cancer (defined as a disease-free interval > 5 years)
White blood cells < 4000/mm3
Platelets < 100000/mm3
Serum bilirubin > 1.5 mg/100 ml
Serum creatinine > 1.3 mg/100 ml and creatinine clearance <60 ml/min
Recent myocardial infarction (less than 3 months prior to date of diagnosis)
Congestive cardiac failure or cardiac arrhythmia uncontrolled by medical treatment
Uncontrolled infectious disease
Serious medical or psychological factors which may prevent adherence to the treatment schedule
5. STUDY DESIGN.
Eligible patients will be randomised between :
A.
The cisplatin-etoposide regimen (CE): cisplatin (90mg/m2 d1) plus etoposide (100mg/m2 d1
to 3).
B.
The ifosfamide-etoposide-epirubicin regimen (IVE): epirubicin (60 mg/m² d1) plus etoposide
(100mg/m2 d1 to 3) plus ifosfamide (1.5 g/m² d1 to 3).
Courses have to be repeated every three weeks. Evaluation of response will be performed after 3 courses of chemotherapy. In case of no response, patients are off treatment. In case of response, chemotherapy is administered until complete response or unacceptable toxicity or best response, defined as non improved response by three further courses of chemotherapy. A minimum of six courses has to be given. Response has to be assessed every 3 courses. At relapse, if the delay since the last course of chemotherapy is more than 6 months, the same chemotherapy regimen as initially will be given again. Otherwise, patients will be off trial.
9

6. INVESTIGATIONS
6.1.Initial investigations :
- Clinical examination completed by weight, height, surface area and record of performance status.
- Biological tests including haemoglobin, white blood cell count, differential count, platelet count; serum urea, creatinine; serum bilirubin, alkaline phosphatase, SGOT, SGPT, LDH; calcium, magnesium, uric acid, electrolytes (Na, K, Cl, HCO3).
Chest X-ray (P.A. and lateral) and CT scan
Bronchoscopy with biopsy or sample
Electrocardiogram and echocardiogram or isotopic left ventricular ejection fraction
Bone isotopic scan
CT scan or echography of the liver and adrenals
Brain CT scan or NMR
6.2. Evaluation during treatment :
Weekly ( first courses) : Hb, WBC, diff, platelets, serum creatinine
Before each new course : clinical examination, PS, weight, biological tests (cf 6.1.), chest Xray, ECG
After the 3rd and every 3 courses of chemotherapy : same investigations as initially.
6.3. Follow-up after chemotherapy :
The patient should be seen after discontinuation of therapy at least every 2 months for the first six months and thereafter every 3 months.
Following investigations have to be performed : clinical examination, PS, weight, biological tests
(cf 6.1.), chest X-ray.
At relapse, a complete work up (cf. 6.1) should be performed.
7. TREATMENT PLAN.
7.1 CE.
a. Etoposide: to be diluted in 250 ml NaCl 0.9 % and infused iv over one hour, just after cisplatin administration. b. Cisplatin : to be given iv over 30 minutes in 250 ml NaCl 3 %, after prehydration with
1,000 ml of 5 % dextrose in 0.45 % NaCl for 4 hours and followed by a mannitol induced diuresis (12.5g of mannitol injected as an iv bolus immediately prior to cisplatin administration and then as a continuous 20% solution 60ml/h for the next 6 hours) and a posthydration with 4,000 ml of 5% dextrose in 0.45% NaCl with 1.5g KCl/l for the next 24 hours. Diuresis and emesis have to be measured every 6 hours up to 24 hours thereafter and if urine output decreases to < 75 ml/h, furosemide (40mg) has to be administered iv.
10

