Primary:  To compare efficacy (survival) of Irinotecan hydrochloride with Cisplatin versus Etoposide with Cisplatin as first line chemotherapy in patients with ED-SCLC.

Secondary:  To assess tolerance, overall response rate and duration of response, tumor related symptoms, quality of life.

Open label, randomised multicentre phase III study.

Treatment arm A :

Irinotecan, HCl :            

80 mg/m²  

day 1,8

Cisplatin :           

80 mg/m²  

day 1
Both drugs repeated every 3 weeks.

Treatment arm B :

Etoposide :           

100 mg/m²  

day 1,2,3

Cisplatin :             

80 mg/m²           

day 1
Both drugs repeated every 3 weeks.

Prophylactic regimen :

Inclusion criteria :

- Consent form obtained, signed and dated before beginning specific protocol procedures.

Histology and staging disease :

- Histologically or cytologically proven SCLC;

- Newly diagnosed SCLC

- Extensive disease SCLC (not candidate to curative lung and mediastinal radiotherapy).

General conditions :

- Age :  from 18 to 75 years;

- WHO performance status :  0, 1, 2;

- Life expectancy :  3 months or more;

- Adequate bone marrow function :
Hb ³ 10 g/dl and no blood cell transfusion within the previous 2 weeks;
Absolute neutrophil count ³ 2.0 x 10⁹/l;
Platelets ³ 100 ´ 10⁹/l;

- Adequate renal function :
 Creatinine £ upper normal limit (UNL) or £ 100 mmol/l.
If plasmatic creatinine value is ³ 100mmol/l,
actual creatinine clearance should be ³ 60 ml/min;

- Adequate hepatic function :
Total bilirubin £ 1.5 x UNL,
AST (SGOT) and ALT (SGPT) £ 2.5 ´ UNL,
Alkaline phosphatase £ 5 x UNL;

- Serum magnesium should be within the normal value;

- Serum calcium £ UNL;

- At least one measurable and/or evaluable lesion, according to the RECIST criteria.

Prior therapy :

- previous radiotherapy is allowed only on bone metastases;

- no prior surgery on the primary tumor

- no prior chemotherapy for SCLC or for any other kind of disease

Initial work-up :

- Complete initial work-up within 21 days prior to the first infusion for imaging procedures and within 7 days prior to the first infusion for clinical evaluation and biological work-up.

Other :

- Able to comply with scheduled follow-up and with management of toxicity.

Non inclusion criteria :

General conditions :

- Pregnant or lactating patients;

- Patients (M/F) with reproductive potential not implementing adequate contraceptive methods;

- Previous systemic chemotherapy or immunotherapy for any reason;

- Chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis) and unresolved bowel obstruction (or sub-obstruction). History extensive intestinal resection (> hemicolectomy or extensive small intestine resection with chronic diarrhea).

Prior or current history:

- Symptomatic peripheral neuropathy and neuro-hearing grade > 2 NCI-CTC criteria except if due to trauma or mechanical impairment due to tumor mass;

- Patients with symptomatic brain metastases (despite adequate corticosteroid treatment)

- Active infection (infection requiring I.V antibiotics), including active tuberculosis;

- Active disseminated intravascular coagulation;

- Past or current history of neoplasm except for curatively treated non melanoma skin cancer or in situ carcinoma of the cervix or other cancer curatively treated and with no evidence of disease for at least 5 years;

- Pre-existing ascites NCI grade ³ 2 and / or pericardial effusion NCI grade ³ 2;

- Patient with compression spinal cord

- Any other severe condition:

-      Unstable cardiac disease despite treatment, myocardial infarction within 6 months prior to study entry, congestive heart disease, uncontrolled cardiac insufficiency;

-      superior vena cava syndrome contra-indicating hydration;

-      History of significant neurologic or psychiatric disorders including dementia, seizures, bipolar disorder;

- Other severe underlying medical conditions, which could impair the ability of the patient to participate in the study as cirrhosis, active peptic ulcer, unstable diabetes mellitus.

Concomitant treatments:

- Previous or concomitant treatment with any other experimental anti-cancer therapy;

- Concomitant or within 4 week period administration of any other experimental drug under investigation;

- History of allergy to one of the excipients of Irinotecan hydrochloride.

- Patients who have previously been treated with the investigational product

Other:

- Hypercalcemia (³ grade 1) not controlled by the use of bisphosphonates (IV);

- Patients clearly intending to withdraw from the study if not randomised in a given arm or patients who cannot be regularly followed up for psychological, social, familial or geographic reasons;

- Usual contra-indications to the use of atropine sulfate subcutaneously;

- Patient with expected non-compliance to toxicity management guidelines.

Planned duration of the study : 28 months

Planned enrollment duration : 15 months