7.2 IVE . a. Epirubicin: to be given by iv short infusion b. Etoposide: to be diluted in 250 ml NaCl 0.9 % and infused iv over one hour, just after epirubicin administration. c. Ifosfamide: to be diluted in 1l NaCl 0.9% and administered iv over 3 hrs. Mesna will be infused at a dose of 300 mg/m² just before ifosfamide and then every 4 hours for 72 hours.
8.
TRIAL QUALITY CONTROL.
Each patient record will be evaluated for response in regular meetings of the group. Patient's original record and radiological documents have to be available at this time.
9.
DRUG PROCUREMENT, PREPARATION, STORAGE AND SIDE EFFECTS.
Each drug may have different commercial names and pharmaceutical presentations according to the country. Investigators have to get local information.
9.1. ETOPOSIDE
1) How supplied :vial 100mg (100mg/5ml)
2) Storage:at room temperature
3) Reconstitution : add 250ml dextrose 5% or NaCl 0.9%. Contact with P.V.C. must be avoided; use glass container.
4) Stability after reconstitution: 24 hours at room temperature (do not refrigerate because of risk of precipitation)
5) Procurement: commercially available under the tradename Vepesid
6) Side effects :
myelosuppression : dose-dependent, leukopenia more pronounced than thrombocytopenia
alopecia
mucositis dose-dependent
mild nausea and vomiting
mild diarrhea
fever, chills
peripheral neuropathy
9.2 CISPLATIN
1) How supplied :10mg, 50mg vials as lyophilisate powder
2) Storage: stable in a cold (+ 2°C /+ 8°C) and dark place for 18 months.
3) Reconstitution :with sterile water for injection (1mg/ml).
4) Stability after reconstitution :1 hour at light and room temperature, 8 hours at dark and room temperature in refrigerator : risk of cristallisation.
5) Procurement :commercially available under the tradename Platinol
7) Side effects :
- renal failure (concomitant use of nephrotoxic drugs like aminoglycosides, methotrexate or amphotericin B should be undertaken with great caution)
- ototoxicity : tinnitis, hearing loss
- nausea and vomiting : severe
- myelosuppression : modest
- hypomagnesemia, hypokalemia, hyperuricemia
11

neurotoxicity : peripheral neuropathy, seizures, loss of taste, papilledema, retinitis, blindness
anaphylactic reactions : wheezing, flushing, hypotension, tachycardia
extravasation : thrombophlebitis with tissue damage if infiltrated.
9.3.
EPIRUBICIN
1) How supplied :10mg, 50mg vials as lyophilisate powder
2)
Storage : at 50°C and protected from light
3) Reconstitution :with sterile water for infusion (5ml/10mg); for infusion add this volume to
50 to 150ml Dextrose 5% or NaCl 0.9 %
4) Stability after reconstitution :24 hours at room temperature, 48 hours at 5øC, protected from light
5) Procurement : commercially available (Farmorubicin)
6). Side effects :
myelosuppression : leukopenia more common than thrombopenia
nausea, vomiting (frequent)
mucositis (common)
alopecia
acute arrhythmia (usually transient and reversible)
dose-related cardiomyopathy congestive failure (the left ventricular ejection fraction is a useful guide to toxicity)
phlebitis, dermatitis, paresthesias, skin staining, fatigue and headache.
9.4. IFOSFAMIDE
1) How supplied: 200mg, 500mg, 1g, 2g dry powder vial for injection
2) Storage :at room temperature (storage temperature must not exceed 25°C because of risk of liquefaction); maximum duration of storage : 5 years
3) Reconstitution : with sterile water for injection (25ml/1g)
4) Stability after reconstitution :reconstituted solutions are chemically stable for prolonged periods of time. However, since vials for injection do not contain a preservative, use reconstituted solutions as soon as possible (no later than 6 hours when refrigerated)
4) Procurement : commercially available (Holoxan)
6) Side effects :
urotoxicity (toxic cystitis with haematuria) : prevented by mesna.
Microhaematuriacan be observed
leucopenia and less frequently thrombocytopenia
fall in haemoglobin : of more than 4% in 10% of the cases
CNS symptoms (10%) : somnolence, disorientation, confusion and lethargy, occurring within hours after ifosfamide and lasting for one or two days
nausea and vomiting
alopecia
mild and transient liver tests abnormalities.
9.5. MESNA
1) How supplied: 400 mg ampoules (4ml)
2) Storage : at room temperature
12

3) Stability :
- after opening of ampoule : extemporaneous use
- after dilution for infusion in NaCl 0.9% : 6 hours, at light, at 4°C or room temperature.
4) Procurement : commercially available (Uromitexan)
5) Side effects :
- rarely nausea, vomiting, diarrhea.
10.
DOSE ADAPTATION PLAN.
10.1
Dose reduction
10.11 CE
Drug dose
Neutrophils nadir < 500/mm³
Platelet nadir < 25,000/mm³
Creatinine peak > 2mg/dl
Creatinine day 1 new course >1.5 mg/dl
Cisplatin
75 %
75 %
50 %
Etoposide
75%
75 %
100 %
STOP for this 100 % course
10.11. IVE
Ifosfamide Epirubicin
Neutrophils nadir < 500/mm³
Platelet nadir < 25,000/mm³
Creatinine peak - 2mg/dl
75%
75%
50%
Creatinine day 1 new course >1.5mg/dl 50%
100%
75 %
75 %
100 %
100%
ST0P Any new cardiac problem
10.2 Chemotherapy delay.
Etoposide
75%
75 %
100 %
100%
100%
If haematological function has not recovered on day 21, i.e. neutrophils < 1,500/mm3 and platelets
< 100,000/mm3, treatment has to be delayed by one week. If on day 36, haematological function has not recovered, patients are off treatment.
10.3 Occurrence of anaemia.
If anaemia is observed in the CE arm, when the haemoglobin level is < 10 g/dl and if it is attributed to cisplatin treatment, patient may be proposed to be treated by erythropoietin (Eprex
R
), 10000 U subcutaneously three times per week until one month after the administration of the last dose of cisplatin.
11. CRITERIA OF EVALUATION
Patients are considered as evaluable if they complete 3 courses of treatment. Patients with early progression or death prior to evaluation due to malignant disease or to toxicity or treatment stopping due to toxicity are considered as treatment failures and incorporated in the evaluable patients. The
13

duration of overall response is the period between the first day of treatment and the date of first progression or first relapse. Survival will be dated from the day of registration.
11.1 Measurability of the disease
* Are considered measurable, lesions which are measurable in two perpendicular diameters as
-
-
* lung tumour surrounded by aerated lung a superficial lymph node
Are considered evaluable, lesions that are deeply located and not measurable in two
-
-
- diameters : a lung tumour not completely surrounded by aerated lung a palpable deep lymph node a bronchial lesion evaluable by endoscopy.
11.2.
Response criteria
Complete response : complete disappearance of all tumoral lesions, for a duration of at least 4 weeks.
Partial response : defined as a decrease of > 50% in the product of cross-sectional diameters of well-outlined lesions or > 50% decrease of poorly-outlined lesions for at least 4 weeks in the absence of progressive disease elsewhere or occurrence of new lesions elsewhere.Patients who have had a complete clinical response but a positive repeat bronchoscopy with biopsy will be considered partial responders.
Progressive disease : > 25% increase in the product of cross-sectional diameters of one or more outlined lesions or the occurrence of new lesions irrespective of response elsewhere.
Stable disease : This includes all patients who have reductions of < 50% or increases of < 25% of well-outlined lesions whether progressing or improving, for a period of at least 4 weeks.
11.3. Death
Early death : death prior to time of response evaluation.
Toxic death : death occurring as a result of drug toxicity.
11.4. Toxicity
Will be evaluated according to standard W.H.O. criteria (appendix II).
12.
OFF TREATMENT REGIMEN AND OFF STUDY DEFINITIONS AND PROCEDURES
12.1. Treatment regimen
A course of treatment and follow up, modified for toxicity and supplemented by supportive therapy, as laid down in this protocol.
12.2. Off treatment regimen
A patient is off treatment regimen when it is no longer possible to continue treatment in accordance with the protocol, including those cases of patient's refusal of treatment. Follow up continues.
12.3. Off trial
Patients can only be withdrawn from the trial for one of the following reasons. An appropriate form has to be sent to the data centre.
(1) Initial ineligibility discovered after registration : cite reason by letter; survival follow-up should be provided.
(2) Death. Submit form 7.
(3) Patient refuses follow-up : report by letter the stated and apparent reasons.
14

13.
ENTRY AND RANDOMISATION PROCEDURES
All patients eligible for this study must be randomised by calling the data manager at 02/539.04.96 between 9 a.m. and 12 a.m.
The following information will be required :
trial number
treatment centre
Patient's name
Birthday
Performance status
Brain CT scan or NMR results
Disease stage.
Neutrophil count
Stratification will be done by using the ELCWP prognostic factors :
1. Centre
2. P.S.
3. Metastatic disease or not
4. Neutrophil count
14. DATA MANAGEMENT AND TRIAL COORDINATION
Study coordinator and data manager
The study coordinator is Dr Jean-Paul Sculier (tel. : 02/539.04.96) and the data manager is Mrs
Paule Mommen (Institut Jules Bordet, rue Héger-Bordet 1, 1000 Bruxelles, tél. : 02/539.04.96 or fax : 02/534.37.56).
Forms to be submitted
The following forms have to be submitted :
Form A: Current tumour status : at the registration and at each evaluation
Form 2:
Form 3: form A
Registration report : at the time of initial allocation together with form A
Evaluation report :after 1st evaluation (3 courses of chemotherapy) together with
Form B:
Form 5 :
Form 7 :
Chemotherapy report : after each course of chemotherapy
Post-treatment follow-up or failure report : every 3 months following the end of the chemotherapy or at progression of the disease
Final report : on death of the patient
15

15. ETHICAL CONSIDERATIONS
15.1.
The protocol will be approved by the ethical committee of the investigator's hospital and the local rules for ethic and responsibility have to be respected.
15.2.
Any major side effect has to be reported as soon as possible to the data centre. Investigators will be accordingly informed.
15.3.
Patients will be asked to agree to participate to the study. The outline of the trial will be explained by the investigator and patient will have to give consent. Patient will be informed of the modalities, anticipated benefits and possible hazards and discomforts in taking part in the trial. The patient will be informed that the trial will comply with the principles present in the Declaration of Helsinki. If during the study, the patient wants to stop the treatment, this will be respected by the investigator.
15.4.
Patient verbal consent will be noted in the hospital file.
16.
STATISTICAL CONSIDERATIONS .
Survival will be the primary endpoint of the study. On the basis of the systematic review performed by the Group, regimens based on cisplatin and etoposide could improve survival patients survival compared to regimens including etoposide but not cisplatin. Using the meta-analysis results, we would like to demonstrate that the amplitude of the benefit can be expressed by a hazard ratio of death of 0.70 (for a patient treated with both drugs compared to a patient receiving a regimen based on etoposide only). Such a hazard ratio should be detectable with a power of 80% using a test level of 5%. To achieve this objective, we need to observe an overall number of events (deaths) of 315
(39). Assuming that 90 % of the patients will be followed until death, this requirement is equivalent to the randomisation of 175 patients per arm in the study.
17.
PUBLICATION AND AUTHORSHIP.
Authors on publication include the study co-ordinators, the authors of the protocol, the statistician and a member of each institution entering at least 10% of evaluable patients for abstracts and 5% of evaluable patients for full papers. Authorship will also include the data manager for full papers. All information generated by the study is full property of the European Lung Cancer Working Party.
No information may be used for publication or presentation without written approval of the study coordinator and the chairman of the group.
16

18.
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Thorax, 1989,44 :218-19.
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Treatment of limited stage small-cell lung cancer. Two-drug with cyclophosphamide, doxorubicin and vincristine with or without etoposide : a randomized trial of the North
Central Cancer Treatment Group. J Clin Oncol 1990;8:33-9.
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NORMAN E. Vincristine, doxorubicin and cyclophosphamide with and without etoposide in limited small cell lung cancer. Acta Oncologica 1990;29:421-4
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JONES A., HOLBORN J., ASHLEY S., Smith I. Effective new low toxicity chemotherapy with carboplatin, vinblastine and methotrexate for small cell lung cancer : a randomised trial against doxorubicin, cyclophosphamide and etoposide. Eur. J. Cancer , 1991,27:866-70.
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Oncologica ,1992,31:853-60.
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CURRAN D., SAHMOUD T., KIRKPATRICKA., GIACCONE G., SPLINTER T. Standard versus alternating non-cross-resistant chemotherapy in extensive small cell lung cancer as : an EORTC phase III trial. Eur. J. Cancer , 1996,32 :1498-1503.
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ERKISI M., UNSAL M., TUNALI C., BURGUT R., DORAN F. A randomized study comparing cyclophosphamide, doxorubicin, vincristine (CAV) with cyclophosphamide, etoposide, vincristine, methotrexate (CEVM in patients with small cell lung cancer. J.
Chemo ,1993,5 :56-9.
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ABRATT R., SALTON D., MALAN J., WILLCOX P. A prospective randomised study in limited disease small cell carcinoma – doxorubicin and vincristine plus either cyclophosphamide or etoposide. Eur. J. Cancer ,31,1995,1637-39.
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EVANS WK, FELD R, MURRAY N, WILLAN A, COY P, OSOBA D, SHEPHERD FA,
CLARK DA, LEVITT M, MacDONALD A, WILSON K, SHELLEY W, PATER
J.Superiority of alternating non-cross resistant chemotherapy in extensive small-cell lung cancer. A multicenter, randomized clinical trial by the National Cancer Institute of Canada.
Ann Int Med 1987;107:451-8.
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HAVEMANN K, WOLF M, HOLLE R, GROPP C, DRINGS P, MANKE HG, HANS K,
SCHROEDER M, HEIM M, VICTOR N, GEORGII A, THOMAS C, PFLÜGER KH,
BEPLER G. Alternating versus sequential chemotherapy in small-cell lung cancer. A randomized german multicenter trial. Cancer 1987;59:1072-82.
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EINHORN LH, CRAWFORD J, BIRCH R, OMURA G, JOHNSON DH, GRECO
FA.Cisplatin plus etoposide consolidation following cyclophosphamide, doxorubicin and vincristine in limited small-cell lung cancer. J Clin Oncol 1988; 6:451-6.
18

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SHIMOYAMA M, SUEMASU K. Randomized trial of cyclophosphamide, doxorubicin and vincristine versus cisplatin and etoposide versus alternation of these regimens in small cell lung cancer. J Natl Cancer Inst 1991;83:855-61.
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WAMPLER GL, HEIM WJ, ELLISON NM, AHLGREN JD, FRYER JG for the Mid-
Atlantic Oncology Program. Comparison of cyc_ophosphamide, doxorubicin and vincristine with an alternating regimen of methotrexate, etoposide and cisplatin/cyclophosphamide, doxorubicin and vincristine in the treatment of extensive-disease small cell lung carcinoma : a Mid-Atlantic Oncology Program Study. J Clin Oncol 1991;9:1438-45.
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MONNET I., CHARIOT P., QOUIX E., RUFFIE P., VOISIN S., LE CHEVALIER T.,
SALTIEL J., DE CREMOUX H., & Association pour le traitement des tumeurs intrathoraciques (ATTIT). Extensive small-cell lung cancer. A randomized comparison of two chemotherapy programs with early crossover in instances of failure. Ann of
Oncol, 1992,3:813-17.
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ROTH BJ, JOHNSON DH, EINHORN LH, SCHACTER LP, CHERNG NC, COHEN HJ,
CRAWFORD J, RANDOLPH JA, GOODLOW JL, BROUN GO, OMURA GA, GRECO
FA. Randomized study of cyclophosphamide, doxorubicin and vincristine versus etoposide and cisplatin versus alternation of the two regimens in extensive small cell lung cancer : a phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 1992 ;10:282-91.
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FARRIS A., BISAIL M., SAROBBA M., SANNA G., SCOTTO T., VALZELLI S., INTINI
C. Cisplatin-VP16 alternating with cyclophosphamide-epirubicin versus cyclophosphamideepirubicin-vincristine in small cell lung cancer. J. Chemo ,1993,5:344-47.
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VERONESI A., CARTEI G., CRIVELLARI D., MAGRI M., DELLA VALENTINA M.,
FOLADORE S., TROVO M., NASCIMBEN O., SIBAU A., TALAMINI R.,
MONFARDINI S. Cisplatin and etoposide versus cyclophosphamide, epirubicin and vincristine in small cell lung cancer : a randomised study. Eur. J. Cancer ,1994,30:1474-
1478.
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WOLF M., HAVEMANN K., HOLLE R., GROPP C., DRINGS P., HANS K.,
SCHROEDER M., HEIM M., DOMMES M., MENDE S., THIEL H., HRUSKA D.,
VICTOR N., GEORGII A., BRAUN C. Cisplatin/etoposide versus ifosfamide/etoposide combination chemotherapy in small-cell lung cancer : a multicenter german randomized trial. J. Clin. Oncol., 1987,5:1880-89.
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GOODMAN GE, CROWLEY JJ, BLASKO JC, LIVINGSTON RB, BECK TM,
DEMATTIA MD, BUKOWSKI RM. Treatment of limited small-cell lung cancer with etoposide and cisplatin alternating with vincristine, doxorubicin and cyclophosphamide versus concurrent etoposide, vincristine, doxorubicin, and cyclophosphamide and chest radiotherapy : a Southwest Oncology Group study. J Clin Oncol 1990;8:39-47.
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G, VAN CUTSEM O, BERCHIER MC, RIES F, MICHEL J, SERGYSELS R, MOMMEN
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20

Appendix I Performance scale (Karnofsky)
PERFORMANCE STATUS SCALE (KARNOFSKY INDEX)
________________________________________________________________________________
Able to carry on normal activity; 100 Normal, no complaints, no evidence of no special care is needed disease
90 Able to carry on normal activity; minor signs or symptoms of disease
80 Normal activity with effort, some signs or symptoms of disease
________________________________________________________________________________
Unable to work, able to live at home, 70 Care for self, unable to carry on normal a care for most personal needs; a varying amount of assistance is needed activity or do active work
60 Requires occasional assistance, but is able to care for most of his needs
50 Requires considerable assistance, and frequent medical care
________________________________________________________________________________
Unable to care for self; requires 40 Disabled, required special care and equivalent of institutional or hospital care; disease may be progressing rapidely. assistance
30 Severely disabled; hospitalization is indicated, although death not immiment
20 Very sick; hospitalization necessary; active supportive treatment necessary
10 Moribund; fatal process progressing rapidely
0 Dead
________________________________________________________________________________
(Cancer 1 : 634 (1948) )
21

Appendix II : Staging classification
A. TNM :
T : primary tumors
TX Tumor proven by the presence of malignant cells in bronchopulmonary secretions but not visualized by roentgenography or bronchoscopy, or any tumor that cannot be assessed as in a pretreatment staging.
TO
T1S
No evidence of primary tumor
Carcinoma in situ
T1 A tumor that is 3.0 cm or less in greatest dimension,surrounded by lung or visceral pleura, and without evidence of invasion proximal to a lobar bronchus at bronchoscopy*
T2 A tumor more than 3.0 cm in greatest dimension, or a tumor of any size that either invades the visceral pleura or has associated atelectasis or obstructivepneumonitis extending to the hilar region. At bronchoscopy, the proximal extent of demonstrable tumor must be within a lobar bronchus or at least 2.0 cm distal to the carina. Any associated atelectasis or obstructive pneumonitis must involve less than an entire lung.
T3 A tumor of any size with direct extension into the chest wall (including superior sulcus tumors), diaphragm, or the mediastinal pleura or pericardium without involving the heart, great vessels, trachea, esophagus, or vertebral body, or a tumor in the main bronchus within 2.0 cm of the carina without involving the carina.
T4 A tumor of any size with invasion of the mediastinum or involving heart, great vessels, trachea, esophagus, vertebral body, or carina or with presence of malignant pleural effusion.**
NB :
* The uncommon superficial tumor of any size whose invasive component is limited to the bronchial wall and that may extend proximal to the main bronchus is classified as T1.
** Most pleural effusions associated with lung cancer are due to tumor. There are, however, some few patients in whom cytopathologic examination of pleural fluid (on more than one specimen) is negative for tumor and the fluid is nonbloody and is not an esudate. When these elements and clinical judgment dictate that the effusion is not related to the tumor, the cases should be staged T1, T2 or T3, with effusion being excluded as a staging element.
22

N : regional lymph nodes
N0 No demonstrable metastasis to regional lymph nodes
N1 Metastasis to lumph nodes in the peribronchial or the ipsilateral hilar region, or both, including direct extension
N2 Metastasis to ipsilateral mediastinal lymph nodes and subcardinal lymph nodes
N3 Metastasis to contralateral mediastinal lymph nodes, contralateral hilar lymph nodes, or ipsilateral or contralateral scalene or supraclavicular lymph nodes.
M : distant metastasis
M0 No (known) distant metastasis
M1 Distant metastasis present-specify site(s).
B. AJCC/UICC 1987 Staging :
Stage
Occult carcinoma
O
I
T
X
IS
1
N
0
0
0
M
0
0
0
II
III A
IIIB
IV
2
3
Any
4
Any
2
I
2
1
0
1
1
2
2
0,1,2
3
Any
Any
0
0
0
0
0
0
0
0
1
23

Appendix III WHO's Criteria of toxicity
24

25

26

27

Appendix IV
THE WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI
Recommandations guiding physicians in biomedical research involving Human Subjects Adopted by the 18th World Medical Assembly, Helsinki, Finland, June 1964., amended by the 29th World
Medical Assembly, Tokyo, Japan, October 1975, and the 35th World Medical Assembly, Venice,
Italy, October 1983 and the 41st World Medical Assembly, Hong Kong, September 1989.
INTRODUCTION
It is the mission of the physician to safeguard the health of the people. His or her knowledge and conscience are dedicated to the fulfillment of this mission.
The Declaration of Geneva of the World Medical association binds the physician with the words,
"The health of my patient will be my first consideration," and The International Code of Medical
Ethics declares that, "A physician shall act only in the patient's interest when providing medical care which might have the effects of weakening the physical and mental condition of the patient".
The purpose of biomedical research involving human subjects must be to improve diagnostic, therapeutic and prophylactic procedures and the understanding of the aetiology and pathologenesis of disease.
In current medical practice most diagnostic, therapeutic or prophylactic procedures involve hazards.
This applies especially to biomedical research.
Medical progress is based on research which ultimately must rest in part on experimentation involving human sujects.
In the field of biomedical research a fundamental distinction must be recognized between medical research in which the aim is essentially diagnostic or therapeutic for a patient, and medical research, the essential object of which is purely scientific and without implying direct diagnostic or therapeutic value to the person subjected to the research.
Special caution must be exercised in the conduct of research which may affect the environment, and the welfare of animals used for research must be respected.
Because it is essential that the results of laboratory experiments be applied to human beings to further scientific knowledge and to help suffering humanity, the World Medical Association has prepared the following recommendationd as a guide to every physician in biomedical research involving human subjects. They should be kept under review in the future. It must be stressed that the standards as drafted are only a guide to physicians all over the world. Physicians are not relieved from criminal, civil and ethical responsibilities under the laws of their own countries.
28

I. BASIC PRINCIPLES
1. Biomedical research involving human subjects must conform to generally accepted scientific principles and should be based on adequately performed laboratory and animal experimentation and on a thorough knowledge of the science literature.
2. The design and performance of each experimental procedure involving human subjects should be clearly formulated in an experimental protocol which should be transmitted to consideration, comment and guidance to a specially appointed committee independent of the investigator and the sponsor, provided that this independent committee is in conformity with the laws and regulations of the country in which the research experiment is performed.
3. Biomedical research involving human subjects should be conducted only by scientifically qualified persons and under the supervision of a clinically competent medical person. The responsibility for the human subject must always rest with a medically qualified person and never rest on the subject of the research, even though the subject has given his or her consent.
4. Biomedical research involving human subjects cannot legitimately be carried out unless the importance of the objective is in proportion to the inherent risk to the subject.
5. Every biomedical research project involving human subjects should be preceded by careful assessment of predicatable risks in comparison with foreseeable benefits to the subject or to others. Concern for the interests of the subject must always prevail over the interests of science and society.
6. The right of the research subject to safeguard his or her integrity must always be respected.
Every precaution should be taken to respect the privacy of the subject and to minimize the impact of the study on the subject's physical and mental integrity and on the personality of the subject.
7. Physicians should abstain from engaging in research projects involving human subjects unless they are satisdied that the hazards involved are believed to be predictable. Physicians should cease any investigation if the hazards are found to outweigh the potential benefits.
8. In publication of the results of his or her research, the physician is obliged to preserve the accuracy of the results. Reports of experimentation not in accordance with the principles laid down in this Declaration should not be accepted for publication.
9. In any research on human beings, each potential subject must be adequately informed of the aims, methods, anticipated benefits and potential hazards of the study and the discomfort it may entail. He or she should be informed that he or she is at liberty to obtain from participation in the study and that he or she is free to withdraw his or her consent to participation in any time. The physician should then obtain the subject's freely-given informed consent, preferably in writing.
10. When obtaining informed consent for the research project the physician should be particularly cautious if the subject is in a dependent relationship to him or her or may consent under duress. In that case the informed consent should be obtain by a ohysician who
29

is not engaged in the investigation and who is completely independent of this official relationship.
11. In case of legal incompetence, informed consent should be obtained from the legal guardian in accordance with national legislation. Where physical or mental incapacity makes it impossible to obtain informed consent, or when the subject is a minor, permission from the responsible relative replaces that of the subject in accordance with national legislation.
Whenever the minor child is in fact able to give a consent, the minor's consent must be obtained in addition to the consent of the minor's legal guardian.
12. The research protocol should always contain a statement of the ethical considerations involved and should indicate that the principles enunciated in the present Declaration are complied with.
II. MEDICAL RESEARCH COMBINED WITH PROFESSIONAL CARE
(Clinical Research)
1. In the treatment of the sick person, the physician must be free to use a new diagnostic and therapeutic measure, if in his or her judgment it offers hope of saving life, re-establishing health or alleviating suffering.
2. The potential benefits, hazards and discomfort a new method should be weighted against the advantages of the best current diagnostic and therapeutic methods.
3. In any medical study, every patient including those of a control group, if any should be assured of the nest proven diagnostic and therapeutic methods.
4. The refusal of the patient to participate in a study must never interfere with the physicianpatient relationship.
5. If the physician considers it essential not to obtain informed consent, the specific reasons for this proposal should be stated in the experimental protocol for transmission to the independent committee (1, 2).
6. The physician can combine medical research with professional care, the objective being the acquisition of new medical knowledge, only to the extent that medical research is justified by its potential diagnostic or therapeutic value from the patient.
III. NON-THERAPEUTIC BIOMEDICAL RESEARCH INVOLVING HUMAN SUBJECTS
(Non-clinical biomedical research)
1. In the purely scientific application of medical research carried out on a human being, it is the duty of the physician to remain the protector of the life and health of that person on whom biomedical research is being carried out.
2. The subjects should be voluntaires either healthy persons or patients for whom the experimental design is not related to the patient's illness.
3. The investigator or the investigating team should discontinue the research if in his/her or their judgment it may, if continued, be harmful to the individual.
30

4. In research on man, the interest of science and society should never take precedence over considerations related to the well-being of the subject.
31